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Sample records for ischemic renal injury

  1. Renal ischemic injury affects renal hemodynamics and excretory functions in Sprague Dawley rats: involvement of renal sympathetic tone.

    PubMed

    Salman, Ibrahim M; Sattar, Munavvar A; Abdullah, Nor A; Ameer, Omar Z; Yam, Mun F; Kaur, Gurjeet; Hye Khan, Md Abdul; Johns, Edward J

    2010-01-01

    The role of renal sympathetic nerves in the pathogenesis of ischemic acute renal failure (ARF) and the immediate changes in the renal excretory functions following renal ischemia were investigated. Two groups of male Sprague Dawley (SD) rats were anesthetized (pentobarbitone sodium, 60 mg kg(-1) i.p.) and subjected to unilateral renal ischemia by clamping the left renal artery for 30 min followed by reperfusion. In group 1, the renal nerves were electrically stimulated and the responses in the renal blood flow (RBF) and renal vascular resistance (RVR) were recorded, while group 2 was used to study the early changes in the renal functions following renal ischemia. In post-ischemic animals, basal RBF and the renal vasoconstrictor reperfusion to renal nerve stimulation (RNS) were significantly lower (all p < 0.05 vs. control). Mean arterial pressure (MAP), basal RVR, urine flow rate (UFR), absolute and fractional excretions of sodium (U(Na)V and FE(Na)), and potassium (U(K)V and FE(K)) were higher in ARF rats (all p < 0.05 vs. control). Post-ischemic animals showed markedly lower glomerular filtration rate (GFR) (p < 0.05 vs. control). No appreciable differences were observed in urinary sodium to potassium ratio (U(Na)/U(K)) during the early reperfusion phase of renal ischemia (p > 0.05 vs. control). The data suggest an immediate involvement of renal sympathetic nerve action in the pathogenesis of ischemic ARF primarily through altered renal hemodynamics. Diuresis, natriuresis, and kaliuresis due to impaired renal tubular functions are typical responses to renal ischemia and of comparable magnitudes.

  2. Minocycline inhibits apoptosis and inflammation in a rat model of ischemic renal injury.

    PubMed

    Kelly, K J; Sutton, T A; Weathered, N; Ray, N; Caldwell, E J; Plotkin, Z; Dagher, P C

    2004-10-01

    Tetracyclines exhibit significant anti-inflammatory properties in a variety of rheumatologic and dermatologic conditions. They have also been shown to inhibit apoptosis in certain neurodegenerative disorders. Because ischemic renal injury is characterized by both apoptosis and inflammation, we investigated the therapeutic potential of tetracyclines in a rat model of renal ischemia-reperfusion. Male Sprague-Dawley rats underwent bilateral renal artery clamp for 30 min followed by reperfusion and received either minocycline or saline for 36 h before ischemia. Minocycline reduced tubular cell apoptosis 24 h after ischemia as determined by terminal transferase-mediated dUTP nick end-labeling staining and nuclear morphology. It also decreased cytochrome c release into the cytoplasm and reduced upregulation of p53 and Bax after ischemia. The minocycline-treated group showed a significant reduction in tubular injury and cast formation. In addition, minocycline reduced the number of infiltrating leukocytes, decreased leukocyte chemotaxis both in vitro and ex vivo, and downregulated the expression of ICAM-1. Serum creatinine 24-h postischemia was significantly reduced in the minocycline-treated group. We conclude that minocycline has potent antiapoptotic and anti-inflammatory properties and protects renal function in this model of ischemia-reperfusion. Tetracyclines are among the safest and best-studied antibiotics. They are thus attractive candidates for the therapy of human ischemic acute renal failure. PMID:15172883

  3. Macrophage-derived Lipocalin-2 contributes to ischemic resistance mechanisms by protecting from renal injury

    PubMed Central

    Jung, Michaela; Brüne, Bernhard; Hotter, Georgina; Sola, Anna

    2016-01-01

    Renal ischemia-reperfusion injury triggers an inflammatory response associated to infiltrating macrophages which determines the further outcome of disease. Brown Norway rats are known to show endogenous resistance to ischemia-induced renal damage. By contrast, Sprague Dawley rats exhibit a higher susceptibility to ischemic injury. In order to ascertain cytoprotective mechanisms, we focused on the implication of lipocalin-2 protein in main resistance mechanisms in renal ischemia/reperfusion injury by using adoptive macrophage administration, genetically modified ex vivo either to overexpress or to knockdown lipocalin-2. In vitro experiments with bone marrow-derived macrophages both from Brown Norway rats and from Sprague Dawley rats under hypoxic conditions showed endogenous differences regarding cytokine and lipocalin-2 expression profile in the two strains. Most interestingly, we observed that macrophages of the resistant strain express significantly more lipocalin-2. In vivo studies showed that tubular epithelial cell apoptosis and renal injury significantly increased and reparative markers decreased in Brown Norway rats after injection of lipocalin-2-knockdown macrophages, while the administration of lipocalin-2-overexpressing cells significantly decreased Sprague Dawley susceptibility. These data point to a crucial role of macrophage-derived lipocalin-2 in endogenous cytoprotective mechanisms. We conclude that expression of lipocalin-2 in tissue-infiltrating macrophages is pivotal for kidney-intrinsic cytoprotective pathways during ischemia reperfusion injury. PMID:26911537

  4. Molecular Mechanisms of Renal Ischemic Conditioning Strategies.

    PubMed

    Kierulf-Lassen, Casper; Nieuwenhuijs-Moeke, Gertrude J; Krogstrup, Nicoline V; Oltean, Mihai; Jespersen, Bente; Dor, Frank J M F

    2015-01-01

    Ischemia-reperfusion injury is the leading cause of acute kidney injury in a variety of clinical settings such as renal transplantation and hypovolemic and/or septic shock. Strategies to reduce ischemia-reperfusion injury are obviously clinically relevant. Ischemic conditioning is an inherent part of the renal defense mechanism against ischemia and can be triggered by short periods of intermittent ischemia and reperfusion. Understanding the signaling transduction pathways of renal ischemic conditioning can promote further clinical translation and pharmacological advancements in this era. This review summarizes research on the molecular mechanisms underlying both local and remote ischemic pre-, per- and postconditioning of the kidney. The different types of conditioning strategies in the kidney recruit similar powerful pro-survival mechanisms. Likewise, renal ischemic conditioning mobilizes many of the same protective signaling pathways as in other organs, but differences are recognized. PMID:26330099

  5. Transglutaminase 2 gene ablation protects against renal ischemic injury by blocking constant NF-{kappa}B activation

    SciTech Connect

    Kim, Dae-Seok; Kim, Bora; Tahk, Hongmin; Kim, Dong-Hyun; Ahn, Eu-Ree; Choi, Changsun; Jeon, Yoon; Park, Seo Young; Lee, Ho; Oh, Seung Hyun; Kim, Soo-Youl

    2010-12-17

    Research highlights: {yields} No acute renal tubular necrotic lesions were found in TGase2{sup -/-} mice with ischemic kidney injury. {yields} NF-{kappa}B activation is reduced in TGase2{sup -/-} mice with ischemic kidney injury. {yields} Hypoxic stress did not increase NF-{kappa}B activity in MEFs from TGase2{sup -/-} mice. {yields} COX-2 induction is suppressed in TGase2{sup -/-} mice with ischemic kidney injury. -- Abstract: Transglutaminase 2 knockout (TGase2{sup -/-}) mice show significantly reduced inflammation with decreased myofibroblasts in a unilateral ureteral obstruction (UUO) model, but the mechanism remains to be clarified. Nuclear factor-{kappa}B (NF-{kappa}B) activation plays a major role in the progression of inflammation in an obstructive nephropathy model. However, the key factors extending the duration of NF-{kappa}B activation in UUO are not known. In several inflammatory diseases, we and others recently found that TGase 2 plays a key role in extending NF-{kappa}B activation, which contributes to the pathogenesis of disease. In the current study, we found that NF-{kappa}B activity in mouse embryogenic fibroblasts (MEFs) from TGase2{sup -/-} mice remained at the control level while the NF-{kappa}B activity of wild-type (WT) MEFs was highly increased under hypoxic stress. Using the obstructive nephropathy model, we found that NF-{kappa}B activity remained at the control level in TGase2{sup -/-} mouse kidney tissues, as measured by COX-2 expression, but was highly increased in WT tissues. We conclude that TGase 2 gene ablation reduces the duration of NF-{kappa}B activation in ischemic injury.

  6. No Effect of Remote Ischemic Conditioning Strategies on Recovery from Renal Ischemia-Reperfusion Injury and Protective Molecular Mediators

    PubMed Central

    Kierulf-Lassen, Casper; Kristensen, Marie Louise Vindvad; Birn, Henrik; Jespersen, Bente; Nørregaard, Rikke

    2015-01-01

    Ischemia-reperfusion injury (IRI) is the major cause of acute kidney injury. Remote ischemic conditioning (rIC) performed as brief intermittent sub-lethal ischemia and reperfusion episodes in a distant organ may protect the kidney against IRI. Here we investigated the renal effects of rIC applied either prior to (remote ischemic preconditioning; rIPC) or during (remote ischemic perconditioning; rIPerC) sustained ischemic kidney injury in rats. The effects were evaluated as differences in creatinine clearance (CrCl) rate, tissue tubular damage marker expression, and potential kidney recovery mediators. One week after undergoing right-sided nephrectomy, rats were randomly divided into four groups: sham (n = 7), ischemia and reperfusion (IR; n = 10), IR+rIPC (n = 10), and IR+rIPerC (n = 10). The rIC was performed as four repeated episodes of 5-minute clamping of the infrarenal aorta followed by 5-minute release either before or during 37 minutes of left renal artery clamping representing the IRI. Urine and blood were sampled prior to ischemia as well as 3 and 7 days after reperfusion. The kidney was harvested for mRNA and protein isolation. Seven days after IRI, the CrCl change from baseline values was similar in the IR (δ: 0.74 mL/min/kg [-0.45 to 1.94]), IR+rIPC (δ: 0.21 mL/min/kg [-0.75 to 1.17], p > 0.9999), and IR+rIPerC (δ: 0.41 mL/min/kg [-0.43 to 1.25], p > 0.9999) groups. Kidney function recovery was associated with a significant up-regulation of phosphorylated protein kinase B (pAkt), extracellular regulated kinase 1/2 (pERK1/2), and heat shock proteins (HSPs) pHSP27, HSP32, and HSP70, but rIC was not associated with any significant differences in tubular damage, inflammatory, or fibrosis marker expression. In our study, rIC did not protect the kidney against IRI. However, on days 3–7 after IRI, all groups recovered renal function. This was associated with pAkt and pERK1/2 up-regulation and increased HSP expression at day 7. PMID:26720280

  7. No Effect of Remote Ischemic Conditioning Strategies on Recovery from Renal Ischemia-Reperfusion Injury and Protective Molecular Mediators.

    PubMed

    Kierulf-Lassen, Casper; Kristensen, Marie Louise Vindvad; Birn, Henrik; Jespersen, Bente; Nørregaard, Rikke

    2015-01-01

    Ischemia-reperfusion injury (IRI) is the major cause of acute kidney injury. Remote ischemic conditioning (rIC) performed as brief intermittent sub-lethal ischemia and reperfusion episodes in a distant organ may protect the kidney against IRI. Here we investigated the renal effects of rIC applied either prior to (remote ischemic preconditioning; rIPC) or during (remote ischemic perconditioning; rIPerC) sustained ischemic kidney injury in rats. The effects were evaluated as differences in creatinine clearance (CrCl) rate, tissue tubular damage marker expression, and potential kidney recovery mediators. One week after undergoing right-sided nephrectomy, rats were randomly divided into four groups: sham (n = 7), ischemia and reperfusion (IR; n = 10), IR+rIPC (n = 10), and IR+rIPerC (n = 10). The rIC was performed as four repeated episodes of 5-minute clamping of the infrarenal aorta followed by 5-minute release either before or during 37 minutes of left renal artery clamping representing the IRI. Urine and blood were sampled prior to ischemia as well as 3 and 7 days after reperfusion. The kidney was harvested for mRNA and protein isolation. Seven days after IRI, the CrCl change from baseline values was similar in the IR (δ: 0.74 mL/min/kg [-0.45 to 1.94]), IR+rIPC (δ: 0.21 mL/min/kg [-0.75 to 1.17], p > 0.9999), and IR+rIPerC (δ: 0.41 mL/min/kg [-0.43 to 1.25], p > 0.9999) groups. Kidney function recovery was associated with a significant up-regulation of phosphorylated protein kinase B (pAkt), extracellular regulated kinase 1/2 (pERK1/2), and heat shock proteins (HSPs) pHSP27, HSP32, and HSP70, but rIC was not associated with any significant differences in tubular damage, inflammatory, or fibrosis marker expression. In our study, rIC did not protect the kidney against IRI. However, on days 3-7 after IRI, all groups recovered renal function. This was associated with pAkt and pERK1/2 up-regulation and increased HSP expression at day 7. PMID:26720280

  8. Ischemic preconditioning protects against ischemic brain injury

    PubMed Central

    Ma, Xiao-meng; Liu, Mei; Liu, Ying-ying; Ma, Li-li; Jiang, Ying; Chen, Xiao-hong

    2016-01-01

    In this study, we hypothesized that an increase in integrin αvβ3 and its co-activator vascular endothelial growth factor play important neuroprotective roles in ischemic injury. We performed ischemic preconditioning with bilateral common carotid artery occlusion for 5 minutes in C57BL/6J mice. This was followed by ischemic injury with bilateral common carotid artery occlusion for 30 minutes. The time interval between ischemic preconditioning and lethal ischemia was 48 hours. Histopathological analysis showed that ischemic preconditioning substantially diminished damage to neurons in the hippocampus 7 days after ischemia. Evans Blue dye assay showed that ischemic preconditioning reduced damage to the blood-brain barrier 24 hours after ischemia. This demonstrates the neuroprotective effect of ischemic preconditioning. Western blot assay revealed a significant reduction in protein levels of integrin αvβ3, vascular endothelial growth factor and its receptor in mice given ischemic preconditioning compared with mice not given ischemic preconditioning 24 hours after ischemia. These findings suggest that the neuroprotective effect of ischemic preconditioning is associated with lower integrin αvβ3 and vascular endothelial growth factor levels in the brain following ischemia. PMID:27335560

  9. Preclinical Evidence for the Efficacy of Ischemic Postconditioning against Renal Ischemia-Reperfusion Injury, a Systematic Review and Meta-Analysis

    PubMed Central

    Jonker, Simone J.; Menting, Theo P.; Warlé, Michiel C.; Ritskes-Hoitinga, Merel; Wever, Kimberley E.

    2016-01-01

    Background Renal ischemia-reperfusion injury (IRI) is a major cause of kidney damage after e.g. renal surgery and transplantation. Ischemic postconditioning (IPoC) is a promising treatment strategy for renal IRI, but early clinical trials have not yet replicated the promising results found in animal studies. Method We present a systematic review, quality assessment and meta-analysis of the preclinical evidence for renal IPoC, and identify factors which modify its efficacy. Results We identified 39 publications studying >250 control animals undergoing renal IRI only and >290 animals undergoing renal IRI and IPoC. Healthy, male rats undergoing warm ischemia were used in the vast majority of studies. Four studies applied remote IPoC, all others used local IPoC. Meta-analysis showed that both local and remote IPoC ameliorated renal damage after IRI for the outcome measures serum creatinine, blood urea nitrogen and renal histology. Subgroup analysis indicated that IPoC efficacy increased with the duration of index ischemia. Measures to reduce bias were insufficiently reported. Conclusion High efficacy of IPoC is observed in animal models, but factors pertaining to the internal and external validity of these studies may hamper the translation of IPoC to the clinical setting. The external validity of future animal studies should be increased by including females, comorbid animals, and transplantation models, in order to better inform clinical trial design. The severity of renal damage should be taken into account in the design and analysis of future clinical trials. PMID:26963819

  10. Macrophage-Mediated Injury and Repair After Ischemic Kidney Injury

    PubMed Central

    Huen, Sarah C.; Cantley, Lloyd G.

    2016-01-01

    Acute ischemic kidney injury is a common complication in hospitalized patients. Currently no treatment is available for augmenting kidney repair or preventing progressive kidney fibrosis. Animal models of acute kidney injury demonstrate that activation of the innate immune system plays a major role in the systemic response to ischemia/reperfusion injury. Macrophage depletion studies suggest that macrophages, key participants in the innate immune response, augment the initial injury after reperfusion, but also promote tubular repair and contribute to long-term kidney fibrosis after ischemic injury. The distinct functional outcomes seen following macrophage depletion at different time points after ischemia/reperfusion injury suggest heterogeneity in macrophage activation states. Identifying the pathways that regulate the transitions of macrophage activation is thus critical for understanding the mechanisms that govern both macrophage-mediated injury and repair in the post-ischemic kidney. This review examines our current understanding of the complex and intricately controlled pathways that determine monocyte recruitment, macrophage activation, and macrophage effector functions after renal ischemia/reperfusion injury. Careful delineation of repair and resolution pathways could provide therapeutic targets for the development of effective treatments to offer patients with acute kidney injury. PMID:24442822

  11. [Uncaria tomentosa and acute ischemic kidney injury in rats].

    PubMed

    de Fátima Fernandes Vattimo, Maria; da Silva, Natalia Oliveira

    2011-03-01

    The objective of this study was to evaluate the renoprotective effects of Uncaria Tomentosa (cat's claw) on ischemic acute kidney injury induced by renal clamping in rats. The hypoxia and hypoperfusion increase the production of reactive species already present in the inflammatory process. Results showed that the renal function evaluated by creatinine clearance, the urinary excretion of peroxides and malondealdehyde indexes demonstrated that UT induced renoprotection, probably related to its antioxidant activities.

  12. Ischemic Acute Kidney Injury Perturbs Homeostasis of Serine Enantiomers in the Body Fluid in Mice: Early Detection of Renal Dysfunction Using the Ratio of Serine Enantiomers

    PubMed Central

    Sasabe, Jumpei; Suzuki, Masataka; Miyoshi, Yurika; Tojo, Yosuke; Okamura, Chieko; Ito, Sonomi; Konno, Ryuichi; Mita, Masashi; Hamase, Kenji; Aiso, Sadakazu

    2014-01-01

    The imbalance of blood and urine amino acids in renal failure has been studied mostly without chiral separation. Although a few reports have shown the presence of D-serine, an enantiomer of L-serine, in the serum of patients with severe renal failure, it has remained uncertain how serine enantiomers are deranged in the development of renal failure. In the present study, we have monitored serine enantiomers using a two-dimensional HPLC system in the serum and urine of mice after renal ischemia-reperfusion injury (IRI), known as a mouse model of acute kidney injury. In the serum, the level of D-serine gradually increased after renal IRI in parallel with that of creatinine, whereas the L-serine level decreased sharply in the early phase after IRI. The increase of D-serine was suppressed in part by genetic inactivation of a D-serine-degrading enzyme, D-amino acid oxidase (DAO), but not by disruption of its synthetic enzyme, serine racemase, in mice. Renal DAO activity was detected exclusively in proximal tubules, and IRI reduced the number of DAO-positive tubules. On the other hand, in the urine, D-serine was excreted at a rate nearly triple that of L-serine in mice with sham operations, indicating that little D-serine was reabsorbed while most L-serine was reabsorbed in physiological conditions. IRI significantly reduced the ratio of urinary D−/L-serine from 2.82±0.18 to 1.10±0.26 in the early phase and kept the ratio lower than 0.5 thereafter. The urinary D−/L-serine ratio can detect renal ischemia earlier than kidney injury molecule-1 (KIM-1) or neutrophil gelatinase-associated lipocalin (NGAL) in the urine, and more sensitively than creatinine, cystatin C, or the ratio of D−/L-serine in the serum. Our findings provide a novel understanding of the imbalance of amino acids in renal failure and offer a potential new biomarker for an early detection of acute kidney injury. PMID:24489731

  13. Spectroscopic Monitoring of Kidney Tissue Ischemic Injury

    SciTech Connect

    Demos, S G; Fitzgerald, J T; Michalopoulou, A P; Troppmann, C

    2004-03-11

    Noninvasive evaluation of tissue viability of donor kidneys used for transplantation is an issue that current technology is not able to address. In this work, we explore optical spectroscopy for its potential to assess the degree of ischemic damage in kidney tissue. We hypothesized that ischemic damage to kidney tissue will give rise to changes in its optical properties which in turn may be used to asses the degree of tissue injury. The experimental results demonstrate that the autofluorescence intensity of the injured kidney is decreasing as a function of time exposed to ischemic injury. Changes were also observed in the NIR light scattering intensities most probably arising from changes due to injury and death of the tissue.

  14. TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury.

    PubMed

    White, Laura E; Santora, Rachel J; Cui, Yan; Moore, Frederick A; Hassoun, Heitham T

    2012-09-01

    Despite advancements in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely due to remote organ injury. Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that incite a distinct pulmonary proinflammatory and proapoptotic response. Tumor necrosis factor receptor 1 (TNFR1) has been identified as a prominent death receptor activated in the lungs during ischemic AKI. We hypothesized that circulating TNF-α released from the postischemic kidney induces TNFR1-mediated pulmonary apoptosis, and we aimed to elucidate molecular pathways to programmed cell death. Using an established murine model of kidney IRI, we characterized the time course for increased circulatory and pulmonary TNF-α levels and measured concurrent upregulation of pulmonary TNFR1 expression. We then identified TNFR1-dependent pulmonary apoptosis after ischemic AKI using TNFR1-/- mice. Subsequent TNF-α signaling disruption with Etanercept implicated circulatory TNF-α as a key soluble mediator of pulmonary apoptosis and lung microvascular barrier dysfunction during ischemic AKI. We further elucidated pathways of TNFR1-mediated apoptosis with NF-κB (Complex I) and caspase-8 (Complex II) expression and discovered that TNFR1 proapoptotic signaling induces NF-κB activation. Additionally, inhibition of NF-κB (Complex I) resulted in a proapoptotic phenotype, lung barrier leak, and altered cellular flice inhibitory protein signaling independent of caspase-8 (Complex II) activation. Ischemic AKI activates soluble TNF-α and induces TNFR1-dependent pulmonary apoptosis through augmentation of the prosurvival and proapoptotic TNFR1 signaling pathway. Kidney-lung crosstalk after ischemic AKI represents a complex pathological process, yet focusing on specific biological pathways may yield potential future therapeutic targets.

  15. TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury

    PubMed Central

    White, Laura E.; Santora, Rachel J.; Cui, Yan; Moore, Frederick A.

    2012-01-01

    Despite advancements in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely due to remote organ injury. Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that incite a distinct pulmonary proinflammatory and proapoptotic response. Tumor necrosis factor receptor 1 (TNFR1) has been identified as a prominent death receptor activated in the lungs during ischemic AKI. We hypothesized that circulating TNF-α released from the postischemic kidney induces TNFR1-mediated pulmonary apoptosis, and we aimed to elucidate molecular pathways to programmed cell death. Using an established murine model of kidney IRI, we characterized the time course for increased circulatory and pulmonary TNF-α levels and measured concurrent upregulation of pulmonary TNFR1 expression. We then identified TNFR1-dependent pulmonary apoptosis after ischemic AKI using TNFR1−/− mice. Subsequent TNF-α signaling disruption with Etanercept implicated circulatory TNF-α as a key soluble mediator of pulmonary apoptosis and lung microvascular barrier dysfunction during ischemic AKI. We further elucidated pathways of TNFR1-mediated apoptosis with NF-κB (Complex I) and caspase-8 (Complex II) expression and discovered that TNFR1 proapoptotic signaling induces NF-κB activation. Additionally, inhibition of NF-κB (Complex I) resulted in a proapoptotic phenotype, lung barrier leak, and altered cellular flice inhibitory protein signaling independent of caspase-8 (Complex II) activation. Ischemic AKI activates soluble TNF-α and induces TNFR1-dependent pulmonary apoptosis through augmentation of the prosurvival and proapoptotic TNFR1 signaling pathway. Kidney-lung crosstalk after ischemic AKI represents a complex pathological process, yet focusing on specific biological pathways may yield potential future therapeutic targets. PMID:22728466

  16. Curcumin protects against ischemic spinal cord injury: The pathway effect

    PubMed Central

    Zhang, Jinhua; Wei, Hao; Lin, Meimei; Chen, Chunmei; Wang, Chunhua; Liu, Maobai

    2013-01-01

    Inducible nitric oxide synthase and N-methyl-D-aspartate receptors have been shown to participate in nerve cell injury during spinal cord ischemia. This study observed a protective effect of curcumin on ischemic spinal cord injury. Models of spinal cord ischemia were established by ligating the lumbar artery from the left renal artery to the bifurcation of the abdominal aorta. At 24 hours after model establishment, the rats were intraperitoneally injected with curcumin. Reverse transcription-polymerase chain reaction and immunohistochemical results demonstrated that after spinal cord ischemia, inducible nitric oxide synthase and N-methyl-D-aspartate receptor mRNA and protein expression significantly increased. However, curcumin significantly decreased inducible nitric oxide synthase and N-methyl-D-aspartate receptor mRNA and protein expression in the ischemic spinal cord. Tarlov scale results showed that curcumin significantly improved motor function of the rat hind limb after spinal cord ischemia. The results demonstrate that curcumin exerts a neuroprotective fect against ischemic spinal cord injury by decreasing inducible nitric oxide synthase and N-methyl-D-aspartate receptor expression. PMID:25206661

  17. White matter injury in ischemic stroke.

    PubMed

    Wang, Yuan; Liu, Gang; Hong, Dandan; Chen, Fenghua; Ji, Xunming; Cao, Guodong

    2016-06-01

    Stroke is one of the major causes of disability and mortality worldwide. It is well known that ischemic stroke can cause gray matter injury. However, stroke also elicits profound white matter injury, a risk factor for higher stroke incidence and poor neurological outcomes. The majority of damage caused by stroke is located in subcortical regions and, remarkably, white matter occupies nearly half of the average infarct volume. Indeed, white matter is exquisitely vulnerable to ischemia and is often injured more severely than gray matter. Clinical symptoms related to white matter injury include cognitive dysfunction, emotional disorders, sensorimotor impairments, as well as urinary incontinence and pain, all of which are closely associated with destruction and remodeling of white matter connectivity. White matter injury can be noninvasively detected by MRI, which provides a three-dimensional assessment of its morphology, metabolism, and function. There is an urgent need for novel white matter therapies, as currently available strategies are limited to preclinical animal studies. Optimal protection against ischemic stroke will need to encompass the fortification of both gray and white matter. In this review, we discuss white matter injury after ischemic stroke, focusing on clinical features and tools, such as imaging, manifestation, and potential treatments. We also briefly discuss the pathophysiology of WMI and future research directions. PMID:27090751

  18. White matter injury in ischemic stroke.

    PubMed

    Wang, Yuan; Liu, Gang; Hong, Dandan; Chen, Fenghua; Ji, Xunming; Cao, Guodong

    2016-06-01

    Stroke is one of the major causes of disability and mortality worldwide. It is well known that ischemic stroke can cause gray matter injury. However, stroke also elicits profound white matter injury, a risk factor for higher stroke incidence and poor neurological outcomes. The majority of damage caused by stroke is located in subcortical regions and, remarkably, white matter occupies nearly half of the average infarct volume. Indeed, white matter is exquisitely vulnerable to ischemia and is often injured more severely than gray matter. Clinical symptoms related to white matter injury include cognitive dysfunction, emotional disorders, sensorimotor impairments, as well as urinary incontinence and pain, all of which are closely associated with destruction and remodeling of white matter connectivity. White matter injury can be noninvasively detected by MRI, which provides a three-dimensional assessment of its morphology, metabolism, and function. There is an urgent need for novel white matter therapies, as currently available strategies are limited to preclinical animal studies. Optimal protection against ischemic stroke will need to encompass the fortification of both gray and white matter. In this review, we discuss white matter injury after ischemic stroke, focusing on clinical features and tools, such as imaging, manifestation, and potential treatments. We also briefly discuss the pathophysiology of WMI and future research directions.

  19. B Cell Subsets Contribute to Both Renal Injury and Renal Protection after Ischemia/Reperfusion

    PubMed Central

    Renner, Brandon; Strassheim, Derek; Amura, Claudia R.; Kulik, Liudmila; Ljubanovic, Danica; Glogowska, Magdalena J.; Takahashi, Kazue; Carroll, Michael C.; Holers, V. Michael; Thurman, Joshua M.

    2011-01-01

    Ischemia/reperfusion (I/R) triggers a robust inflammatory response within the kidney. Numerous components of the immune system contribute to the resultant renal injury including the complement system. We sought to identify whether natural antibodies bind to the post-ischemic kidney and contribute to complement activation after I/R. We depleted peritoneal B cells in mice by hypotonic shock. Depletion of the peritoneal B cells prevented the deposition of IgM within the glomeruli after renal I/R, and attenuated renal injury after I/R. We found that glomerular IgM activates the classical pathway of complement but does not cause substantial deposition of C3 within the kidney. Furthermore, mice deficient in classical pathway proteins were not protected from injury, indicating that glomerular IgM does not cause injury through activation of the classical pathway. We also subjected mice deficient in all mature B cells (μMT mice) to renal I/R and found that they sustained worse renal injury than wild-type controls. Serum IL-10 levels were lower in the μMT mice. Regarded together, these results indicate that natural antibody produced by peritoneal B cells binds within the glomerulus after renal I/R and contributes to functional renal injury. However, non-peritoneal B cells attenuate renal injury after I/R, possibly through the production of IL-10. PMID:20810984

  20. Cerebrospinal fluid may mediate CNS ischemic injury

    PubMed Central

    Wang, Yanming F; Gwathmey, Judith K; Zhang, Guorong; Soriano, Sulpicio G; He, Shunli; Wang, Yanguang

    2005-01-01

    Background The central nervous system (CNS) is extremely vulnerable to ischemic injury. The details underlying this susceptibility are not completely understood. Since the CNS is surrounded by cerebrospinal fluid (CSF) that contains a low concentration of plasma protein, we examined the effect of changing the CSF in the evolution of CNS injury during ischemic insult. Methods Lumbar spinal cord ischemia was induced in rabbits by cross-clamping the descending abdominal aorta for 1 h, 2 h or 3 h followed by 7 d of reperfusion. Prior to ischemia, rabbits were subjected to the following procedures; 1) CSF depletion, 2) CSF replenishment at 0 mmHg intracranial pressure (ICP), and 3) replacement of CSF with 8% albumin- or 1% gelatin-modified artificial CSF, respectively. Motor function of the hind limbs and histopathological changes of the spinal cord were scored. Post-ischemic microcirculation of the spinal cord was visualized by fluorescein isothiocyanate (FITC) albumin. Results The severity of histopathological damage paralleled the neurological deficit scores. Paraplegia and associated histopathological changes were accompanied by a clear post-ischemic deficit in blood perfusion. Spinal cord ischemia for 1 h resulted in permanent paraplegia in the control group. Depletion of the CSF significantly prevented paraplegia. CSF replenishment with the ICP reduced to 0 mmHg, did not prevent paraplegia. Replacement of CSF with albumin- or gelatin-modified artificial CSF prevented paraplegia in rabbits even when the ICP was maintained at 10–15 mmHg. Conclusion We conclude that the presence of normal CSF may contribute to the vulnerability of the spinal cord to ischemic injury. Depletion of the CSF or replacement of the CSF with an albumin- or gelatin-modified artificial CSF can be neuroprotective. PMID:16174300

  1. [Mechanisms of repair after renal injury].

    PubMed

    Menè, P; Polci, R; Festuccia, F

    2003-01-01

    Recovery from kidney injury through repair mechanisms often linked to inflammation is conditioned by nature and severity of the insult. In the assessment of kidney repair, functional recovery should be kept distinct from structural repair: compensatory hypertrophy/function of intact nephrons often masks the inability of the kidney to heal or replace damaged structures. The mechanisms of repair reflect three degrees of injury, differently handled by the kidney. First, repair of DNA damage is accomplished through proofreading DNA polymerases, along with other controls for sequence misalignment / nucleotide replacement. If DNA cannot be repaired, cells carrying mutation(s) are disposed of through apoptosis, which is also critical to clearing damaged kidney cells and infiltrating leukocytes in acute and chronic ischemic, immunological, or chemical damage. A second mechanism of repair is linked to proliferation of surviving cells. At least 5 types of reparative proliferation are known to occur, some of which implicate stem cell immigration from distant reservoirs, followed by in situ differentiation. A third mode of repair could be referred to as structural repair, indeed limited in the human kidney by the absence of postnatal nephrogenesis. Recovery from acute tubular necrosis involves remodelling of the proximal tubule, with a strict requirement for integrity of the basement membrane. Contrary to the current dogma that only acute injury can be repaired, whereas chronic damage leads to irreversible loss of nephrons, evidence is emerging that some degree of renal remodelling occurs even in chronic renal disease, despite the occurrence of stabilized structural changes.

  2. Renal ischemia/reperfusion injury; from pathophysiology to treatment

    PubMed Central

    Malek, Maryam; Nematbakhsh, Mehdi

    2015-01-01

    Ischemia/reperfusion injury (IRI) is caused by a sudden temporary impairment of the blood flow to the particular organ. IRI usually is associated with a robust inflammatory and oxidative stress response to hypoxia and reperfusion which disturbs the organ function. Renal IR induced acute kidney injury (AKI) contributes to high morbidity and mortality rate in a wide range of injuries. Although the pathophysiology of IRI is not completely understood, several important mechanisms resulting in kidney failure have been mentioned. In ischemic kidney and subsequent of re-oxygenation, generation of reactive oxygen species (ROS) at reperfusion phase initiates a cascade of deleterious cellular responses leading to inflammation, cell death, and acute kidney failure. Better understanding of the cellular pathophysiological mechanisms underlying kidney injury will hopefully result in the design of more targeted therapies to prevent and treatment the injury. In this review, we summarize some important potential mechanisms and therapeutic approaches in renal IRI. PMID:26060833

  3. Cellular Basis of Anoxic-Ischemic Brain Injury

    PubMed Central

    Bronshvag, Michael M.

    1978-01-01

    Anoxic-ischemic cerebral disease is an important primary cause of morbidity and mortality, and also complicates a number of systemic diseases. Its clinical manifestations, such as hemiparesis and coma, represent cellular injury sustained by the complex, inhomogeneous brain. An understanding of the nature and pattern of anoxic-ischemic cerebral injury, and of the logical basis for avenues of therapy, is necessary to the management of patients with the various anoxic-ischemic disorders. PMID:685270

  4. [Ischemic colitis after renal transplantation:etiology and pathogenesis].

    PubMed

    Alperovich, G; Idiarte, L; Besasso, O; Avagnina, A

    2003-01-01

    Ischemic colitis is a well-recognized complication occurring in renal transplant recipients. It has often been associated with cytomegalovirus (CMV) vasculitis. However, the diagnosis of this pathology in the absence of CMV suggests that other etiological factors might be involved. Drugs inducing mesenteric vasoconstriction, such as non-steroidal anti-inflamatory drugs (NSAIDs) and cyclosporine could be related to this entity.

  5. Combined iron sucrose and protoporphyrin treatment protects against ischemic and toxin-mediated acute renal failure.

    PubMed

    Zager, Richard A; Johnson, Ali C M; Frostad, Kirsten B

    2016-07-01

    Tissue preconditioning, whereby various short-term stressors initiate organ resistance to subsequent injury, is well recognized. However, clinical preconditioning of the kidney for protection against acute kidney injury (AKI) has not been established. Here we tested whether a pro-oxidant agent, iron sucrose, combined with a protoporphyrin (Sn protoporphyrin), can induce preconditioning and protect against acute renal failure. Mice were pretreated with iron sucrose, protoporphyrin, cyanocobalamin, iron sucrose and protoporphyrin, or iron sucrose and cyanocobalamin. Eighteen hours later, ischemic, maleate, or glycerol models of AKI were induced, and its severity was assessed the following day (blood urea nitrogen, plasma creatinine concentrations; post-ischemic histology). Agent impact on cytoprotective gene expression (heme oxygenase 1, hepcidin, haptoglobin, hemopexin, α1-antitrypsin, α1-microglobulin, IL-10) was assessed as renal mRNA and protein levels. AKI-associated myocardial injury was gauged by plasma troponin I levels. Combination agent administration upregulated multiple cytoprotective genes and, unlike single agent administration, conferred marked protection against each tested model of acute renal failure. Heme oxygenase was shown to be a marked contributor to this cytoprotective effect. Preconditioning also blunted AKI-induced cardiac troponin release. Thus, iron sucrose and protoporphyrin administration can upregulate diverse cytoprotective genes and protect against acute renal failure. Associated cardiac protection implies potential relevance to both AKI and its associated adverse downstream effects. PMID:27165818

  6. Unilateral Renal Ischemia as a Model of Acute Kidney Injury and Renal Fibrosis in Cats.

    PubMed

    Schmiedt, C W; Brainard, B M; Hinson, W; Brown, S A; Brown, C A

    2016-01-01

    The objectives of this study were to define the acute and chronic effects of 1-hour unilateral in vivo renal ischemia on renal function and histology in cats. Twenty-one adult purpose-bred research cats were anesthetized, and 1 kidney underwent renal artery and vein occlusion for 1 hour. Serum creatinine and urea concentrations, urine protein:creatinine ratio, urine-specific gravity, glomerular filtration rate, hematocrit, platelet concentration and function, and white blood cell count were measured at baseline and variable time points after ischemia. Renal histopathology was evaluated on days 3, 6, 12, 21, 42, and 70 postischemia; changes in smooth muscle actin and interstitial collagen were examined. Following ischemia, whole animal glomerular filtration rate was significantly reduced (57% of baseline on day 6; P < .05). At the early time points, the ischemic kidneys exhibited severe acute epithelial necrosis accompanied by evidence of regeneration of tubules predominantly within the corticomedullary junction. At later periods, postischemic kidneys had evidence of tubular atrophy and interstitial inflammation with significantly more smooth muscle actin and interstitial collagen staining and interstitial fibrosis when compared with the contralateral control kidneys. This study characterizes the course of ischemic acute kidney injury in cats and demonstrates that ischemic acute kidney injury triggers chronic fibrosis, interstitial inflammation, and tubular atrophy in feline kidneys. These late changes are typical of those observed in cats with naturally occurring chronic kidney disease. PMID:26319781

  7. Leukocyte Recruitment and Ischemic Brain Injury

    PubMed Central

    Yilmaz, Gokhan

    2010-01-01

    Leukocytes are recruited into the cerebral microcirculation following an ischemic insult. The leukocyte–endothelial cell adhesion manifested within a few hours after ischemia (followed by reperfusion, I/R) largely reflects an infiltration of neutrophils, while other leukocyte populations appear to dominate the adhesive interactions with the vessel wall at 24 h of reperfusion. The influx of rolling and adherent leukocytes is accompanied by the recruitment of adherent platelets, which likely enhances the cytotoxic potential of the leukocytes to which they are attached. The recruitment of leukocytes and platelets in the postischemic brain is mediated by specific adhesion glycoproteins expressed by the activated blood cells and on cerebral microvascular endothelial cells. This process is also modulated by different signaling pathways (e.g., CD40/CD40L, Notch) and cytokines (e.g., RANTES) that are activated/released following I/R. Some of the known risk factors for cardiovascular disease, including hypercholesterolemia and obesity appear to exacerbate the leukocyte and platelet recruitment elicited by brain I/R. Although lymphocyte–endothelial cell and –platelet interactions in the postischemic cerebral microcirculation have not been evaluated to date, recent evidence in experimental animals implicate both CD4+ and CD8+ T-lymphocytes in the cerebral microvascular dysfunction, inflammation, and tissue injury associated with brain I/R. Evidence implicating regulatory T-cells as cerebroprotective modulators of the inflammatory and tissue injury responses to brain I/R support a continued focus on leukocytes as a target for therapeutic intervention in ischemic stroke. PMID:19579016

  8. Ischemic Postconditioning and Subanesthetic S(+)-Ketamine Infusion: Effects on Renal Function and Histology in Rats

    PubMed Central

    de Resende, Marco A. C.; Pantoja, Alberto V.; Barcellos, Bruno M.; Reis, Eduardo P.; Consolo, Thays D.; Módolo, Renata P.; Domingues, Maria A. C.; Assad, Alexandra R.; Cavalcanti, Ismar L.; Castiglia, Yara M. M.; Módolo, Norma S. P.

    2015-01-01

    Background. Ischemic postconditioning (IP) in renal Ischemia reperfusion injury (IRI) models improves renal function after IRI. Ketamine affords significant benefits against IRI-induced acute kidney injury (AKI). The present study investigated the effects of IP and IP associated with subanesthetic S(+)-ketamine in ischemia-reperfusion-induced AKI. Methods. Forty-one Wistar rats were randomized into four groups: CG (10), control; KG (10), S(+)-ketamine infusion; IPG (10), IP; and KIPG (11), S(+)-ketamine infusion + IP. All rats underwent right nephrectomy. IRI and IP were induced only in IPG and KIPG by left kidney arterial occlusion for 30 min followed by reperfusion for 24 h. Complete reperfusion was preceded by three cycles of 2 min of reocclusion followed by 2 min of reperfusion. Renal function was assessed by measuring serum neutrophil gelatinase-associated lipocalin (NGAL), creatinine, and blood urea nitrogen (BUN). Tubular damage was evaluated by renal histology. Results. Creatinine and BUN were significantly increased. Severe tubular injury was only observed in the groups with IRI (IPG and KIPG), whereas no injury was observed in CG or KG. No significant differences were detected between IPG and KIPG. Conclusions. No synergic effect of the use of subanesthetic S(+)-ketamine and IP on AKI was observed in this rat model. PMID:26413552

  9. Kidney injury molecule-1 (KIM-1) mediates renal epithelial cell repair via ERK MAPK signaling pathway

    PubMed Central

    Zhang, Zhiwei; Cai, Cindy X

    2016-01-01

    The expression of kidney injury molecule-1 (KIM-1), a very promising sensitive and specific urinary biomarker for acute renal injury, is markedly upregulated in injured and regenerating renal proximal tubular epithelial cells following ischemic or toxic insults, suggesting a possible role for this molecule in renal repair process. In the present study we report that expression of KIM-1 facilitates renal tubular epithelial cell repair by promoting cell migration and proliferation. KIM-1 expression also enhances ERK MAPK activation, and the modulatory effect of KIM-1 on cellular repair process is likely mediated via ERK MAPK signaling pathway. PMID:27084535

  10. Altering 5-hydroxymethylcytosine modification impacts ischemic brain injury.

    PubMed

    Miao, Zhigang; He, Yuquan; Xin, Ning; Sun, Miao; Chen, Li; Lin, Li; Li, Jizhen; Kong, Jiming; Jin, Peng; Xu, Xingshun

    2015-10-15

    Epigenetic modifications such as cytosine methylation and histone modification are linked to the pathology of ischemic brain injury. Recent research has implicated 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5-methylcytosine (5mC) via oxidation by ten-eleven translocation (Tet) enzymes, in DNA methylation-related plasticity. Here we show that 5hmC abundance was increased after ischemic injury, and Tet2 was responsible for this increase; furthermore, inhibiting Tet2 expression abolished the increase of 5hmC caused by ischemic injury. The decrease in 5hmC modifications from inhibiting Tet2 activity was accompanied by increased infarct volume after ischemic injury. Genome-wide profiling of 5hmC revealed differentially hydroxymethylated regions (DhMRs) associated with ischemic injury, and DhMRs were enriched among the genes involved in cell junction, neuronal morphogenesis and neurodevelopment. In particular, we found that 5hmC modifications at the promoter region of brain-derived neurotrophic factor (BDNF) increased, which was accompanied by increased BDNF mRNA, whereas the inhibition of Tet2 reduced BDNF mRNA and protein expression. Finally, we show that the abundance of 5hmC in blood samples from patients with acute ischemic stroke was also significantly increased. Together, these data suggest that 5hmC modification could serve as both a potential biomarker and a therapeutic target for the treatment of ischemic stroke.

  11. Bone Fracture Exacerbates Murine Ischemic Cerebral Injury

    PubMed Central

    Degos, Vincent; Maze, Mervyn; Vacas, Susana; Hirsch, Jan; Guo, Yi; Shen, Fanxia; Jun, Kristine; van Rooijen, Nico; Gressens, Pierre; Young, William L.; Su, Hua

    2014-01-01

    Background Bone fracture increases alarmins and pro-inflammatory cytokines in the blood, and provokes macrophage infiltration and pro-inflammatory cytokine expression in the hippocampus. We recently reported that stroke is an independent risk factor after bone surgery for adverse outcome, the impact of bone fracture on stroke outcome is unknown. We tested the hypothesis that bone fracture, shortly after ischemic stroke, enhances stroke-related injuries by augmenting the neuroinflammatory response. Methods Tibia fracture (bone fracture) was induced in mice one day after permanent occlusion of the distal middle cerebral artery (stroke). High-mobility-group box chromosomal protein-1 (HMGB1) was tested to mimic the bone fracture effects. HMGB1 neutralizing antibody and clodrolip (macrophage depletion) were tested to attenuate the bone fracture effects. Neurobehavioral function (n=10), infarct volume, neuronal death, and macrophages/microglia-infiltration (n=6–7) were analyzed three days after. Results We found that mice with both stroke and bone fracture had larger infarct volumes (mean percentage of ipsilateral hemisphere±SD: 30±7% vs. 12±3%, n=6, P<0.001) more severe neurobehavioral dysfunction, and more macrophages/microglia in the peri-infarct region than mice with stroke only. Intraperitoneal injection of HMGB1 mimicked, whereas neutralizing HMGB1 attenuated, the bone fracture effects and the macrophage/microglia infiltration. Depleting macrophages with clodrolip also attenuated the aggravating effects of bone fracture on stroke lesion and behavioral dysfunction. Conclusions These novel findings suggest that bone fracture shortly after stroke enhances stroke injury via augmented inflammation through HMGB1 and macrophage/microglia infiltration. Interventions to modulate early macrophage/microglia activation could be therapeutic goals to limit the adverse consequences of bone fracture after stroke. PMID:23438676

  12. Renal telocytes contribute to the repair of ischemically injured renal tubules

    PubMed Central

    Li, Liping; Lin, Miao; Li, Long; Wang, Rulin; Zhang, Chao; Qi, Guisheng; Xu, Ming; Rong, Ruiming; Zhu, Tongyu

    2014-01-01

    Telocytes (TCs), a distinct type of interstitial cells, have been identified in many organs via electron microscopy. However, their precise function in organ regeneration remains unknown. This study investigated the paracrine effect of renal TCs on renal tubular epithelial cells (TECs) in vitro, the regenerative function of renal TCs in renal tubules after ischaemia–reperfusion injury (IRI) in vivo and the possible mechanisms involved. In a renal IRI model, transplantation of renal TCs was found to decrease serum creatinine and blood urea nitrogen (BUN) levels, while renal fibroblasts exerted no such effect. The results of histological injury assessments and the expression levels of cleaved caspase-3 were consistent with a change in kidney function. Our data suggest that the protective effect of TCs against IRI occurs via inflammation-independent mechanisms in vivo. Furthermore, we found that renal TCs could not directly promote the proliferation and anti-apoptosis properties of TECs in vitro. TCs did not display any advantage in paracrine growth factor secretion in vitro compared with renal fibroblasts. These data indicate that renal TCs protect against renal IRI via an inflammation-independent pathway and that growth factors play a significant role in this mechanism. Renal TCs may protect TECs in certain microenvironments while interacting with other cells. PMID:24758589

  13. Prion Protein Protects against Renal Ischemia/Reperfusion Injury.

    PubMed

    Zhang, Bo; Cowden, Daniel; Zhang, Fan; Yuan, Jue; Siedlak, Sandra; Abouelsaad, Mai; Zeng, Liang; Zhou, Xuefeng; O'Toole, John; Das, Alvin S; Kofskey, Diane; Warren, Miriam; Bian, Zehua; Cui, Yuqi; Tan, Tao; Kresak, Adam; Wyza, Robert E; Petersen, Robert B; Wang, Gong-Xian; Kong, Qingzhong; Wang, Xinglong; Sedor, John; Zhu, Xiongwei; Zhu, Hua; Zou, Wen-Quan

    2015-01-01

    The cellular prion protein (PrPC), a protein most noted for its link to prion diseases, has been found to play a protective role in ischemic brain injury. To investigate the role of PrPC in the kidney, an organ highly prone to ischemia/reperfusion (IR) injury, we examined wild-type (WT) and PrPC knockout (KO) mice that were subjected to 30-min of renal ischemia followed by 1, 2, or 3 days of reperfusion. Renal dysfunction and structural damage was more severe in KO than in WT mice. While PrP was undetectable in KO kidneys, Western blotting revealed an increase in PrP in IR-injured WT kidneys compared to sham-treated kidneys. Compared to WT, KO kidneys exhibited increases in oxidative stress markers heme oxygenase-1, nitrotyrosine, and Nε-(carboxymethyl)lysine, and decreases in mitochondrial complexes I and III. Notably, phosphorylated extracellular signal-regulated kinase (pERK) staining was predominantly observed in tubular cells from KO mice following 2 days of reperfusion, a time at which significant differences in renal dysfunction, histological changes, oxidative stress, and mitochondrial complexes between WT and KO mice were observed. Our study provides the first evidence that PrPC may play a protective role in renal IR injury, likely through its effects on mitochondria and ERK signaling pathways. PMID:26327228

  14. TLR9 Mediates Remote Liver Injury following Severe Renal Ischemia Reperfusion

    PubMed Central

    Bakker, Pieter J.; Scantlebery, Angelique M.; Butter, Loes M.; Claessen, Nike; Teske, Gwendoline J. D.; van der Poll, Tom; Florquin, Sandrine; Leemans, Jaklien C.

    2015-01-01

    Ischemia reperfusion injury is a common cause of acute kidney injury and is characterized by tubular damage. Mitochondrial DNA is released upon severe tissue injury and can act as a damage-associated molecular pattern via the innate immune receptor TLR9. Here, we investigated the role of TLR9 in the context of moderate or severe renal ischemia reperfusion injury using wild-type C57BL/6 mice or TLR9KO mice. Moderate renal ischemia induced renal dysfunction but did not decrease animal well-being and was not regulated by TLR9. In contrast, severe renal ischemia decreased animal well-being and survival in wild-type mice after respectively one or five days of reperfusion. TLR9 deficiency improved animal well-being and survival. TLR9 deficiency did not reduce renal inflammation or tubular necrosis. Rather, severe renal ischemia induced hepatic injury as seen by increased plasma ALAT and ASAT levels and focal hepatic necrosis which was prevented by TLR9 deficiency and correlated with reduced circulating mitochondrial DNA levels and plasma LDH. We conclude that TLR9 does not mediate renal dysfunction following either moderate or severe renal ischemia. In contrast, our data indicates that TLR9 is an important mediator of hepatic injury secondary to ischemic acute kidney injury. PMID:26361210

  15. Perioperative ischemic injury after coronary bypass graft surgery

    SciTech Connect

    Li, W.; Hanelin, L.G.; Riggins, R.C.; Agnew, R.C.; Annest, L.S.; Anderson, R.P.

    1985-07-01

    Two hundred twelve patients who underwent isolated coronary bypass graft surgery were prospectively evaluated for perioperative ischemic injury. All patients underwent preoperative and postoperative testing with technetium 99m pyrophosphate first-pass ventriculography combined with myocardial uptake scans, 12-lead electrocardiography, and serial creatinine phosphokinase MB determination. Fifteen percent of the patients had ischemic injury with at least two test results positive, but only 4 percent had positive results of all three tests. No single test proved adequate. Enzyme levels were highly sensitive and had value as a screening test. The electrocardiogram was specific but only moderately sensitive. The single best test was the radionuclide scan with good sensitivity and no false-positive results. All three tests are required to rigorously diagnose ischemic injury.

  16. Cytoprotective Effect of Ferritin H in Renal Ischemia Reperfusion Injury

    PubMed Central

    2015-01-01

    Oxidative stress is a major contributor to kidney injury following ischemia reperfusion. Ferritin, a highly conserved iron-binding protein, is a key protein in the maintenance of cellular iron homeostasis and protection from oxidative stress. Ferritin mitigates oxidant stress by sequestering iron and preventing its participation in reactions that generate reactive oxygen species. Ferritin is composed of two subunit types, ferritin H and ferritin L. Using an in vivo model that enables conditional tissue-specific doxycycline-inducible expression of ferritin H in the mouse kidney, we tested the hypothesis that an increased level of H-rich ferritin is renoprotective in ischemic acute renal failure. Prior to induction of ischemia, doxycycline increased ferritin H in the kidneys of the transgenic mice nearly 6.5-fold. Following reperfusion for 24 hours, induction of neutrophil gelatinous-associated lipocalin (NGAL, a urine marker of renal dysfunction) was reduced in the ferritin H overexpressers compared to controls. Histopathologic examination following ischemia reperfusion revealed that ferritin H overexpression increased intact nuclei in renal tubules, reduced the frequency of tubular profiles with luminal cast materials, and reduced activated caspase-3 in the kidney. In addition, generation of 4-hydroxy 2-nonenal protein adducts, a measurement of oxidant stress, was decreased in ischemia-reperfused kidneys of ferritin H overexpressers. These studies demonstrate that ferritin H can inhibit apoptotic cell death, enhance tubular epithelial viability, and preserve renal function by limiting oxidative stress following ischemia reperfusion injury. PMID:26379029

  17. mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress

    PubMed Central

    Grahammer, Florian; Haenisch, Nora; Steinhardt, Frederic; Sandner, Lukas; Roerden, Malte; Arnold, Frederic; Cordts, Tomke; Wanner, Nicola; Reichardt, Wilfried; Kerjaschki, Dontscho; Ruegg, Markus A.; Hall, Michael N.; Moulin, Pierre; Busch, Hauke; Boerries, Melanie; Walz, Gerd; Artunc, Ferruh; Huber, Tobias B.

    2014-01-01

    Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell metabolism and autophagy. Despite widespread clinical use of mTORC1 inhibitors, the role of mTORC1 in renal tubular function and kidney homeostasis remains elusive. By using constitutive and inducible deletion of conditional Raptor alleles in renal tubular epithelial cells, we discovered that mTORC1 deficiency caused a marked concentrating defect, loss of tubular cells, and slowly progressive renal fibrosis. Transcriptional profiling revealed that mTORC1 maintains renal tubular homeostasis by controlling mitochondrial metabolism and biogenesis as well as transcellular transport processes involved in countercurrent multiplication and urine concentration. Although mTORC2 partially compensated for the loss of mTORC1, exposure to ischemia and reperfusion injury exaggerated the tubular damage in mTORC1-deficient mice and caused pronounced apoptosis, diminished proliferation rates, and delayed recovery. These findings identify mTORC1 as an important regulator of tubular energy metabolism and as a crucial component of ischemic stress responses. PMID:24958889

  18. Mild ischemic Injury Leads to Long-Term Alterations in the Kidney: Amelioration by Spironolactone Administration

    PubMed Central

    Barrera-Chimal, Jonatan; Pérez-Villalva, Rosalba; Ortega, Juan Antonio; Sánchez, Andrea; Rodríguez-Romo, Roxana; Durand, Marta; Jaisser, Frederic; Bobadilla, Norma A.

    2015-01-01

    Administration of the mineralocorticoid receptor antagonist spironolactone prevents the development of chronic kidney disease (CKD) after a severe ischemic injury. However, whether brief periods of ischemia lead to CKD and whether spironolactone administration after ischemia may be a useful therapeutic strategy to prevent the gradual deterioration of structure and function remains unexplored. Nineteen male Wistar rats were divided into four groups: rats that underwent renal bilateral ischemia for 10, 20, or 45 min were compared with sham operated rats. Additionally, thirteen male Wistar rats that underwent renal bilateral ischemia for 20 min were divided into an untreated ischemic group (I) and two groups receiving spironolactone, 20 mg/kg by gavage, at either 0 (Sp0) or 1.5-h after ischemia (Sp1.5). The rats were followed up and studied after 9 months. Mild (20 min) and severe (45 min) ischemia induced a progressive increase in proteinuria at varying magnitudes, whereas minor ischemia (10 min) did not modify proteinuria. CKD induced by moderate ischemia was characterized by renal hypertrophy and tubulointerstitial fibrosis. These effects were associated with activation of the transforming growth factor β (TGFβ) signaling pathway and up-regulation of endothelin receptor A (ETA) and alpha smooth muscle actin (αSMA). Spironolactone treatment immediately or 1.5-h after the ischemic insult prevented the onset of these disorders. Our results show that moderate ischemic insult leads to long-term structural and molecular changes that may compromise renal function in later stages. Additionally, we demonstrate that spironolactone administration after mild ischemia prevents this detrimental effect. PMID:26157344

  19. [Neonatal hypoxic-ischemic brain injury: pathogenesis and neuropathology].

    PubMed

    Radulova, P; Slancheva, B

    2014-01-01

    The perinatal period represents a clinical setting of potential risk for injury to developing brain secondary to many causes, with the chance for long-lasting, profound neurocognitive deficits. Neonatal hypoxic-ischemic brain injury leads to serious long-term morbidities. The leading pathogenetic mechanisms are hypoxia and/or ischemia, as a result of perinatal asphyxia. Understanding of the underlying pathophysiology will help the physicians in the general supportive management and neuroprotection of the neonatal brain.

  20. Suppression of Acid Sphingomyelinase Protects the Retina from Ischemic Injury

    PubMed Central

    Fan, Jie; Wu, Bill X.; Crosson, Craig E.

    2016-01-01

    Purpose Acid sphingomyelinase (ASMase) catalyzes the hydrolysis of sphingomyelin to ceramide and mediates multiple responses involved in inflammatory and apoptotic signaling. However, the role ASMase plays in ischemic retinal injury has not been investigated. The purpose of this study was to investigate how reduced ASMase expression impacts retinal ischemic injury. Methods Changes in ceramide levels and ASMase activity were determined by high performance liquid chromatography-tandem mass spectrometry analysis and ASMase activity. Retinal function and morphology were assessed by electroretinography (ERG) and morphometric analyses. Levels of TNF-α were determined by ELISA. Activation of p38 MAP kinase was assessed by Western blot analysis. Results In wild-type mice, ischemia produced a significant increase in retinal ASMase activity and ceramide levels. These increases were associated with functional deficits as measured by ERG analysis and significant structural degeneration in most retinal layers. In ASMase+/− mice, retinal ischemia did not significantly alter ASMase activity, and the rise in ceramide levels were significantly reduced compared to levels in retinas from wild-type mice. In ASMase+/− mice, functional and morphometric analyses of ischemic eyes revealed significantly less retinal degeneration than in injured retinas from wild-type mice. The ischemia-induced increase in retinal TNF-α levels was suppressed by the administration of the ASMase inhibitor desipramine, or by reducing ASMase expression. Conclusions Our results demonstrate that reducing ASMase expression provides partial protection from ischemic injury. Hence, the production of ceramide and subsequent mediators plays a role in the development of ischemic retinal injury. Modulating ASMase may present new opportunities for adjunctive therapies when treating retinal ischemic disorders. PMID:27571014

  1. Myocardial neutrophil accumulation during reperfusion after reversible or ischemic injury

    SciTech Connect

    Go, L.O.; Murry, C.E.; Richard, V.J.; Weischedel, G.R.; Jennings, R.B.; Reimer, K.A. )

    1988-11-01

    Recent studies suggest that polymorphonuclear leukocytes (PMNs) may cause additional myocyte injury during reperfusion of ischemic myocardium. The present study was done to investigate whether PMNs accumulate in myocardium during early reperfusion after reversible or irreversible ischemic injury. Open-chest anesthetized dogs underwent circumflex coronary occlusions for 12 min, 40 min, or 90 min, followed by 1 h of reperfusion. Autologous PMNs were radiolabeled with {sup 111}In and reinjected to quantitate myocardial PMN influx during reflow. {sup 125}I-labeled albumin was injected simultaneously to correct for {sup 111}In associated with plasma proteins in myocardial tissue. The number of PMNs was determined in the inner, middle, and outer one-third of nonischemic and ischemic-reperfused myocardium. In the 12-min group, 40% fewer PMNs were present in the reperfused than in the nonischemic control tissue. In contrast, in both the 40- and 90-min groups, PMN accumulation was two- to six-fold greater in the ischemic-reperfused than nonischemic myocardium, with a transmural gradient of PMN influx increasing from the outer to inner layers. Collateral blood flow, measured with radioactive microspheres, was not significantly different among the three groups. The failure of PMNs to accumulate during reperfusion after 12 min of ischemia does not support the hypothesis that PMNs contribute to postischemic dysfunction of reversibly injured myocytes. Whether PMNs cause cell death during early reperfusion after longer ischemic episodes remains unknown; however, the rapidity of PMN accumulation in the zones of predicted infarction is consistent with this possibility.

  2. Investigation of Reperfusion Injury and Ischemic Preconditioning in Microsurgry

    PubMed Central

    Wang, Wei Zhong

    2008-01-01

    Ischemia/reperfusion (I/R) is inevitable in many vascular and musculoskeletal traumas, diseases, free tissue transfers, and during time-consuming reconstructive surgeries in the extremities. Salvage of a prolonged ischemic extremity or flap still remains a challenge for the microvascular surgeon. One of the common complications after microsurgery is I/R-induced tissue death or I/R injury. Twenty years after the discovery, ischemic preconditioning (IPC) has emerged as a powerful method for attenuating I/R injury in a variety of organs or tissues. However, its therapeutic expectations still need to be fulfilled. In this article, the author reviews some important experimental evidences of I/R injury as well as preconditioning-induced protection in the fields relevant to microsurgery. PMID:18946882

  3. Astaxanthin reduces ischemic brain injury in adult rats.

    PubMed

    Shen, Hui; Kuo, Chi-Chung; Chou, Jenny; Delvolve, Alice; Jackson, Shelley N; Post, Jeremy; Woods, Amina S; Hoffer, Barry J; Wang, Yun; Harvey, Brandon K

    2009-06-01

    Astaxanthin (ATX) is a dietary carotenoid of crustaceans and fish that contributes to their coloration. Dietary ATX is important for development and survival of salmonids and crustaceans and has been shown to reduce cardiac ischemic injury in rodents. The purpose of this study was to examine whether ATX can protect against ischemic injury in the mammalian brain. Adult rats were injected intracerebroventricularly with ATX or vehicle prior to a 60-min middle cerebral artery occlusion (MCAo). ATX was present in the infarction area at 70-75 min after onset of MCAo. Treatment with ATX, compared to vehicle, increased locomotor activity in stroke rats and reduced cerebral infarction at 2 d after MCAo. To evaluate the protective mechanisms of ATX against stroke, brain tissues were assayed for free radical damage, apoptosis, and excitoxicity. ATX antagonized ischemia-mediated loss of aconitase activity and reduced glutamate release, lipid peroxidation, translocation of cytochrome c, and TUNEL labeling in the ischemic cortex. ATX did not alter physiological parameters, such as body temperature, brain temperature, cerebral blood flow, blood gases, blood pressure, and pH. Collectively, our data suggest that ATX can reduce ischemia-related injury in brain tissue through the inhibition of oxidative stress, reduction of glutamate release, and antiapoptosis. ATX may be clinically useful for patients vulnerable or prone to ischemic events. PMID:19218497

  4. Astaxanthin reduces ischemic brain injury in adult rats.

    PubMed

    Shen, Hui; Kuo, Chi-Chung; Chou, Jenny; Delvolve, Alice; Jackson, Shelley N; Post, Jeremy; Woods, Amina S; Hoffer, Barry J; Wang, Yun; Harvey, Brandon K

    2009-06-01

    Astaxanthin (ATX) is a dietary carotenoid of crustaceans and fish that contributes to their coloration. Dietary ATX is important for development and survival of salmonids and crustaceans and has been shown to reduce cardiac ischemic injury in rodents. The purpose of this study was to examine whether ATX can protect against ischemic injury in the mammalian brain. Adult rats were injected intracerebroventricularly with ATX or vehicle prior to a 60-min middle cerebral artery occlusion (MCAo). ATX was present in the infarction area at 70-75 min after onset of MCAo. Treatment with ATX, compared to vehicle, increased locomotor activity in stroke rats and reduced cerebral infarction at 2 d after MCAo. To evaluate the protective mechanisms of ATX against stroke, brain tissues were assayed for free radical damage, apoptosis, and excitoxicity. ATX antagonized ischemia-mediated loss of aconitase activity and reduced glutamate release, lipid peroxidation, translocation of cytochrome c, and TUNEL labeling in the ischemic cortex. ATX did not alter physiological parameters, such as body temperature, brain temperature, cerebral blood flow, blood gases, blood pressure, and pH. Collectively, our data suggest that ATX can reduce ischemia-related injury in brain tissue through the inhibition of oxidative stress, reduction of glutamate release, and antiapoptosis. ATX may be clinically useful for patients vulnerable or prone to ischemic events.

  5. Respiratory Syncytial Virus Aggravates Renal Injury through Cytokines and Direct Renal Injury

    PubMed Central

    Zhai, Songhui; Hu, Lijuan; Zhong, Lin; Guo, Yannan; Dong, Liqun; Jia, Ruizhen; Wang, Zheng

    2016-01-01

    The purpose of this study was to investigate the relationship between renal injury and reinfection that is caused by respiratory syncytial virus (RSV) and to analyze the mechanism of renal injury. Rats were repeatedly infected with RSV on days 4, 8, 14, and 28, then sacrificed and examined on day 56 after the primary infection. Renal injury was examined by transmission electron microscopy and histopathology. The F protein of RSV was detected in the renal tissue by indirect immunofluorescence. Proteinuria and urinary glycosaminoglycans (GAGs), serum levels of albumin, urea nitrogen, and creatinine, secretion of cytokines, T lymphocyte population and subsets, and dendritic cell (DC) activation state were examined. The results showed that renal injury was more serious in the reinfection group than in the primary infection group. At a higher infection dose, 6 × 106 PFU, the renal injury was more severe, accompanied by higher levels of proteinuria and urinary GAGs excretion, and lower levels of serum albumin. Podocyte foot effacement was more extensive, and hyperplasia of mesangial cells and proliferation of mesangial matrix were observed. The maturation state of DCs was specific, compared with the primary infection. There was also a decrease in the ratio of CD4+ to CD8+ T lymphocytes, due to an increase in the percentage of CD8+ T lymphocytes and a decrease in the percentage of CD4+ T lymphocytes, and a dramatic increase in the levels of IL-6 and IL-17. In terms of the different reinfection times, the day 14 reinfection group yielded the most serious renal injury and the most significant change in immune function. RSV F protein was still expressed in the glomeruli 56 days after RSV infection. Altogether, these results reveal that RSV infection could aggravate renal injury, which might be due to direct renal injury caused by RSV and the inflammatory lesions caused by the anti-virus response induced by RSV. PMID:27747195

  6. Role of Endogenous Vitamin E in Renal Ischemic Preconditioning Process: Differences between Male and Female Rats

    PubMed Central

    Aryamanesh, Simin; Ebrahimi, Seyyed Meisam; Abotaleb, Nahid; Nobakht, Maliheh; Rahimi-Moghaddam, Parvaneh

    2012-01-01

    Background: Antioxidants such as α-tocopherol (vitamin E) and β-carotene (vitamin A) play an important role in protective effect of repeated brief periods of ischemia, namely ischemic preconditioning (IPC). Values of these antioxidants were investigated and compared after induction of ischemia reperfusion (IR) and kidney IPC in both male and female rats. Methods: Forty eight Wistar rats were divided randomly into six groups of 8: groups A and B (male and female controls, respectively), group C (male IR or IR cases), group D (female IR cases) and groups E and F (male and female IPC cases, respectively). In groups C and D, ischemia was induced by clamping of left renal arteries for 45 min. In groups E and F, rats underwent four cycles of 4 min of arterial clamping and 11 min of de-clamping before final 45 min ischemia induction. Afterward, serum was collected to assess the blood urea nitrogen, creatinine and vitamins E and A values. Renal tissues were obtained for histological assessments. Results: α-tocopherol levels in male and female rats showed a significant increase in IPC compared with IR group (P<0.01) and also in female IPC compared with male IPC group. β-carotene levels had no significant variations. Histological evaluation showed that IR-induced renal injuries were less in female rats. Also, protective effects of IPC were more in female rats (P<0.01). Conclusions: Renal IPC reduced damages in both male and female rats, but tissue injuries in females were decreased much more along with the increase of endogenous vitamin E. PMID:22562032

  7. Renal Vein Injury During Percutaneous Nephrolithotomy Procedure

    PubMed Central

    Toffeq, Hewa Mahmood

    2016-01-01

    Abstract Background: Percutaneous nephrostolithotomy is an important approach for removing kidney stones. Puncturing and dilatation are two mandatory steps in percutaneous nephrolithotomy (PCNL). Uncommonly, during dilatation, the dilators can cause direct injury to the main renal vein or to their tributaries. Case Presentation: A 75-year-old female underwent PCNL for partial staghorn stone in the left kidney. During puncturing and dilatation, renal vein tributary was injured, and the nephroscope entered the renal vein and inferior vena cava, which was clearly recognized. Injection of contrast material through the nephroscope confirms the false pathway to the great veins (renal vein and inferior vena cava). Bleeding was controlled intraoperatively by applying Amplatz sheath over the abnormal tract, the procedure was continued and stones were removed. At the end of the procedure, a Foley catheter was used as a nephrostomy tube and its balloon was inflated inside the renal pelvis and pulled back with light pressure to the lower calix, which was the site of injury to the renal vein tributaries, then the nephrostomy tube was closed; by this we effectively controlled the bleeding. The patient remained hemodynamically stable; antegrade pyelography was done on the second postoperative day, there was distally patent ureter with no extravasation, neither contrast leak to renal vein, and was discharged home at third postoperative day. After 2 weeks, the nephrostomy tube was gradually removed in the operative room, without bleeding, on the next day, Double-J stent was removed. Conclusion: Direct injury and false tract to the renal vein tributaries during PCNL can result in massive hemorrhage, and can be treated conservatively in hemodynamically stable patients, using a nephrostomy catheter as a tamponade. PMID:27704054

  8. Kidney Injury Molecule-1 Protects against Gα12 Activation and Tissue Damage in Renal Ischemia-Reperfusion Injury

    PubMed Central

    Ismail, Ola Z.; Zhang, Xizhong; Wei, Junjun; Haig, Aaron; Denker, Bradley M.; Suri, Rita S.; Sener, Alp; Gunaratnam, Lakshman

    2016-01-01

    Ischemic acute kidney injury is a serious untreatable condition. Activation of the G protein α12 (Gα12) subunit by reactive oxygen species is a major cause of tissue damage during renal ischemia-reperfusion injury. Kidney injury molecule-1 (KIM-1) is a transmembrane glycoprotein that is highly up-regulated during acute kidney injury, but the physiologic significance of this up-regulation is unclear. Here, we report for the first time that Kim-1 inhibits Gα12 activation and protects mice against renal ischemia-reperfusion injury. We reveal that Kim-1 physically interacts with and inhibits cellular Gα12 activation after inflammatory stimuli, including reactive oxygen species, by blocking GTP binding to Gα12. Compared with Kim-1+/+ mice, Kim-1−/− mice exhibited greater Gα12 and downstream Src activation both in primary tubular epithelial cells after in vitro stimulation with H2O2 and in whole kidneys after unilateral renal artery clamping. Finally, we show that Kim-1–deficient mice had more severe kidney dysfunction and tissue damage after bilateral renal artery clamping, compared with wild-type mice. Our results suggest that KIM-1 is an endogenous protective mechanism against renal ischemia-reperfusion injury through inhibition of Gα12. PMID:25759266

  9. Renal artery injury during robot-assisted renal surgery.

    PubMed

    Lee, Jae Won; Yoon, Young Eun; Kim, Dae Keun; Park, Sung Yul; Moon, Hong Sang; Lee, Tchun Yong

    2010-07-01

    Laparoscopic partial nephrectomy (LPN) is becoming the standard of care for incidentally diagnosed, small renal tumors. With its seven degrees of freedom and three-dimensional vision, the DaVinci robotic surgical system has been used to assist in LPNs. The main disadvantage of robot-assisted surgery, however, is the lack of tactile feedback. We present a case of renal artery injury during robot-assisted renal surgery. Robot-assisted partial nephrectomy (RPN) was planned for 47-year-old man with a 3.5-cm right renal mass. After standard bowel mobilization, renal hilar dissection was performed. In the attempt to complete the dissection posteriorly, however, there was sudden profuse bleeding. The intraperitoneal pressure immediately increased to 20 mm Hg, and an additional suction device was inserted through the 5-mm liver retractor port. On inspection, there was an injury at the takeoff of the posterior segmental artery. A decision was made to convert to robot-assisted laparoscopic radical nephrectomy. The main renal artery and renal vein were controlled with Hem-o-Lok clips. The estimated blood loss was 2,000 mL. Four units of packed red blood cells were transfused intraoperatively. The post-transfusion hemoglobin level was 12.6 g/dL. There were no other perioperative complications. The surgeon should keep in mind that the robotic arms are very powerful and can easily injure major vessels because of lack of tactile feedback. A competent and experienced tableside surgeon is very important in robot-assisted surgery because the unsterile console surgeon cannot immediately react to intraoperative complications.

  10. Bone Fracture Pre-Ischemic Stroke Exacerbates Ischemic Cerebral Injury in Mice

    PubMed Central

    Zou, Dingquan; Zhan, Lei; Li, Zhengxi; Zhu, Wan; Su, Hua

    2016-01-01

    Ischemic stroke is a devastating complication of bone fracture. Bone fracture shortly after stroke enhances stroke injury by augmenting inflammation. We hypothesize that bone fracture shortly before ischemic stroke also exacerbates ischemic cerebral injury. Tibia fracture was performed 6 or 24 hours before permanent middle cerebral artery occlusion (pMCAO) on C57BL/6J mice or Ccr2RFP/+Cx3cr1GFP/+ mice that have the RFP gene knocked into one allele of Ccr2 gene and GFP gene knocked into one allele of Cx3cr1 gene. Behavior was tested 3 days after pMCAO. Infarct volume, the number of CD68+ cells, apoptotic neurons, bone marrow-derived macrophages (RFP+), and microgila (GFP+) in the peri-infarct region were quantified. Compared to mice subjected to pMCAO only, bone fracture 6 or 24 hours before pMCAO increased behavioral deficits, the infarct volume, and the number of CD68+ cells and apoptotic neurons in the peri-infarct area. Both bone marrow-derived macrophages (CCR2+) and microglia (CX3CR1+) increased in the peri-infarct regions of mice subjected to bone fracture before pMCAO compared to stroke-only mice. The mice subjected to bone fracture 6 hours before pMCAO had more severe injury than mice that had bone fracture 24 hours before pMCAO. Our data showed that bone fracture shortly before stroke also increases neuroinflammation and exacerbates ischemic cerebral injury. Our findings suggest that inhibition of neuroinflammation or management of stroke risk factors before major bone surgery would be beneficial for patients who are likely to suffer from stroke. PMID:27089041

  11. Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy

    PubMed Central

    Park, Sang Won; Chen, Sean W.C.; Kim, Mihwa; Brown, Kevin M.; Kolls, Jay K.; D’Agati, Vivette D.; Lee, H. Thomas

    2010-01-01

    Patients with acute kidney injury (AKI) frequently suffer from extra-renal complications including hepatic dysfunction and systemic inflammation. We aimed to determine the mechanisms of AKI induced hepatic dysfunction and systemic inflammation. Mice subjected to AKI [renal ischemia reperfusion (IR) or nephrectomy] rapidly developed acute hepatic dysfunction and suffered significantly worse hepatic IR injury. After AKI, rapid peri-portal hepatocyte necrosis, vacuolization, neutrophil infiltration and pro-inflammatory mRNA upregulation were observed suggesting an intestinal source of hepatic injury. Small intestine histology after AKI demonstrated profound villous lacteal capillary endothelial apoptosis, disruption of vascular permeability and epithelial necrosis. After ischemic or non-ischemic AKI, plasma TNF-α, IL-17A and IL-6 increased significantly. Small intestine appears to be the source of IL-17A as IL-17A levels were higher in the portal circulation and small intestine compared to the levels measured from the systemic circulation and liver. Wild type mice treated with neutralizing antibodies against TNF-α, IL-17A or IL-6 or mice deficient in TNF-α, IL-17A, IL-17A receptor or IL-6 were protected against hepatic and small intestine injury due to ischemic or non-ischemic AKI. For the first time, we implicate the increased release of IL-17A from small intestine together with induction of TNF-α and IL-6 as a cause of small intestine and liver injury after ischemic or non-ischemic AKI. Modulation of the inflammatory response and cytokine release in the small intestine after AKI may have important therapeutic implications in reducing complications arising from AKI. PMID:20697374

  12. Antisense oligonucleotide for tissue factor inhibits hepatic ischemic reperfusion injury.

    PubMed

    Nakamura, Kenji; Kadotani, Yayoi; Ushigome, Hidetaka; Akioka, Kiyokazu; Okamoto, Masahiko; Ohmori, Yoshihiro; Yaoi, Takeshi; Fushiki, Shinji; Yoshimura, Rikio; Yoshimura, Norio

    2002-09-27

    Tissue factor (TF) is an initiation factor for blood coagulation and its expression is induced on endothelial cells during inflammatory or immune responses. We designed an antisense oligodeoxynucleotide (AS-1/TF) for rat TF and studied its effect on hepatic ischemic reperfusion injury. AS-1/TF was delivered intravenously to Lewis rats. After 10 h, hepatic artery and portal vein were partially clamped. Livers were reperfused after 180 min and harvested. TF expression was studied using immunohistochemical staining. One of 10 rats survived in a 5-day survival rate and TF was strongly stained on endothelial cells in non-treatment group. However, by treatment with AS-1/TF, six of seven survived and TF staining was significantly reduced. Furthermore, we observed that fluorescein-labeled AS-1/TF was absorbed into endothelial cells. These results suggest that AS-1/TF can strongly suppress the expression of TF and thereby inhibit ischemic reperfusion injury to the rat liver. PMID:12270110

  13. Ischemic postconditioning protects against ischemic brain injury by up-regulation of acid-sensing ion channel 2a

    PubMed Central

    Duanmu, Wang-sheng; Cao, Liu; Chen, Jing-yu; Ge, Hong-fei; Hu, Rong; Feng, Hua

    2016-01-01

    Ischemic postconditioning renders brain tissue tolerant to brain ischemia, thereby alleviating ischemic brain injury. However, the exact mechanism of action is still unclear. In this study, a rat model of global brain ischemia was subjected to ischemic postconditioning treatment using the vessel occlusion method. After 2 hours of ischemia, the bilateral common carotid arteries were blocked immediately for 10 seconds and then perfused for 10 seconds. This procedure was repeated six times. Ischemic postconditioning was found to mitigate hippocampal CA1 neuronal damage in rats with brain ischemia, and up-regulate acid-sensing ion channel 2a expression at the mRNA and protein level. These findings suggest that ischemic postconditioning up-regulates acid-sensing ion channel 2a expression in the rat hippocampus after global brain ischemia, which promotes neuronal tolerance to ischemic brain injury. PMID:27212927

  14. Macrophage diversity in renal injury and repair

    PubMed Central

    Ricardo, Sharon D.; van Goor, Harry; Eddy, Allison A.

    2008-01-01

    Monocyte-derived macrophages can determine the outcome of the immune response and whether this response contributes to tissue repair or mediates tissue destruction. In addition to their important role in immune-mediated renal disease and host defense, macrophages play a fundamental role in tissue remodeling during embryonic development, acquired kidney disease, and renal allograft responses. This review summarizes macrophage phenotype and function in the orchestration of kidney repair and replacement of specialized renal cells following injury. Recent advances in our understanding of macrophage heterogeneity in response to their microenvironment raise new and exciting therapeutic possibilities to attenuate or conceivably reverse progressive renal disease in the context of fibrosis. Furthermore, parallels with pathological processes in many other organs also exist. PMID:18982158

  15. Oxidant Mechanisms in Renal Injury and Disease

    PubMed Central

    Ratliff, Brian B.; Abdulmahdi, Wasan; Pawar, Rahul

    2016-01-01

    Abstract Significance: A common link between all forms of acute and chronic kidney injuries, regardless of species, is enhanced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during injury/disease progression. While low levels of ROS and RNS are required for prosurvival signaling, cell proliferation and growth, and vasoreactivity regulation, an imbalance of ROS and RNS generation and elimination leads to inflammation, cell death, tissue damage, and disease/injury progression. Recent Advances: Many aspects of renal oxidative stress still require investigation, including clarification of the mechanisms which prompt ROS/RNS generation and subsequent renal damage. However, we currently have a basic understanding of the major features of oxidative stress pathology and its link to kidney injury/disease, which this review summarizes. Critical Issues: The review summarizes the critical sources of oxidative stress in the kidney during injury/disease, including generation of ROS and RNS from mitochondria, NADPH oxidase, and inducible nitric oxide synthase. The review next summarizes the renal antioxidant systems that protect against oxidative stress, including superoxide dismutase and catalase, the glutathione and thioredoxin systems, and others. Next, we describe how oxidative stress affects kidney function and promotes damage in every nephron segment, including the renal vessels, glomeruli, and tubules. Future Directions: Despite the limited success associated with the application of antioxidants for treatment of kidney injury/disease thus far, preventing the generation and accumulation of ROS and RNS provides an ideal target for potential therapeutic treatments. The review discusses the shortcomings of antioxidant treatments previously used and the potential promise of new ones. Antioxid. Redox Signal. 25, 119–146. PMID:26906267

  16. Optical spectroscopy for the detection of ischemic tissue injury

    DOEpatents

    Demos, Stavros; Fitzgerald, Jason; Troppmann, Christoph; Michalopoulou, Andromachi

    2009-09-08

    An optical method and apparatus is utilized to quantify ischemic tissue and/or organ injury. Such a method and apparatus is non-invasive, non-traumatic, portable, and can make measurements in a matter of seconds. Moreover, such a method and apparatus can be realized through optical fiber probes, making it possible to take measurements of target organs deep within a patient's body. Such a technology provides a means of detecting and quantifying tissue injury in its early stages, before it is clinically apparent and before irreversible damage has occurred.

  17. Neuroprotective agents for neonatal hypoxic-ischemic brain injury.

    PubMed

    Wu, Qiaofeng; Chen, Wu; Sinha, Bharati; Tu, Yanyang; Manning, Simon; Thomas, Niranjan; Zhou, Shuanhu; Jiang, Hong; Ma, He; Kroessler, Daphne A; Yao, Jiemin; Li, Zhipu; Inder, Terry E; Wang, Xin

    2015-11-01

    Hypoxic-ischemic (H-I) brain injury in newborns is a major cause of morbidity and mortality that claims thousands of lives each year. In this review, we summarize the promising neuroprotective agents tested on animal models and pilot clinical studies of neonatal H-I brain injury according to the different phases of the disease. These agents target various phases of injury including the early phase of excitotoxicity, oxidative stress and apoptosis as well as late-phase inflammatory reaction and neural repair. We analyze the cell survival and cell death pathways modified by these agents in neonatal H-I brain injury. We aim to 'build a bridge' between animal trials of neuroprotective agents and potential candidate treatments for future clinical applications against H-I encephalopathy. PMID:26360053

  18. Automated core-penumbra quantification in neonatal ischemic brain injury.

    PubMed

    Ghosh, Nirmalya; Yuan, Xiangpeng; Turenius, Christine I; Tone, Beatriz; Ambadipudi, Kamalakar; Snyder, Evan Y; Obenaus, Andre; Ashwal, Stephen

    2012-12-01

    Neonatal hypoxic-ischemic brain injury (HII) and arterial ischemic stroke (AIS) result in irreversibly injured (core) and salvageable (penumbral) tissue regions. Identification and reliable quantification of salvageable tissue is pivotal to any effective and safe intervention. Magnetic resonance imaging (MRI) is the current standard to distinguish core from penumbra using diffusion-perfusion mismatch (DPM). However, subtle MR signal variations between core-penumbral regions make their visual delineation difficult. We hypothesized that computational analysis of MRI data provides a more accurate assessment of core and penumbral tissue evolution in HII/AIS. We used two neonatal rat-pup models of HII/AIS (unilateral and global hypoxic-ischemia) and clinical data sets from neonates with AIS to test our noninvasive, automated computational approach, Hierarchical Region Splitting (HRS), to detect and quantify ischemic core-penumbra using only a single MRI modality (T2- or diffusion-weighted imaging, T2WI/DWI). We also validated our approach by comparing core-penumbral images (from HRS) to DPM with immunohistochemical validation of HII tissues. Our translational and clinical data results showed that HRS could accurately and reliably distinguish the ischemic core from penumbra and their spatiotemporal evolution, which may aid in the vetting and execution of effective therapeutic interventions as well as patient selection.

  19. Glucose modulation of ischemic brain injury: review and clinical recommendations.

    PubMed

    Wass, C T; Lanier, W L

    1996-08-01

    Ischemic brain injury is the third-leading cause of death among Americans and the leading cause of serious disability. Based on studies of animal models, a substantial amount of experimental evidence shows that hyperglycemia at the onset of brain ischemia worsens postischemic neurologic outcome. Consistent with these observations, hyperglycemia also is associated with a worsening of postischemic brain injury in humans. In humans, however, data are often difficult to interpret because of problems in determining the timing of hyperglycemia relative to a critical ischemic event and in elucidating the effect of coexisting pathophysiologic processes (for example, a stress response) on outcome. Glucose modulation of neurologic injury is observed when ischemia is either global (for example, that accompanying cardiac arrest or severe systemic hypotension) or focal (for example, that accompanying thrombotic or embolic stroke). Toxicity is probably the result of an intracellular lactic acidosis. Specifically, the associated hydrogen ions are injurious to neurons and glia. On the basis of these factors, we recommend diligent monitoring of blood glucose concentrations in patients who are at increased risk for new-onset, ongoing, or recurring cerebral ischemia. In such patients, the use of fluid infusions, corticosteroid drugs, and insulin, as well as stress management, should be tailored to treat preexisting hyperglycemia and prevent new-onset hyperglycemia. Maintenance of normoglycemia is recommended. When one attempts to treat preexisting hyperglycemia, care should be taken to avoid rapid fluid shifts, electrolyte abnormalities, and hypoglycemia, all of which can be detrimental to the brain.

  20. Computational Biology: Modeling Chronic Renal Allograft Injury.

    PubMed

    Stegall, Mark D; Borrows, Richard

    2015-01-01

    New approaches are needed to develop more effective interventions to prevent long-term rejection of organ allografts. Computational biology provides a powerful tool to assess the large amount of complex data that is generated in longitudinal studies in this area. This manuscript outlines how our two groups are using mathematical modeling to analyze predictors of graft loss using both clinical and experimental data and how we plan to expand this approach to investigate specific mechanisms of chronic renal allograft injury.

  1. Hepatic Sulfotransferase as a Nephropreventing Target by Suppression of the Uremic Toxin Indoxyl Sulfate Accumulation in Ischemic Acute Kidney Injury

    PubMed Central

    Saito, Hideyuki; Yoshimura, Misato; Saigo, Chika; Komori, Megumi; Nomura, Yui; Yamamoto, Yuko; Sagata, Masataka; Wakida, Ayaka; Chuman, Erina; Nishi, Kazuhiko; Jono, Hirofumi

    2014-01-01

    Ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) is evoked by diverse pathophysiological conditions and/or surgical procedures. Here, we evaluated the nephropreventive effect of sulfotransferase (SULT) inhibitors, quercetin, and resveratrol, which hamper hepatic indoxyl sulfate (IS) production. I/R of the kidney caused severe renal injury with marked accumulation of serum and renal IS and urinary excretion of kidney injury molecule-1. Oral administration of AST-120 resulted in a significant restoration of kidney injury, suggesting that uremic toxins, which can be suppressed or adsorbed by AST-120 in the intestine, contribute to the progression or development of I/R-induced AKI. Oral administration of resveratrol or quercetin, SULT inhibitors, suppressed IS accumulation, accompanied by significant amelioration of renal dysfunction. The expression of nuclear factor E2-related factor 2 (Nrf2) in the renal nuclear fractions was markedly elevated by renal I/R, but suppressed by treatment with SULT inhibitors. IS is primarily taken up by HK-2 cells derived from human proximal tubular cells via organic anion transporters, which then evokes activation of Nrf2, most likely due to intracellular oxidative stress. Renal basolateral organic anion transporters OAT1 and OAT3, which mediate renal tubular uptake of IS in basolateral membrane, were markedly downregulated by renal I/R, but restored by SULT inhibitors. Our results suggest that renal accumulation of IS in ischemic AKI induces oxidative stress and downregulation of organic anion transporters resulting in kidney damage, which could be restored to some extent by inhibiting hepatic SULT activity as a nephropreventive target. PMID:24958931

  2. Protective effect of ischemic postconditioning against ischemia reperfusion-induced myocardium oxidative injury in IR rats.

    PubMed

    Zhang, Li; Ma, Jiangwei; Liu, Huajin

    2012-03-27

    Brief episodes of myocardial ischemia-reperfusion (IR) employed during reperfusion after a prolonged ischemic insult may attenuate the total ischemia-reperfusion injury. This phenomenon has been termed ischemic postconditioning. In the present study, we studied the possible effect of ischemic postconditioning on an ischemic reperfusion (IR)-induced myocardium oxidative injury in rat model. Results showed that ischemic postconditioning could improve arrhythmia cordis, reduce myocardium infarction and serum creatin kinase (CK), lactate dehydrogenase (LDH) and aspartate transaminase (AST) activities in IR rats. In addition, ischemic postconditioning could still decrease myocardium malondialdehyde (MDA) level, and increased myocardium Na+-K+-ATPase, Ca2+-Mg2+-ATPase, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) activities. It can be concluded that ischemic postconditioning possesses strong protective effects against ischemia reperfusion-induced myocardium oxidative injury in IR rats.

  3. The volatile anesthetic isoflurane induces ecto-5′-nucleotidase (CD73) to protect against renal ischemia and reperfusion injury

    PubMed Central

    Kim, Mihwa; Ham, Ahrom; Kim, Joo Yun; Brown, Kevin M.; D’Agati, Vivette D.; Lee, H. Thomas

    2013-01-01

    The volatile anesthetic isoflurane protects against renal ischemia and reperfusion injury by releasing renal tubular TGF-β1. Since adenosine is a powerful cytoprotective molecule, we tested whether TGF-β1 generated by isoflurane induces renal tubular ecto-5′-nucleotidase (CD73) and adenosine to protect against renal ischemia and reperfusion injury. Isoflurane induced new CD73 synthesis and increased adenosine generation in cultured kidney proximal tubule cells and in mouse kidney. Moreover, a TGF-β1 neutralizing antibody prevented isoflurane-mediated induction of CD73 activity. Mice anesthetized with isoflurane after renal ischemia and reperfusion had significantly reduced plasma creatinine and decreased renal tubular necrosis, neutrophil infiltration and apoptosis compared to pentobarbital-anesthetized mice. Isoflurane failed to protect against renal ischemia and reperfusion injury in CD73 deficient mice, in mice pretreated with a selective CD73 inhibitor or mice treated with an adenosine receptor antagonist. The TGF-β1 neutralizing antibody or the CD73 inhibitor attenuated isoflurane-mediated protection against HK-2 cell apoptosis. Thus, isoflurane causes TGF-β1-dependent induction of renal tubular CD73 and adenosine generation to protect against renal ischemia and reperfusion injury. Modulation of this pathway may have important therapeutic implications to reduce morbidity and mortality arising from ischemic acute kidney injury. PMID:23423261

  4. Autophagy activation attenuates renal ischemia-reperfusion injury in rats

    PubMed Central

    Zhang, Ya-Li; Cui, Li-Yan; Yang, Shuo

    2015-01-01

    Ischemia-reperfusion (I/R) injury is a leading cause of acute kidney injury (AKI), which is a common clinical complication but lacks effective therapies. This study investigated the role of autophagy in renal I/R injury and explored potential mechanisms in an established rat renal I/R injury model. Forty male Wistar rats were randomly divided into four groups: Sham, I/R, I/R pretreated with 3-methyladenine (3-MA, autophagy inhibitor), or I/R pretreated with rapamycin (autophagy activator). All rats were subjected to clamping of the left renal pedicle for 45 min after right nephrectomy, followed by 24 h of reperfusion. The Sham group underwent the surgical procedure without ischemia. 3-MA and rapamycin were injected 15 min before ischemia. Renal function was indicated by blood urea nitrogen and serum creatinine. Tissue samples from the kidneys were scored histopathologically. Autophagy was indicated by light chain 3 (LC3), Beclin-1, and p62 levels and the number of autophagic vacuoles. Apoptosis was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method and expression of caspase-3. Autophagy was activated after renal I/R injury. Inhibition of autophagy by 3-MA before I/R aggravated renal injury, with worsened renal function, higher renal tissue injury scores, and more tubular apoptosis. In contrast, rapamycin pretreatment ameliorated renal injury, with improved renal function, lower renal tissue injury scores, and inhibited apoptosis based on fewer TUNEL-positive cells and lower caspase-3 expression. Our results demonstrate that autophagy could be activated during I/R injury and play a protective role in renal I/R injury. The mechanisms were involved in the regulation of several autophagy and apoptosis-related genes. Furthermore, autophagy activator may be a promising therapy for I/R injury and AKI in the future. PMID:25898836

  5. Myricetin and quercetin attenuate ischemic injury in glial cultures by different mechanisms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have demonstrated that polyphenols from cinnamon and green tea reduce cell swelling and mitochondrial dysfunction in C6 glial cultures following ischemic injury. We tested the protective effects of the flavonoid polyphenols, myricetin and quercetin, on key features of ischemic injury. C6 cultures...

  6. Update in the classification and treatment of complex renal injuries.

    PubMed

    Reis, Leonardo Oliveira; Kim, Fernando J; Moore, Ernest E; Hirano, Elcio Shiyoiti; Fraga, Gustavo Pereira; Nascimento, Barto; Rizoli, Sandro

    2013-01-01

    The "Evidence-Based Telemedicine - Trauma and Acute Care Surgery" (EBT-TACS) Journal Club performed a critical review of the literature and selected three up-to-date articles on the management of renal trauma defined as American Association for the Surgery of Trauma (AAST) injury grade III-V. The first paper was the proposal for the AAST grade 4renal injury substratification into grades 4a (Low Risk) and 4b (High Risk). The second paper was a revision of the current AAST renal injury grading system, expanding to include segmental vascular injuries and to establish a more rigorous definition of severe grade IV and V renal injuries.The last article analyses the diagnostic angiography and angioembolization in the acute management of renal trauma using a national data set in the USA. The EBT-TACS Journal Club elaborated conclusions and recommendations for the management of high-grade renal trauma. PMID:24173488

  7. Suppression of Etk/Bmx protects against ischemic brain injury.

    PubMed

    Chen, Kai-Yun; Wu, Chung-Che; Chang, Cheng-Fu; Chen, Yuan-Hao; Chiu, Wen-Ta; Lou, Ya-Hsin; Chen, Yen-Hua; Shih, Hsiu-Ming; Chiang, Yung-Hsiao

    2012-01-01

    Etk/Bmx (epithelial and endothelial tyrosine kinase, also known as BMX), a member of the Tec (tyrosine kinase expressed in hepatocellular carcinoma) family of protein-tyrosine kinases, is an important regulator of signal transduction for the activation of cell growth, differentiation, and development. We have previously reported that activation of Etk leads to apoptosis in MDA-MB-468 cells. The purpose of this study was to examine the role of Etk in neuronal injury induced by H(2)O(2) or ischemia. Using Western blot analysis and immunohistochemistry, we found that treatment with H(2)O(2) significantly enhanced phosphorylation of Etk and its downstream signaling molecule Stat1 in primary cortical neurons. Inhibiting Etk activity by LFM-A13 or knocking down Etk expression by a specific shRNA increased the survival of primary cortical neurons. Similarly, at 1 day after a 60-min middle cerebral artery occlusion (MCAo) in adult rats, both phosphorylated Etk and Stat1 were coexpressed with apoptotic markers in neurons in the penumbra. Pretreatment with LFM-A13 or an adenoviral vector encoding the kinase deletion mutant Etkk attenuated caspase-3 activity and infarct volume in ischemic brain. All together, our data suggest that Etk is activated after neuronal injury. Suppressing Etk activity protects against neurodegeneration in ischemic brain. PMID:21929872

  8. RGS4 inhibits angiotensin II signaling and macrophage localization during renal reperfusion injury independent of vasospasm

    PubMed Central

    Pang, Paul; Jin, Xiaohua; Proctor, Brandon M.; Farley, Michelle; Roy, Nilay; Chin, Matthew S.; von Andrian, Ulrich H.; Vollmann, Elisabeth; Perro, Mario; Hoffman, Ryan J.; Chung, Joseph; Chauhan, Nikita; Mistri, Murti; Muslin, Anthony J.; Bonventre, Joseph V.; Siedlecki, Andrew M.

    2014-01-01

    Vascular inflammation is a major contributor to the severity of acute kidney injury. In the context of vasospasm-independent reperfusion injury we studied the potential anti-inflammatory role of the Gα-related RGS protein, RGS4. Transgenic RGS4 mice were resistant to 25 minute injury, although post-ischemic renal arteriolar diameter was equal to the wild type early after injury. A 10 minute unilateral injury was performed to study reperfusion without vasospasm. Eighteen hours after injury blood flow was decreased in the inner cortex of wild type mice with preservation of tubular architecture. Angiotensin II levels in the kidneys of wild type and transgenic mice were elevated in a sub-vasoconstrictive range 12 and 18 hours after injury. Angiotensin II stimulated pre-glomerular vascular smooth muscle cells (VSMC) to secrete the macrophage chemoattractant, RANTES; a process decreased by angiotensin II R2 (AT2) inhibition. However, RANTES increased when RGS4 expression was suppressed implicating Gα protein activation in an AT2-RGS4-dependent pathway. RGS4 function, specific to VSMC, was tested in a conditional VSMC-specific RGS4 knockout showing high macrophage density by T2 MRI compared to transgenic and non-transgenic mice after the 10 minute injury. Arteriolar diameter of this knockout was unchanged at successive time points after injury. Thus, RGS4 expression, specific to renal VSMC, inhibits angiotensin II-mediated cytokine signaling and macrophage recruitment during reperfusion, distinct from vasomotor regulation. PMID:25469849

  9. Intestinal ischemic preconditioning reduces liver ischemia reperfusion injury in rats

    PubMed Central

    XUE, TONG-MIN; TAO, LI-DE; ZHANG, JIE; ZHANG, PEI-JIAN; LIU, XIA; CHEN, GUO-FENG; ZHU, YI-JIA

    2016-01-01

    The aim of the current study was to investigate whether intestinal ischemic preconditioning (IP) reduces damage to the liver during hepatic ischemia reperfusion (IR). Sprague Dawley rats were used to model liver IR injury, and were divided into the sham operation group (SO), IR group and IP group. The results indicated that IR significantly increased Bax, caspase 3 and NF-κBp65 expression levels, with reduced expression of Bcl-2 compared with the IP group. Compared with the IR group, the levels of AST, ALT, MPO, MDA, TNF-α and IL-1 were significantly reduced in the IP group. Immunohistochemistry for Bcl-2 and Bax indicated that Bcl-2 expression in the IP group was significantly increased compared with the IR group. In addition, IP reduced Bax expression compared with the IR group. The average liver injury was worsened in the IR group and improved in the IP group, as indicated by the morphological evaluation of liver tissues. The present study suggested that IP may alleviates apoptosis, reduce the release of pro-inflammatory cytokines, ameloriate reductions in liver function and reduce liver tissue injury. To conclude, IP provided protection against hepatic IR injury. PMID:26821057

  10. Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure

    PubMed Central

    Konkalmatt, Prasad R.; Asico, Laureano D.; Zhang, Yanrong; Yang, Yu; Drachenberg, Cinthia; Zheng, Xiaoxu; Han, Fei; Jose, Pedro A.; Armando, Ines

    2016-01-01

    Dopamine D2 receptor (DRD2) deficiency increases renal inflammation and blood pressure in mice. We show here that long-term renal-selective silencing of Drd2 using siRNA increases renal expression of proinflammatory and profibrotic factors and blood pressure in mice. To determine the effects of renal-selective rescue of Drd2 expression in mice, the renal expression of DRD2 was first silenced using siRNA and 14 days later rescued by retrograde renal infusion of adeno-associated virus (AAV) vector with DRD2. Renal Drd2 siRNA treatment decreased the renal expression of DRD2 protein by 55%, and DRD2 AAV treatment increased the renal expression of DRD2 protein by 7.5- to 10-fold. Renal-selective DRD2 rescue reduced the expression of proinflammatory factors and kidney injury, preserved renal function, and normalized systolic and diastolic blood pressure. These results demonstrate that the deleterious effects of renal-selective Drd2 silencing on renal function and blood pressure were rescued by renal-selective overexpression of DRD2. Moreover, the deleterious effects of 45-minute bilateral ischemia/reperfusion on renal function and blood pressure in mice were ameliorated by a renal-selective increase in DRD2 expression by the retrograde ureteral infusion of DRD2 AAV immediately after the induction of ischemia/reperfusion injury. Thus, 14 days after ischemia/reperfusion injury, the renal expression of profibrotic factors, serum creatinine, and blood pressure were lower in mice infused with DRD2 AAV than in those infused with control AAV. These results indicate an important role of renal DRD2 in limiting renal injury and preserving normal renal function and blood pressure. PMID:27358912

  11. Trans-system mechanisms against ischemic myocardial injury.

    PubMed

    Liu, Shu Q; Ma, Xin-Liang; Qin, Gangjian; Liu, Qingping; Li, Yan-Chun; Wu, Yu H

    2015-01-01

    A mammalian organism possesses a hierarchy of naturally evolved protective mechanisms against ischemic myocardial injury at the molecular, cellular, and organ levels. These mechanisms comprise regional protective processes, including upregulation and secretion of paracrine cell-survival factors, inflammation, angiogenesis, fibrosis, and resident stem cell-based cardiomyocyte regeneration. There are also interactive protective processes between the injured heart, circulation, and selected remote organs, defined as trans-system protective mechanisms, including upregulation and secretion of endocrine cell-survival factors from the liver and adipose tissue as well as mobilization of bone marrow, splenic, and hepatic cells to the injury site to mediate myocardial protection and repair. The injured heart and activated remote organs exploit molecular and cellular processes, including signal transduction, gene expression, cell proliferation, differentiation, migration, mobilization, and/or extracellular matrix production, to establish protective mechanisms. Both regional and trans-system cardioprotective mechanisms are mediated by paracrine and endocrine messengers and act in coordination and synergy to maximize the protective effect, minimize myocardial infarction, and improve myocardial function, ensuring the survival and timely repair of the injured heart. The concept of the trans-system protective mechanisms may be generalized to other organ systems-injury in one organ may initiate regional as well as trans-system protective responses, thereby minimizing injury and ensuring the survival of the entire organism. Selected trans-system processes may serve as core protective mechanisms that can be exploited by selected organs in injury. These naturally evolved protective mechanisms are the foundation for developing protective strategies for myocardial infarction and injury-induced disorders in other organ systems.

  12. Ouabain Contributes to Kidney Damage in a Rat Model of Renal Ischemia-Reperfusion Injury

    PubMed Central

    Villa, Luca; Buono, Roberta; Ferrandi, Mara; Molinari, Isabella; Benigni, Fabio; Bettiga, Arianna; Colciago, Giorgia; Ikehata, Masami; Messaggio, Elisabetta; Rastaldi, Maria Pia; Montorsi, Francesco; Salonia, Andrea; Manunta, Paolo

    2016-01-01

    Warm renal ischemia performed during partial nephrectomy has been found to be associated with kidney disease. Since endogenous ouabain (EO) is a neuro-endocrine hormone involved in renal damage, we evaluated the role of EO in renal ischemia-reperfusion injury (IRI). We measured plasma and renal EO variations and markers of glomerular and tubular damage (nephrin, KIM-1, Kidney-Injury-Molecule-1, α1 Na-K ATPase) and the protective effect of the ouabain inhibitor, rostafuroxin. We studied five groups of rats: (1) normal; (2) infused for eight weeks with ouabain (30 µg/kg/day, OHR) or (3) saline; (4) ouabain; or (5) saline-infused rats orally treated with 100 µg/kg/day rostafuroxin for four weeks. In group 1, 2–3 h after IRI, EO increased in ischemic kidneys while decreased in plasma. Nephrin progressively decreased and KIM-1 mRNA increased starting from 24 h. Ouabain infusion (group 2) increased blood pressure (from 111.7 to 153.4 mmHg) and ouabain levels in plasma and kidneys. In OHR ischemic kidneys at 120 h from IRI, nephrin, and KIM-1 changes were greater than those detected in the controls infused with saline (group 3). All these changes were blunted by rostafuroxin treatment (groups 4 and 5). These findings support the role of EO in IRI and suggest that rostafuroxin pre-treatment of patients before partial nephrectomy with warm ischemia may reduce IRI, particularly in those with high EO. PMID:27754425

  13. [Heavy metal poisoning and renal injury in children].

    PubMed

    Rong, Li-Ping; Xu, Yuan-Yuan; Jiang, Xiao-Yun

    2014-04-01

    Along with global environmental pollution resulting from economic development, heavy metal poisoning in children has become an increasingly serious health problem in the world. It can lead to renal injury, which tends to be misdiagnosed due to the lack of obvious or specific early clinical manifestations in children. Early prevention, diagnosis and intervention are valuable for the recovery of renal function and children's good health and growth. This paper reviews the mechanism of renal injury caused by heavy metal poisoning in children, as well as the clinical manifestations, diagnosis, and prevention and treatment of renal injury caused by lead, mercury, cadmium, and chromium.

  14. Acute renal failure complicating muscle crush injury.

    PubMed

    Abassi, Z A; Hoffman, A; Better, O S

    1998-09-01

    Extensive skeletal muscle injury, whether caused by mechanical crush or by extreme physical exertion, is incompatible with life, unless treated early and vigorously. The immediate cause of morbidity is leakiness of the sarcolemmal membrane to cardiotoxic or nephrotoxic cations and metabolites (K, PO4, myoglobin and urate) of the sarcoplasma, and rapid massive uptake by the muscles of extracellular fluid, sodium and calcium, leading to profound hypovolemic and hyocalcemic shock. Casualties who survive the early steep of hyperkalemia and arterial hypotension are susceptible to myoglubinuric acute renal failure owing mainly to the combination of renal vasoconstriction, nephrotoxicity, and tubular obstruction by myoglobin plugs and urate. Management includes immediate (prehospital) intravenous volume replacement followed by mannitol-alkaline diuresis. The alkali regimen ameliorates the acidosis associated with shock and the hyperkalemia, and protects against the nephrotoxicity of myoglobin and urate by alkalinization of the urine. Mannitol, through its impermeant hyperoncotic properties, decompresses and mobilizes muscle edema and promotes renal tubular flow, thus flushing myoglobin plugs and enhancing urinary elimination of nephrotoxic metabolites. With this regimen and when necessary also with the use of dialysis, a substantial salvage of lives, limbs, and kidney function has been achieved recently compared with invariable mortality for casualties who were buried for 3 to 4 hours or more in the early 1940s (World War 2).

  15. [Rupture of simple renal cyst after minimal renal injury].

    PubMed

    Fernández Férnandez, A; Mayayo Dehesa, T; Rodríguez Luna, J M; Platas Sancho, A; Gómez Aguinaga, M A; Castaño Llaneza, C; Berenguer Sánchez, A

    1989-01-01

    A case is presented of minimum renal trauma, leading to a retroperitoneal hematoma as a consequence of a simple renal cyst rupture as well as an artery contained therein. The etiopathogenicity of this phenomenon is commented. The different clinical manifestations of renal trauma are highlighted, as well as the suspicion of previous renal pathology when a large renal lesion is found secondary to minimum renal trauma. The approach of the renal pediculum must be the first step in the surgical treatment of renal trauma.

  16. Importance of adenosine triphosphate in phospholipase A2-induced rabbit renal proximal tubule cell injury.

    PubMed Central

    Nguyen, V D; Cieslinski, D A; Humes, H D

    1988-01-01

    The pathogenesis of ischemic renal tubular cell injury involves a complex interaction of different processes, including membrane phospholipid alterations and depletion of high-energy phosphate stores. To assess the role of membrane phospholipid changes due to activation of phospholipases in renal tubule cell injury, suspensions enriched in rabbit renal proximal tubule segments were incubated with exogenous phospholipase A2 (PLA2). Exogenous PLA2 did not produce any significant change in various metabolic parameters reflective of cell injury in control nonhypoxic preparations despite a significant decrease in phosphatidylethanolamine (PE) and moderate increases in lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE). In contrast, exogenous PLA2 treatment of hypoxic tubules resulted in a severe degree of cell injury, as demonstrated by marked declines in tubule K+ and ATP contents and significant decreases in tubule uncoupled respiratory rates, and was associated with significant phospholipid alterations, including marked declines in phosphatidylcholine (PC) and PE and significant rises in LPC, LPE, and free fatty acids (FFA). The injurious metabolic effects of exogenous PLA2 on hypoxic tubules were reversed by addition of ATP-MgCl2 to the tubules. The protective effect of ATP-MgCl2 was associated with increases in tubule PC and PE contents and declines in LPC, LPE, and FFA contents. These experiments thus indicate that an increase in exogenous PLA2 activity produces renal proximal tubule cell injury when cell ATP levels decline, at which point phospholipid resynthesis cannot keep pace with phospholipid degradation with resulting depletion of phospholipids and accumulation of lipid by-products. High-energy phosphate store depletion appears to be an important condition for exogenous PLA2 activity to induce renal tubule cell injury. PMID:3417866

  17. Cardioprotection against experimental myocardial ischemic injury using cornin

    PubMed Central

    Xu, Y.; Xu, Y.; Luan, H.; Jiang, Y.; Tian, X.; Zhang, S.

    2016-01-01

    Phosphorylated-cyclic adenosine monophosphate response element-binding protein (Phospho-CREB) has an important role in the pathogenesis of myocardial ischemia. We isolated the iridoid glycoside cornin from the fruit of Verbena officinalis L, investigated its effects against myocardial ischemia and reperfusion (I/R) injury in vivo, and elucidated its potential mechanism in vitro. Effects of cornin on cell viability, as well as expression of phospho-CREB and phospho-Akt in hypoxic H9c2 cells in vitro, and myocardial I/R injury in vivo, were investigated. Cornin attenuated hypoxia-induced cytotoxicity significantly in H9c2 cells in a concentration-dependent manner. Treatment of H9c2 cells with cornin (10 µM) blocked the reduction of expression of phospho-CREB and phospho-Akt in a hypoxic condition. Treatment of rats with cornin (30 mg/kg, iv) protected them from myocardial I/R injury as indicated by a decrease in infarct volume, improvement in hemodynamics, and reduction of severity of myocardial damage. Cornin treatment also attenuated the reduction of expression of phospho-CREB and phospho-Akt in ischemic myocardial tissue. These data suggest that cornin exerts protective effects due to an increase in expression of phospho-CREB and phospho-Akt. PMID:26871971

  18. Cardioprotection against experimental myocardial ischemic injury using cornin.

    PubMed

    Xu, Y; Xu, Y; Luan, H; Jiang, Y; Tian, X; Zhang, S

    2016-02-01

    Phosphorylated-cyclic adenosine monophosphate response element-binding protein (Phospho-CREB) has an important role in the pathogenesis of myocardial ischemia. We isolated the iridoid glycoside cornin from the fruit of Verbena officinalis L, investigated its effects against myocardial ischemia and reperfusion (I/R) injury in vivo, and elucidated its potential mechanism in vitro. Effects of cornin on cell viability, as well as expression of phospho-CREB and phospho-Akt in hypoxic H9c2 cells in vitro, and myocardial I/R injury in vivo, were investigated. Cornin attenuated hypoxia-induced cytotoxicity significantly in H9c2 cells in a concentration-dependent manner. Treatment of H9c2 cells with cornin (10 µM) blocked the reduction of expression of phospho-CREB and phospho-Akt in a hypoxic condition. Treatment of rats with cornin (30 mg/kg, iv) protected them from myocardial I/R injury as indicated by a decrease in infarct volume, improvement in hemodynamics, and reduction of severity of myocardial damage. Cornin treatment also attenuated the reduction of expression of phospho-CREB and phospho-Akt in ischemic myocardial tissue. These data suggest that cornin exerts protective effects due to an increase in expression of phospho-CREB and phospho-Akt.

  19. Pharmacologic inhibition of the NLRP3 inflammasome preserves cardiac function after ischemic and non-ischemic injury in the mouse

    PubMed Central

    Marchetti, Carlo; Toldo, Stefano; Chojnacki, Jeremy; Mezzaroma, Eleonora; Liu, Kai; Salloum, Fadi N.; Nordio, Andrea; Carbone, Salvatore; Mauro, Adolfo Gabriele; Das, Anindita; Zalavadia, Ankit A.; Halquist, Matthew S.; Federici, Massimo; Van Tassell, Benjamin W.; Zhang, Shijun; Abbate, Antonio

    2015-01-01

    Background Sterile inflammation resulting from myocardial injury activates the NLRP3 inflammasome and amplifies the inflammatory response mediating further damage. Methods We used two experimental models of ischemic injury (acute myocardial infarction [AMI] with and without reperfusion) and a model of non-ischemic injury due to doxorubicin 10 mg/Kg, to determine whether the NLRP3 inflammasome preserved cardiac function after injury. Results Treatment with the NLRP3 inflammasome inhibitor in the reperfused AMI model caused a significant reduction in infarct size measured at pathology or as serum cardiac troponin I level (−56% and −82% respectively, both p<0.001), and preserved LV fractional shortening (LVFS, 31±2 vs vehicle 26±1%, p=0.003). In the non-reperfused AMI model treatment with the NLRP3 inhibitor significantly limited LV systolic dysfunction at 7 days (LVFS of 20±2 vs 14±1%, p=0.002), without a significant effect on infarct size. In the DOX model, a significant increase in myocardial interstitial fibrosis and a decline in systolic function were seen in vehicle-treated mice, whereas treatment with the NLRP3 inhibitor significantly reduced fibrosis (−80%, p=0.001) and preserved systolic function (LVFS 35±2 vs vehicle 27±2%, p=0.017). Conclusion Pharmacological inhibition of the NLRP3 inflammasome limits cell death and LV systolic dysfunction following ischemic and non-ischemic injury in the mouse. PMID:25915511

  20. Fructokinase activity mediates dehydration-induced renal injury

    PubMed Central

    Roncal Jimenez, Carlos A; Ishimoto, Takuji; Lanaspa, Miguel A; Rivard, Christopher J; Nakagawa, Takahiko; Ejaz, A. Ahsan; Cicerchi, Christina; Inaba, Shinichiro; Le, MyPhuong; Miyazaki, Makoto; Glaser, Jason; Correa-Rotter, Ricardo; González, Marvin A; Aragón, Aurora; Wesseling, Catharina; Sánchez-Lozada, Laura G; Johnson, Richard J

    2014-01-01

    The epidemic of chronic kidney disease in Nicaragua (Mesoamerican nephropathy) has been linked with recurrent dehydration. Here we tested whether recurrent dehydration may cause renal injury by activation of the polyol pathway, resulting in the generation of endogenous fructose in the kidney that might subsequently induce renal injury via metabolism by fructokinase. Wild-type and fructokinase-deficient mice were subjected to recurrent heat-induced dehydration. One group of each genotype was provided water throughout the day and the other group was hydrated at night, after the dehydration. Both groups received the same total hydration in 24 h. Wild-type mice that received delayed hydration developed renal injury, with elevated serum creatinine, increased urinary NGAL, proximal tubular injury, and renal inflammation and fibrosis. This was associated with activation of the polyol pathway, with increased renal cortical sorbitol and fructose levels. Fructokinase-knockout mice with delayed hydration were protected from renal injury. Thus, recurrent dehydration can induce renal injury via a fructokinase-dependent mechanism, likely from the generation of endogenous fructose via the polyol pathway. Access to sufficient water during the dehydration period can protect mice from developing renal injury. These studies provide a potential mechanism for Mesoamerican nephropathy. PMID:24336030

  1. Ischemic stroke injury is mediated by aberrant Cdk5.

    PubMed

    Meyer, Douglas A; Torres-Altoro, Melissa I; Tan, Zhenjun; Tozzi, Alessandro; Di Filippo, Massimiliano; DiNapoli, Vincent; Plattner, Florian; Kansy, Janice W; Benkovic, Stanley A; Huber, Jason D; Miller, Diane B; Greengard, Paul; Calabresi, Paolo; Rosen, Charles L; Bibb, James A

    2014-06-11

    Ischemic stroke is one of the leading causes of morbidity and mortality. Treatment options are limited and only a minority of patients receive acute interventions. Understanding the mechanisms that mediate neuronal injury and death may identify targets for neuroprotective treatments. Here we show that the aberrant activity of the protein kinase Cdk5 is a principal cause of neuronal death in rodents during stroke. Ischemia induced either by embolic middle cerebral artery occlusion (MCAO) in vivo or by oxygen and glucose deprivation in brain slices caused calpain-dependent conversion of the Cdk5-activating cofactor p35 to p25. Inhibition of aberrant Cdk5 during ischemia protected dopamine neurotransmission, maintained field potentials, and blocked excitotoxicity. Furthermore, pharmacological inhibition or conditional knock-out (CKO) of Cdk5 prevented neuronal death in response to ischemia. Moreover, Cdk5 CKO dramatically reduced infarctions following MCAO. Thus, targeting aberrant Cdk5 activity may serve as an effective treatment for stroke.

  2. Critical Role of Interleukin-11 in Isoflurane-mediated Protection against Ischemic Acute Kidney Injury in Mice

    PubMed Central

    Ham, Ahrom; Kim, Mihwa; Kim, Joo Yun; Brown, Kevin M.; Yeh, James; D’Agati, Vivette D.; Lee, H. Thomas

    2013-01-01

    Background Isoflurane releases renal tubular transforming growth factor-beta 1 (TGF-β1) and protects against ischemic acute kidney injury (AKI). Recent studies suggest that TGF-β1 can induce a cytoprotective cytokine interleukin (IL)-11. Here, we tested the hypothesis that isoflurane protects against ischemic AKI by direct induction of renal tubular IL-11 synthesis. Methods Human kidney proximal tubule (HK-2) cells were treated with 1.25-2.5% isoflurane or carrier gas (room air+5% carbon dioxide) for 0-16 h. We also anesthetized C57BL/6 mice with 1.2% isoflurane or with equi-anesthetic dose of pentobarbital for 4 h. In addition, we subjected IL-11 receptor (IL-11R) wild type, IL-11R deficient or IL-11 neutralized mice to 30-min renal ischemia followed by reperfusion under 4 h of pentobarbital or isoflurane (1.2%) anesthesia. Results Isoflurane increased IL-11 synthesis in human (~300-500% increase, N = 6) and mouse (23 ± 4 (mean ± SD) fold over carrier gas group, N = 4) proximal tubule cells that were attenuated by a TGF-β1 neutralizing antibody. Mice anesthetized with isoflurane showed significantly increased kidney IL-11 messenger RNA (13.8 ± 2 fold over carrier gas group, N = 4) and protein (31 ± 9 vs. 18±2 pg/mg protein or ~80% increase, N = 4) expression compared to pentobarbital anesthetized mice and this increase was also attenuated by a TGF-β1 neutralizing antibody. Furthermore, isoflurane-mediated renal protection in IL-11R wild-type mice were absent in IL-11R deficient mice or in IL-11R wild-type mice treated with IL-11 neutralizing antibody (N = 4-6). Conclusions Our studies suggest that isoflurane induces renal tubular IL-11 via TGF-β1 signaling to protect against ischemic AKI. PMID:24037316

  3. Rip1 (receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury.

    PubMed

    Linkermann, Andreas; Bräsen, Jan H; Himmerkus, Nina; Liu, Shuya; Huber, Tobias B; Kunzendorf, Ulrich; Krautwald, Stefan

    2012-04-01

    Loss of kidney function in renal ischemia/reperfusion injury is due to programmed cell death, but the contribution of necroptosis, a newly discovered form of programmed necrosis, has not been evaluated. Here, we identified the presence of death receptor-mediated but caspase-independent cell death in murine tubular cells and characterized it as necroptosis by the addition of necrostatin-1, a highly specific receptor-interacting protein kinase 1 inhibitor. The detection of receptor-interacting protein kinase 1 and 3 in whole-kidney lysates and freshly isolated murine proximal tubules led us to investigate the contribution of necroptosis in a mouse model of renal ischemia/reperfusion injury. Treatment with necrostatin-1 reduced organ damage and renal failure, even when administered after reperfusion, resulting in a significant survival benefit in a model of lethal renal ischemia/reperfusion injury. Unexpectedly, specific blockade of apoptosis by zVAD, a pan-caspase inhibitor, did not prevent the organ damage or the increase in urea and creatinine in vivo in renal ischemia/reperfusion injury. Thus, necroptosis is present and has functional relevance in the pathophysiological course of ischemic kidney injury and shows the predominance of necroptosis over apoptosis in this setting. Necrostatin-1 may have therapeutic potential to prevent and treat renal ischemia/reperfusion injury. PMID:22237751

  4. [Current concepts of perinatal ischemic injury in the brain neurovascular unit: molecular targets for neuroprotection].

    PubMed

    Morgun, A V; Kuvacheva, N V; Taranushenko, T E; Khilazheva, E D; Malinovskaia, N A; Gorina, Ia V; Pozhilenkova, E A; Frolova, O V; Salmina, A B

    2013-01-01

    Perinatal hypoxic-ischemic brain injury is a relevant medical and social problem. Among many pathological processes in the neonatal period perinatal hypoxic-ischemic injury is a major cause of further hemorrhage, necrotic and atrophic changes in the brain. This review presents recent data on the basic mechanisms of the hypoxic-ischemic brain injury along the concept of neurovascular unit (neurons, astrocytes, endothelial cells, pericytes) with the focus on alterations in cell-to-cell communication. Pathological changes caused by ischemia-hypoxia are considered within two phases of injury (ischemic phase and reperfusion phase). The review highlights changes in each individual component of the neurovascular unit and their interactions. Molecular targets for pharmacological improvement of intercellular communication within neurovascular unit as a therapeutic strategy in perinatal brain injury are discussed.

  5. Bilateral renal lymphoma: rapid recovery from an acute kidney injury after open renal biopsy.

    PubMed

    Mitome, Taku; Furuya, Kazuhiro; Imano, Masashi; Osaka, Kimito; Yokomizo, Yumiko; Hayashi, Narihiko; Nakaigawa, Noboru; Yamanaka, Shoji; Yao, Masahiro

    2016-01-01

    Renal lymphoma as an initial lesion is relatively rare. Bilateral renal lymphoma frequently presents as acute kidney injury. With systematic chemotherapy for the lymphoma, patients usually recover their kidney function. However, in the case we describe here, the patient's kidney function recovered greatly after an open renal biopsy. Here, we review and discuss this unique case.

  6. Using the endocannabinoid system as a neuroprotective strategy in perinatal hypoxic-ischemic brain injury

    PubMed Central

    Lara-Celador, I.; Goñi-de-Cerio, F.; Alvarez, Antonia; Hilario, Enrique

    2013-01-01

    One of the most important causes of brain injury in the neonatal period is a perinatal hypoxic-ischemic event. This devastating condition can lead to long-term neurological deficits or even death. After hypoxic-ischemic brain injury, a variety of specific cellular mechanisms are set in motion, triggering cell damage and finally producing cell death. Effective therapeutic treatments against this phenomenon are still unavailable because of complex molecular mechanisms underlying hypoxic-ischemic brain injury. After a thorough understanding of the mechanism underlying neural plasticity following hypoxic-ischemic brain injury, various neuroprotective therapies have been developed for alleviating brain injury and improving long-term outcomes. Among them, the endocannabinoid system emerges as a natural system of neuroprotection. The endocannabinoid system modulates a wide range of physiological processes in mammals and has demonstrated neuroprotective effects in different paradigms of acute brain injury, acting as a natural neuroprotectant. The aim of this review is to study the use of different therapies to induce long-term therapeutic effects after hypoxic-ischemic brain injury, and analyze the important role of the endocannabinoid system as a new neuroprotective strategy against perinatal hypoxic-ischemic brain injury. PMID:25206720

  7. Effect of melatonin on kidney cold ischemic preservation injury

    PubMed Central

    Aslaner, Arif; Gunal, Omer; Turgut, Hamdi Taner; Celik, Erdal; Yildirim, Umran; Demirci, Rojbin Karakoyun; Gunduz, Umut Riza; Calis, Hasan; Dogan, Sami

    2013-01-01

    Melatonin is a potent free radical scavenger of reactive oxygen species, nitric oxide synthase inhibitor and a well-known antioxidant secreted from pineal gland. This hormone has been reported to protect tissue from oxidative damage. In this study, we aim to investigate the effect of melatonin on kidney cold ischemia time when added to preservation solution. Thirty male Wistar albino rats were divided equally into three groups; Ringer Lactate (RL) solution, University of Wisconsin (UW) solution with and without melatonin. The serum Lactate Dehydrogenase (LDH) activities of the preservation solutions at 2nd, 24th, 36th, and 48th hours were determined. Tissue malondialdehyde (MDA) levels were also measured and a histological examination was performed at 48th hour. Melatonin that added to preservation solution prevented enzyme elevation and decreased lipid peroxidation in preservation solution when compared to the control group (p<0.05). The histological examination revealed that UW solution containing melatonin significantly prevented the kidney from pathological injury (p<0.05). Melatonin added to preservation solutions such as UW solution seemed to protect the tissue preserved effectively from cold ischemic injury for up to 48 hour. PMID:24179573

  8. Methyleugenol reduces cerebral ischemic injury by suppression of oxidative injury and inflammation.

    PubMed

    Choi, Yoo Keum; Cho, Geum-Sil; Hwang, Sunyoung; Kim, Byung Woo; Lim, Ji H; Lee, Jae-Chul; Kim, Hyoung Chun; Kim, Won-Ki; Kim, Yeong Sik

    2010-08-01

    The present study tested the cytoprotective effect of methyleugenol in an in vivo ischemia model (i.e. middle cerebral artery occlusion (MCAO) for 1.5 h and subsequent reperfusion for 24 h) and further investigated its mechanism of action in in vitro cerebral ischemic models. When applied shortly after reperfusion, methyleugenol largely reduced cerebral ischemic injury. Methyleugenol decreased the caspase-3 activation and death of cultured cerebral cortical neurons caused by oxygen-glucose deprivation (OGD) for 1 h and subsequent re-oxygenation for 24 h. Methyleugenol markedly reduced superoxide generation in the ischemic brain and decreased the intracellular oxidative stress caused by OGD/re-oxygenation. It was found that methyleugenol elevated the activities of superoxide dismutase and catalase. Further, methyleugenol inhibited the production of nitric oxide and decreased the protein expression of inducible nitric oxide synthase. Methyleugenol down-regulated the production of pro-inflammatory cytokines in the ischemic brain as well as in immunostimulated mixed glial cells. The results indicate that methyleugenol could be useful for the treatment of ischemia/inflammation-related diseases.

  9. PROGRESSIVE RENAL VASCULAR PROLIFERATION AND INJURY IN OBESE ZUCKER RATS

    PubMed Central

    Iliescu, Radu; Chade, Alejandro R.

    2010-01-01

    Objective Obesity, an independent risk factor for chronic kidney disease, may induce renal injury by promoting inflammation. Inflammatory cytokines can induce neovascularization in different organs, including the kidneys. However, whether obesity triggers renal neovascularization and, if so, its effect on renal function has never been investigated. Methods Blood pressure, proteinuria and glomerular-filtration-rate (GFR) were measured in-vivo. Renal microvascular (MV) architecture was studied by 3D micro-CT in lean and obese Zucker rats (LZR and OZR, n=7/group) at 12, 22, and 32 weeks of age. Renal inflammation was assessed by quantifying interleukin (IL)-6, tumor-necrosis-factor (TNF)-alpha, and ED-1 expression, as renal fibrosis in trichrome-stained cross-sections. Results Mild inflammation and lower GFR was only observed in younger OZR, without renal fibrosis or changes in MV density. Interestingly, renal MV density increased in OZR at 32 weeks of age, accompanied by pronounced increase in renal IL-6 and TNF-alpha, ED-1+ cells, proteinuria, decreased GFR, and fibrosis. Conclusion This study shows increased renal cortical vascularization in experimental obesity, suggesting neovascularization as an evolving process as obesity progresses. Increased renal vascularization, possibly triggered by inflammation, may reflect an initially compensatory mechanism in obesity. However, increased inflammation and inflammatory-induced neovascularization may further promote renal injury as obesity advances. PMID:20536738

  10. Neurotoxic lipid peroxidation species formed by ischemic stroke increase injury

    PubMed Central

    Zeiger, Stephanie L. H.; Musiek, Erik S.; Zanoni, Giuseppe; Vidari, Giovanni; Morrow, Jason D.; Milne, Ginger J.; McLaughlin, BethAnn

    2009-01-01

    Stroke is the third leading cause of death in the United States yet no neuroprotective agents for treatment are clinically available. There is a pressing need to understand the signaling molecules which mediate ischemic cell death and identify novel neuroprotective targets. Cyclopentenone isoprostanes (IsoP), formed following free radical mediated peroxidation of arachidonic acid, are used as markers of stress but their bioactivity is poorly understood. We have recently shown that 15-A2t-Isop is a potent neurotoxin in vitro and increases the free radical burden in neurons. In this work, we demonstrate that 15-A2t-IsoP is abundantly produced in stroke infarcted human cortical tissue. Using primary neuronal cultures we found that minimally toxic exposure to 15-A2t-IsoP does not alter ATP content, but in combination with oxygen glucose deprivation resulted in a significant hyperpolarization of the mitochondrial membrane and dramatically increased neuronal cell death. In the presence of Ca2+, 15-A2t-IsoP led to a rapid induction of the permeability transition pore and release of cytochrome c. Taken with our previous work, these data support a model in which ischemia causes generation of reactive oxygen species, calcium influx, lipid peroxidation and 15-A2t-IsoP formation. These factors combine to enhance opening of the permeability transition pore leading to cell death subsequent to mitochondrial cytochrome c release. This data is the first documentation of significant 15-A2t-IsoP formation following acute ischemic stroke and suggests addition of 15-A2t-IsoP to in vitro models of ischemia may help to more fully recapitulate stroke injury. PMID:19699297

  11. Galacto-oligosaccharides attenuate renal injury with microbiota modification.

    PubMed

    Furuse, Satoshi U; Ohse, Takamoto; Jo-Watanabe, Airi; Shigehisa, Akira; Kawakami, Koji; Matsuki, Takahiro; Chonan, Osamu; Nangaku, Masaomi

    2014-07-01

    Tubulointerstitial injury is central to the progression of end-stage renal disease. Recent studies have revealed that one of the most investigated uremic toxins, indoxyl sulfate (IS), caused tubulointerstitial injury through oxidative stress and endoplasmic reticulum (ER) stress. Because indole, the precursor of IS, is synthesized from dietary tryptophan by the gut microbiota, we hypothesized that the intervention targeting the gut microbiota in kidney disease with galacto-oligosaccharides (GOS) would attenuate renal injury. After 2 weeks of GOS administration for 5/6 nephrectomized (Nx) or sham-operated (Sham) rats, cecal indole and serum IS were measured, renal injury was evaluated, and the effects of GOS on the gut microbiota were examined using pyrosequencing methods. Cecal indole and serum IS were significantly decreased and renal injury was improved with decreased infiltrating macrophages in GOS-treated Nx rats. The expression levels of ER stress markers and apoptosis were significantly increased in the Nx rats and decreased with GOS. The microbiota analysis indicated that GOS significantly increased three bacterial families and decreased five families in the Nx rats. In addition, the analysis also revealed that the bacterial family Clostridiaceae was significantly increased in the Nx rats compared with the Sham rats and decreased with GOS. Taken altogether, our data show that GOS decreased cecal indole and serum IS, attenuated renal injury, and modified the gut microbiota in the Nx rats, and that the gut microbiota were altered in kidney disease. GOS could be a novel therapeutic agent to protect against renal injury.

  12. Atherosclerotic ischemic renal disease. Diagnosis and prevalence in an hypertensive and/or uremic elderly population

    PubMed Central

    Coen, Giorgio; Calabria, Santo; Lai, Silvia; Moscaritolo, Eleonora; Nofroni, Italo; Ronga, Giuseppe; Rossi, Michele; Ventroni, Guido; Sardella, Daniela; Ferrannini, Michele; Zaccaria, Alvaro; Cianci, Rosario

    2003-01-01

    Background Atherosclerotic ischemic renal disease is a frequent cause of end-stage renal failure leading to dialysis among the elderly; Its prevalence is inferred from autopsy or retrospective arteriographic studies. This study has been conducted on 269 subjects over 50 with hypertension and/or CRF, unrelated to other known causes of renal disease. Methods All 269 patients were studied either by color-flow duplex sonography (n = 238) or by renal scintigraphy (n = 224), and 199 of the 269 patients were evaluated using both of these techniques. 40 patients, found to have renal artery stenosis (RAS), were subjected to 3D-contrast enhancement Magnetic Resonance Angiography (MRA) and/or Selective Angiography (SA). An additional 23 cases, negative both to scintigraphy and to ultrasound study, underwent renal angiography (MRA and/or SA). Results Color-duplex sonography, carried out in 238 patients, revealed 49 cases of RAS. MR or SA was carried out in 35 of these 49 patients, and confirmed the diagnosis in 33. Color-duplex sonography showed a PPV value of 94.3% and NPV of 87.0% while renal scintigraphy, carried out in 224 patients, had a PPV of 72.2% and a NPV of 29.4%. Patients with RAS showed a higher degree of renal insufficiency compared to non stenotic patients while there were no differences in proteinuria. RAS, based on color-duplex sonography studies, was present in 11% of patients in the age group 50–59, 18% in the 60–69 and 23% at age 70 and above. Conclusions A relatively large percentage of the elderly population with renal insufficiency and/or hypertension is affected by RAS and is at risk of developing end-stage renal failure. Color-duplex ultrasonography is a valid routine method of investigation of population at risk for renal artery stenosis. PMID:12622875

  13. Role of Mitochondria in Neonatal Hypoxic-Ischemic Brain Injury

    PubMed Central

    Lu, Yujiao; Tucker, Donovan; Dong, Yan; Zhao, Ningjun; Zhuo, Xiaoying; Zhang, Quanguang

    2016-01-01

    Hypoxic-ischemia (HI) causes severe brain injury in neonates. It’s one of the leading causes to neonatal death and pediatric disability, resulting in devastating consequences, emotionally and economically, to their families. A series of events happens in this process, e.g. excitatory transmitter release, extracelluar Ca2+ influxing, mitochondrial dysfunction, energy failure, and neuron death. There are two forms of neuron death after HI insult: necrosis and apoptosis, apoptosis being the more prevalent form. Mitochondria handle a series of oxidative reactions, and yield energy for various cellular activities including the maintainance of membrane potential and preservation of intracellular ionic homeostasis. Therefore mitochondria play a critical role in neonatal neurodegeneration following HI, and mitochondrial dysfunction is the key point in neurodegenerative evolution. Because of this, exploring effective mitochondria-based clinical strategies is crucial. Today the only efficacious clinic treatment is hypothermia. However, due to its complex management, clinical complication and autoimmune decrease, its clinical application is limited. So far, many mitochondria-based strategies have been reported neuroprotective in animal models, which offers promise on neonatal therapy. However, since their clinical effectiveness are still unclear, plenty of studies need to be continued in the future. According to recent reports, two novel strategies have been proposed: methylene blue (MB) and melatonin. Although they are still in primary stage, the underlying mechanisms indicate promising clinical applications. Every neurological therapeutic strategy has its intrinsic deficit and limited efficacy, therefore in the long run, the perfect clinical therapy for hypoxic-ischemic neonatal brain injury will be based on the combination of multiple strategies. PMID:27441209

  14. Acute renal injury after partial hepatectomy

    PubMed Central

    Peres, Luis Alberto Batista; Bredt, Luis Cesar; Cipriani, Raphael Flavio Fachini

    2016-01-01

    Currently, partial hepatectomy is the treatment of choice for a wide variety of liver and biliary conditions. Among the possible complications of partial hepatectomy, acute kidney injury (AKI) should be considered as an important cause of increased morbidity and postoperative mortality. Difficulties in the data analysis related to postoperative AKI after liver resections are mainly due to the multiplicity of factors to be considered in the surgical patients, moreover, there is no consensus of the exact definition of AKI after liver resection in the literature, which hampers comparison and analysis of the scarce data published on the subject. Despite this multiplicity of risk factors for postoperative AKI after partial hepatectomy, there are main factors that clearly contribute to its occurrence. First factor relates to large blood losses with renal hypoperfusion during the operation, second factor relates to the occurrence of post-hepatectomy liver failure with consequent distributive circulatory changes and hepatorenal syndrome. Eventually, patients can have more than one factor contributing to post-operative AKI, and frequently these combinations of acute insults can be aggravated by sepsis or exposure to nephrotoxic drugs. PMID:27478539

  15. Acute renal injury after partial hepatectomy.

    PubMed

    Peres, Luis Alberto Batista; Bredt, Luis Cesar; Cipriani, Raphael Flavio Fachini

    2016-07-28

    Currently, partial hepatectomy is the treatment of choice for a wide variety of liver and biliary conditions. Among the possible complications of partial hepatectomy, acute kidney injury (AKI) should be considered as an important cause of increased morbidity and postoperative mortality. Difficulties in the data analysis related to postoperative AKI after liver resections are mainly due to the multiplicity of factors to be considered in the surgical patients, moreover, there is no consensus of the exact definition of AKI after liver resection in the literature, which hampers comparison and analysis of the scarce data published on the subject. Despite this multiplicity of risk factors for postoperative AKI after partial hepatectomy, there are main factors that clearly contribute to its occurrence. First factor relates to large blood losses with renal hypoperfusion during the operation, second factor relates to the occurrence of post-hepatectomy liver failure with consequent distributive circulatory changes and hepatorenal syndrome. Eventually, patients can have more than one factor contributing to post-operative AKI, and frequently these combinations of acute insults can be aggravated by sepsis or exposure to nephrotoxic drugs. PMID:27478539

  16. RGS4 inhibits angiotensin II signaling and macrophage localization during renal reperfusion injury independent of vasospasm.

    PubMed

    Pang, Paul; Jin, Xiaohua; Proctor, Brandon M; Farley, Michelle; Roy, Nilay; Chin, Matthew S; von Andrian, Ulrich H; Vollmann, Elisabeth; Perro, Mario; Hoffman, Ryan J; Chung, Joseph; Chauhan, Nikita; Mistri, Murti; Muslin, Anthony J; Bonventre, Joseph V; Siedlecki, Andrew M

    2015-04-01

    Vascular inflammation is a major contributor to the severity of acute kidney injury. In the context of vasospasm-independent reperfusion injury we studied the potential anti-inflammatory role of the Gα-related RGS protein, RGS4. Transgenic RGS4 mice were resistant to 25 min injury, although post-ischemic renal arteriolar diameter was equal to the wild type early after injury. A 10 min unilateral injury was performed to study reperfusion without vasospasm. Eighteen hours after injury, blood flow was decreased in the inner cortex of wild-type mice with preservation of tubular architecture. Angiotensin II levels in the kidneys of wild-type and transgenic mice were elevated in a sub-vasoconstrictive range 12 and 18 h after injury. Angiotensin II stimulated pre-glomerular vascular smooth muscle cells (VSMCs) to secrete the macrophage chemoattractant RANTES, a process decreased by angiotensin II R2 (AT2) inhibition. However, RANTES increased when RGS4 expression was suppressed implicating Gα protein activation in an AT2-RGS4-dependent pathway. RGS4 function, specific to VSMC, was tested in a conditional VSMC-specific RGS4 knockout showing high macrophage density by T2 MRI compared with transgenic and non-transgenic mice after the 10 min injury. Arteriolar diameter of this knockout was unchanged at successive time points after injury. Thus, RGS4 expression, specific to renal VSMC, inhibits angiotensin II-mediated cytokine signaling and macrophage recruitment during reperfusion, distinct from vasomotor regulation. PMID:25469849

  17. RGS4 inhibits angiotensin II signaling and macrophage localization during renal reperfusion injury independent of vasospasm.

    PubMed

    Pang, Paul; Jin, Xiaohua; Proctor, Brandon M; Farley, Michelle; Roy, Nilay; Chin, Matthew S; von Andrian, Ulrich H; Vollmann, Elisabeth; Perro, Mario; Hoffman, Ryan J; Chung, Joseph; Chauhan, Nikita; Mistri, Murti; Muslin, Anthony J; Bonventre, Joseph V; Siedlecki, Andrew M

    2015-04-01

    Vascular inflammation is a major contributor to the severity of acute kidney injury. In the context of vasospasm-independent reperfusion injury we studied the potential anti-inflammatory role of the Gα-related RGS protein, RGS4. Transgenic RGS4 mice were resistant to 25 min injury, although post-ischemic renal arteriolar diameter was equal to the wild type early after injury. A 10 min unilateral injury was performed to study reperfusion without vasospasm. Eighteen hours after injury, blood flow was decreased in the inner cortex of wild-type mice with preservation of tubular architecture. Angiotensin II levels in the kidneys of wild-type and transgenic mice were elevated in a sub-vasoconstrictive range 12 and 18 h after injury. Angiotensin II stimulated pre-glomerular vascular smooth muscle cells (VSMCs) to secrete the macrophage chemoattractant RANTES, a process decreased by angiotensin II R2 (AT2) inhibition. However, RANTES increased when RGS4 expression was suppressed implicating Gα protein activation in an AT2-RGS4-dependent pathway. RGS4 function, specific to VSMC, was tested in a conditional VSMC-specific RGS4 knockout showing high macrophage density by T2 MRI compared with transgenic and non-transgenic mice after the 10 min injury. Arteriolar diameter of this knockout was unchanged at successive time points after injury. Thus, RGS4 expression, specific to renal VSMC, inhibits angiotensin II-mediated cytokine signaling and macrophage recruitment during reperfusion, distinct from vasomotor regulation.

  18. Vascular endothelial growth factor: an attractive target in the treatment of hypoxic/ischemic brain injury.

    PubMed

    Guo, Hui; Zhou, Hui; Lu, Jie; Qu, Yi; Yu, Dan; Tong, Yu

    2016-01-01

    Cerebral hypoxia or ischemia results in cell death and cerebral edema, as well as other cellular reactions such as angiogenesis and the reestablishment of functional microvasculature to promote recovery from brain injury. Vascular endothelial growth factor is expressed in the central nervous system after hypoxic/ischemic brain injury, and is involved in the process of brain repair via the regulation of angiogenesis, neurogenesis, neurite outgrowth, and cerebral edema, which all require vascular endothelial growth factor signaling. In this review, we focus on the role of the vascular endothelial growth factor signaling pathway in the response to hypoxic/ischemic brain injury, and discuss potential therapeutic interventions. PMID:26981109

  19. Vascular endothelial growth factor: an attractive target in the treatment of hypoxic/ischemic brain injury

    PubMed Central

    Guo, Hui; Zhou, Hui; Lu, Jie; Qu, Yi; Yu, Dan; Tong, Yu

    2016-01-01

    Cerebral hypoxia or ischemia results in cell death and cerebral edema, as well as other cellular reactions such as angiogenesis and the reestablishment of functional microvasculature to promote recovery from brain injury. Vascular endothelial growth factor is expressed in the central nervous system after hypoxic/ischemic brain injury, and is involved in the process of brain repair via the regulation of angiogenesis, neurogenesis, neurite outgrowth, and cerebral edema, which all require vascular endothelial growth factor signaling. In this review, we focus on the role of the vascular endothelial growth factor signaling pathway in the response to hypoxic/ischemic brain injury, and discuss potential therapeutic interventions. PMID:26981109

  20. CXCL16 regulates renal injury and fibrosis in experimental renal artery stenosis.

    PubMed

    Ma, Zhiheng; Jin, Xiaogao; He, Liqun; Wang, Yanlin

    2016-09-01

    Recent studies have shown that inflammation plays a critical role in the initiation and progression of hypertensive kidney disease, including renal artery stenosis. However, the signaling mechanisms underlying the induction of inflammation are poorly understood. We found that CXCL16 was induced in the kidney in a murine model of renal artery stenosis. To determine whether CXCL16 is involved in renal injury and fibrosis, wild-type and CXCL16 knockout mice were subjected to renal artery stenosis induced by placing a cuff on the left renal artery. Wild-type and CXCL16 knockout mice had comparable blood pressure at baseline. Renal artery stenosis caused an increase in blood pressure that was similar between wild-type and CXCL16 knockout mice. CXCL16 knockout mice were protected from RAS-induced renal injury and fibrosis. CXCL16 deficiency suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the stenotic kidneys, which was associated with less expression of extracellular matrix proteins. Furthermore, CXCL16 deficiency inhibited infiltration of F4/80(+) macrophages and CD3(+) T cells in the stenotic kidneys compared with those of wild-type mice. Taken together, our results indicate that CXCL16 plays a pivotal role in the pathogenesis of renal artery stenosis-induced renal injury and fibrosis through regulation of bone marrow-derived fibroblast accumulation and macrophage and T-cell infiltration.

  1. Effect of the technique for assisting renal blood circulation on ischemic kidney in acute cardiorenal syndrome.

    PubMed

    Hanada, Shigeru; Takewa, Yoshiaki; Mizuno, Toshihide; Tsukiya, Tomonori; Taenaka, Yoshiyuki; Tatsumi, Eisuke

    2012-06-01

    The technique for assisting renal blood circulation may be a useful therapeutic method in acute cardiorenal syndrome (ACRS), because renal ischemic dysfunction due to the reduced renal blood circulation is a powerful negative prognostic factor in ACRS. We constructed a circuit assisting renal arterial pressure and flow, and performed renal-selective blood perfusion (RSP) to the left kidney in a goat model of ACRS induced by right ventricular rapid pacing (n = 8), with the right kidney left intact as an internal control. Upon induction of ACRS, renal arterial flow (RAF), creatinine clearance (CCr), and renal oxygen consumption (RVO(2)) of the left kidney decreased to 49, 48, and 63% of the respective baseline values accompanied by a significant increase in renal vascular resistance (RVR), and similar results were observed in the right kidney. Then, RSP improved RVR and increased left RAF, CCr, and RVO(2) up to 91, 86, and 93% of baseline values, respectively, without a significant change in systemic hemodynamics. The RSP-treated kidney showed significantly higher CCr and urinary excretion of water and sodium compared to the contralateral kidney. Additional infusion of prostaglandin E(1) with RSP decreased RVR further and enabled the left RAF to increase up to 129% of the baseline value, without a significant change in systemic hemodynamic parameters. The CCr and RVO(2) did not change significantly, and urinary excretion of water and sodium showed a tendency to increase. These findings suggest that the technique for assisting renal blood circulation for both kidneys may offer a new treatment strategy for patients with ACRS.

  2. Dephosphorylation of Ezrin as an Early Event in Renal Microvillar Breakdown and Anoxic Injury

    NASA Astrophysics Data System (ADS)

    Chen, Jing; Cohn, Jonathan A.; Mandel, Lazaro J.

    1995-08-01

    Disruption of the renal proximal tubule (PT) brush border is a prominent early event during ischemic injury to the kidney. The molecular basis for this event is unknown. Within the brush border, ezrin may normally link the cytoskeleton to the cell plasma membrane. Anoxia causes ezrin to dissociate from the cytoskeleton and also causes many cell proteins to become dephosphorylated in renal PTs. This study examines the hypothesis that ezrin dephosphorylation accompanies and may mediate the anoxic disruption of the rabbit renal PT. During normoxia, 73 ±. 3% of the cytoskeleton-associated (Triton-insoluble) ezrin was phosphorylated, but 88 ± 6% of dissociated (Triton-soluble) ezrin was dephosphorylated. Phosphorylation was on serine/threonine residues, since ezrin was not detectable by an antibody against phosphotyrosine. After 60 min of anoxia, phosphorylation of total intracellular ezrin significantly decreased from 72 ± 2% to 21 ± 9%, and ezrin association with the cytoskeleton decreased from 91 ± 2% to 58 ± 2%. Calyculin A (1 μM), the serine/threonine phosphatase inhibitor, inhibited the dephosphorylation of ezrin during anoxia by 57% and also blocked the dissociation of ezrin from the cytoskeleton by 53%. Our results demonstrate that (i) the association of ezrin with the renal microvillar cytoskeleton is correlated with phosphorylation of ezrin serine/threonine residues and (ii) anoxia may cause disruption of the renal brush border by dephosphorylating ezrin and thereby dissociating the brush border membrane from the cytoskeleton.

  3. Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury

    PubMed Central

    Chang, Yoon-Kyung; Choi, Hyunsu; Jeong, Jin Young; Na, Ki-Ryang; Lee, Kang Wook

    2016-01-01

    Dapagliflozin, a new type of drug used to treat diabetes mellitus (DM), is a sodium/glucose cotransporter 2 (SGLT2) inhibitor. Although some studies showed that SGLT2 inhibition attenuated reactive oxygen generation in diabetic kidney the role of SGLT2 inhibition is unknown. We evaluated whether SLT2 inhibition has renoprotective effects in ischemia-reperfusion (IR) models. We evaluated whether dapagliflozin reduces renal damage in IR mice model. In addition, hypoxic HK2 cells were treated with or without SGLT2 inhibitor to investigate cell survival, the apoptosis signal pathway, and the induction of hypoxia-inducible factor 1 (HIF1) and associated proteins. Dapagliflozin improved renal function. Dapagliflozin reduced renal expression of Bax, renal tubule injury and TUNEL-positive cells and increased renal expression of HIF1 in IR-injured mice. HIF1 inhibition by albendazole negated the renoprotective effects of dapagliflozin treatment in IR-injured mice. In vitro, dapagliflozin increased the expression of HIF1, AMP-activated protein kinase (AMPK), and ERK and increased cell survival of hypoxic HK2 cells in a dose-dependent manner. In conclusion, dapagliflozin attenuates renal IR injury. HIF1 induction by dapagliflozin may play a role in renoprotection against renal IR injury. PMID:27391020

  4. Galacto‐oligosaccharides attenuate renal injury with microbiota modification

    PubMed Central

    Furuse, Satoshi U.; Ohse, Takamoto; Jo‐Watanabe, Airi; Shigehisa, Akira; Kawakami, Koji; Matsuki, Takahiro; Chonan, Osamu; Nangaku, Masaomi

    2014-01-01

    Abstracts Tubulointerstitial injury is central to the progression of end‐stage renal disease. Recent studies have revealed that one of the most investigated uremic toxins, indoxyl sulfate (IS), caused tubulointerstitial injury through oxidative stress and endoplasmic reticulum (ER) stress. Because indole, the precursor of IS, is synthesized from dietary tryptophan by the gut microbiota, we hypothesized that the intervention targeting the gut microbiota in kidney disease with galacto‐oligosaccharides (GOS) would attenuate renal injury. After 2 weeks of GOS administration for 5/6 nephrectomized (Nx) or sham‐operated (Sham) rats, cecal indole and serum IS were measured, renal injury was evaluated, and the effects of GOS on the gut microbiota were examined using pyrosequencing methods. Cecal indole and serum IS were significantly decreased and renal injury was improved with decreased infiltrating macrophages in GOS‐treated Nx rats. The expression levels of ER stress markers and apoptosis were significantly increased in the Nx rats and decreased with GOS. The microbiota analysis indicated that GOS significantly increased three bacterial families and decreased five families in the Nx rats. In addition, the analysis also revealed that the bacterial family Clostridiaceae was significantly increased in the Nx rats compared with the Sham rats and decreased with GOS. Taken altogether, our data show that GOS decreased cecal indole and serum IS, attenuated renal injury, and modified the gut microbiota in the Nx rats, and that the gut microbiota were altered in kidney disease. GOS could be a novel therapeutic agent to protect against renal injury. PMID:24994892

  5. Renal injury, nephrolithiasis and Nigella sativa: A mini review

    PubMed Central

    Hayatdavoudi, Parichehr; Khajavi Rad, Abolfazl; Rajaei, Ziba; Hadjzadeh, Mousa AL-Reza

    2016-01-01

    Objective: The incidence and prevalence of kidney stone is increasing worldwide. After the first recurrence the risk of subsequent relapses is higher and the time period between relapses is shortened. Urinary stones can be severely painful and make a huge economic burden. The stone disease may increase the vulnerability of patients to other diseases such as renal failure. Medicinal herbs are rich sources of antioxidants which are increasingly consumed globally for their safety, efficacy and low price. Nigella sativa is a spice plant that is widely used for prevention and treatment of many ailments in Muslim countries and worldwide. This review aims at investigation of the effects of Nigella sativa on renal injury and stone formation. Materials and Methods: The scientific resources including PubMed, Scopus, and Google scholar were searched using key words such as: nephrolithiasis, urolithiasis, kidney/renal stone, renal injury, renal failure, urinary retention and black seed, black cumin, Nigella sativa and thymoquinone. Results: N. sativa and its main component, thymoquinone showed positive effects in prevention or curing kidney stones and renal failure through various mechanism such as antioxidative, anti-inflammatory, anti-eicosanoid and immunomodulatory effects. The putative candidate in many cases has been claimed to be thymoquinone but it seems that at least in part, particularly in kidney stones, the herbal melanin plays a role which requires further investigation to prove. Conclusion: N. sativa and its components are beneficial in prevention and curing of renal diseases including nephrolithiasis and renal damages. PMID:27247917

  6. Acute Stress Decreases but Chronic Stress Increases Myocardial Sensitivity to Ischemic Injury in Rodents

    PubMed Central

    Eisenmann, Eric D.; Rorabaugh, Boyd R.; Zoladz, Phillip R.

    2016-01-01

    Cardiovascular disease (CVD) is the largest cause of mortality worldwide, and stress is a significant contributor to the development of CVD. The relationship between acute and chronic stress and CVD is well evidenced. Acute stress can lead to arrhythmias and ischemic injury. However, recent evidence in rodent models suggests that acute stress can decrease sensitivity to myocardial ischemia–reperfusion injury (IRI). Conversely, chronic stress is arrhythmogenic and increases sensitivity to myocardial IRI. Few studies have examined the impact of validated animal models of stress-related psychological disorders on the ischemic heart. This review examines the work that has been completed using rat models to study the effects of stress on myocardial sensitivity to ischemic injury. Utilization of animal models of stress-related psychological disorders is critical in the prevention and treatment of cardiovascular disorders in patients experiencing stress-related psychiatric conditions. PMID:27199778

  7. Non-Coding RNAs as Potential Neuroprotectants against Ischemic Brain Injury.

    PubMed

    Kaur, Prameet; Liu, Fujia; Tan, Jun Rong; Lim, Kai Ying; Sepramaniam, Sugunavathi; Karolina, Dwi Setyowati; Armugam, Arunmozhiarasi; Jeyaseelan, Kandiah

    2013-03-20

    Over the past decade, scientific discoveries have highlighted new roles for a unique class of non-coding RNAs. Transcribed from the genome, these non-coding RNAs have been implicated in determining the biological complexity seen in mammals by acting as transcriptional and translational regulators. Non-coding RNAs, which can be sub-classified into long non-coding RNAs, microRNAs, PIWI-interacting RNAs and several others, are widely expressed in the nervous system with roles in neurogenesis, development and maintenance of the neuronal phenotype. Perturbations of these non-coding transcripts have been observed in ischemic preconditioning as well as ischemic brain injury with characterization of the mechanisms by which they confer toxicity. Their dysregulation may also confer pathogenic conditions in neurovascular diseases. A better understanding of their expression patterns and functions has uncovered the potential use of these riboregulators as neuroprotectants to antagonize the detrimental molecular events taking place upon ischemic-reperfusion injury. In this review, we discuss the various roles of non-coding RNAs in brain development and their mechanisms of gene regulation in relation to ischemic brain injury. We will also address the future directions and open questions for identifying promising non-coding RNAs that could eventually serve as potential neuroprotectants against ischemic brain injury.

  8. Therapeutic Hypothermia as a Neuroprotective Strategy in Neonatal Hypoxic-Ischemic Brain Injury and Traumatic Brain Injury

    PubMed Central

    Ma, H.; Sinha, B.; Pandya, R.S.; Lin, N.; Popp, A.J.; Li, J.; Yao, J.; Wang, X.

    2014-01-01

    Evidence shows that artificially lowering body and brain temperature can significantly reduce the deleterious effects of brain injury in both newborns and adults. Although the benefits of therapeutic hypothermia have long been known and applied clinically, the underlying molecular mechanisms have yet to be elucidated. Hypoxic-ischemic brain injury and traumatic brain injury both trigger a series of biochemical and molecular events that cause additional brain insult. Induction of therapeutic hypothermia seems to ameliorate the molecular cascade that culminates in neuronal damage. Hypothermia attenuates the toxicity produced by the initial injury that would normally produce reactive oxygen species, neurotransmitters, inflammatory mediators, and apoptosis. Experiments have been performed on various depths and levels of hypothermia to explore neuroprotection. This review summarizes what is currently known about the beneficial effects of therapeutic hypothermia in experimental models of neonatal hypoxic-ischemic brain injury and traumatic brain injury, and explores the molecular mechanisms that could become the targets of novel therapies. In addition, this review summarizes the clinical implications of therapeutic hypothermia in newborn hypoxic-ischemic encephalopathy and adult traumatic brain injury. PMID:22834830

  9. Severe rhabdomyolysis without renal injury associated with lightning strike.

    PubMed

    Navarrete, Norberto; Aldana, Norberto Navarrete

    2013-01-01

    Lightning strikes cause injuries in multiple systems and organs. Early recognition of lightning injury syndromes and anticipation of harmful complications can improve outcomes for these patients. The author has presented a case report of a patient who was struck by lightning and exhibited extensive soft tissue injury with myoglobinuria. He was treated with delayed fasciotomy and had evidence of severe muscle injury with markedly elevated creatine kinase levels that gradually improved with aggressive fluid infusion. The patient did not require alkalinization of urine, mannitol, or dialysis, and his renal function remained normal.

  10. ‘Biologic memory’ in response to acute kidney injury: cytoresistance, toll-like receptor hyper-responsiveness and the onset of progressive renal disease

    PubMed Central

    Zager, Richard A.

    2013-01-01

    Following the induction of ischemic or toxin-mediated acute kidney injury (AKI), cellular adaptations occur that ‘re-program’ how the kidney responds to future superimposed insults. This re-programming is not simply a short-lived phenomenon; rather it can persist for many weeks, implying that a state of ‘biologic memory’ has emerged. These changes can be both adaptive and maladaptive in nature and they can co-exist in time. A beneficial adaptation is the emergence of acquired cytoresistance, whereby a number of physiologic responses develop that serve to protect the kidney against further ischemic or nephrotoxic attack. Conversely, some changes are maladaptive, such as a predisposition to Gram-negative or Gram-positive bacteremia due to a renal tubular up-regulation of toll-like receptor responses. This latter change culminates in exaggerated cytokine production, and with efflux into the systemic circulation, extra-renal tissue injury can result (so-called ‘organ cross talk’). Another maladaptive response is a persistent up-regulation of pro-inflammatory, pro-fibrotic and vasoconstrictive genes, culminating in progressive renal injury and ultimately end-stage renal failure. The mechanisms by which this biologic re-programming, or biologic memory, is imparted remain subjects for considerable debate. However, injury-induced, and stable, epigenetic remodeling at pro-inflammatory/pro-fibrotic genes seems likely to be involved. The goal of this editorial is to highlight that the so-called ‘maintenance phase’ of acute renal failure is not a static one, somewhere between injury induction and the onset of repair. Rather, this period is one in which the induction of ‘biologic memory’ can ultimately impact renal functional recovery, extra-renal injury and the possible transition of AKI into chronic, progressive renal disease. PMID:23761460

  11. Lumican overexpression exacerbates lipopolysaccharide-induced renal injury in mice.

    PubMed

    Lu, Xiao-Mei; Ma, Ling; Jin, Yu-Nan; Yu, Yan-Qiu

    2015-09-01

    The present study aimed to investigate the role of lumican in mice with endotoxin-induced acute renal failure (ARF). Lumican transgenic mice and wild‑type mice were injected with lipopolysaccharide (LPS; 10 mg/kg) to establish a model of ARF. The mice were sacrificed at 24 h and the blood and renal tissue samples were collected. The value of serum creatinine (SCr) and blood urea nitrogen (BUN) were measured to determine renal function. An ELISA was used to determined the concentrations of renal cytokines, including tumor necrosis factor (TNF)α, interleukin (IL)‑6, IL‑4 and IL‑10. The protein expression levels of Toll-like receptor (TLR4) and nuclear factor (NF)κB in renal tissues were assessed using western blot analysis. Terminal deoxynucleotidyl transferase‑mediated dUTP nick end labeling was performed to monitor apoptosis of renal tissue. Light microscopy and electron microscopy were used to observe structural changes in the renal tissues. Following the administration of LPS, the SCr and BUN values of mice in the lumican transgenic group were higher compared with those in the control group. The expression levels of renal TLR4, NFκB, TNFα, IL‑6, IL‑4 and IL‑10 were upregulated in the lumican transgenic mice compared with those in the wild‑type control group. Apoptosis was detected predominantly on the renal tubule. There was a significant difference in the optical density of apoptotic bodies between the control mice and the lumican transgenic mice. Light and electron microscopy demonstrated more severe renal tissue injury in the lumican transgenic mice compared with that in the control mice. In conclusion, LPS may cause excessive apoptosis in the renal tubular cells via the TLR4 signal transduction pathway, a decrease in the number of renal tubular cells and ARF. Lumican may be important in mice with LPS-induced ARF.

  12. Optimal therapeutic dose and time window of picroside II in cerebral ischemic injury

    PubMed Central

    Liu, Guangyi; Zhao, Li; Wang, Tingting; Zhang, Meizeng; Pei, Haitao

    2014-01-01

    A preliminary study from our research group showed that picroside II inhibited neuronal apoptosis in ischemic penumbra, reduced ischemic volume, and improved neurobehavioral function in rats with cerebral ischemia. The aim of the present study was to validate the neuroprotective effects of picroside II and optimize its therapeutic time window and dose in a rat model of cerebral ischemia. We found that picroside II inhibited cell apoptosis and reduced the expression of neuron-specific enolase, a marker of neuronal damage, in rats after cerebral ischemic injury. The optimal treatment time after ischemic injury and dose were determined, respectively, as follows: (1) 2.0 hours and 10 mg/kg according to the results of toluidine blue staining; (2) 1.5 hours and 10 mg/kg according to early apoptotic ratio by flow cytometry; (3) 2.0 hours and 10 mg/kg according to immunohistochemical and western blot analysis; and (4) 1.5 hours and 10 mg/kg according to reverse transcription polymerase chain reaction. The present findings suggest that an intraperitoneal injection of 10 mg/kg picroside II 1.5–2.0 hours after cerebral ischemic injury in rats is the optimal dose and time for therapeutic benefit. PMID:25317155

  13. The Synthetic Tie2 Agonist Peptide Vasculotide Protects Renal Vascular Barrier Function In Experimental Acute Kidney Injury

    PubMed Central

    Rübig, Eva; Stypmann, Jörg; Van Slyke, Paul; Dumont, Daniel J; Spieker, Tilmann; Buscher, Konrad; Reuter, Stefan; Goerge, Tobias; Pavenstädt, Hermann; Kümpers, Philipp

    2016-01-01

    Microvascular barrier dysfunction plays a major role in the pathophysiology of acute kidney injury (AKI). Angiopoietin-1, the natural agonist ligand for the endothelial-specific Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor. Here we evaluate the efficacy of a polyethylene glycol-clustered Tie2 agonist peptide, vasculotide (VT), to protect against endothelial-cell activation with subsequent microvascular dysfunction in a murine model of ischemic AKI. Renal ischemia reperfusion injury (IRI) was induced by clamping of the renal arteries for 35 minutes. Mice were treated with VT or PEGylated cysteine before IRI. Sham-operated animals served as time-matched controls. Treatment with VT significantly reduced transcapillary albumin flux and renal tissue edema after IRI. The protective effects of VT were associated with activation of Tie2 and stabilization of its downstream effector, VE-cadherin in renal vasculature. VT abolished the decline in renal tissue blood flow, attenuated the increase of serum creatinine and blood urea nitrogen after IRI, improved recovery of renal function and markedly reduced mortality compared to PEG [HR 0.14 (95% CI 0.05–0.78) P < 0.05]. VT is inexpensive to produce, chemically stable and unrelated to any Tie2 ligands. Thus, VT may represent a novel therapy to prevent AKI in patients. PMID:26911791

  14. Advance in spinal cord ischemia reperfusion injury: Blood-spinal cord barrier and remote ischemic preconditioning.

    PubMed

    Yu, Qijing; Huang, Jinxiu; Hu, Ji; Zhu, Hongfei

    2016-06-01

    The blood-spinal cord barrier (BSCB) is the physiological and metabolic substance diffusion barrier between blood circulation and spinal cord tissues. This barrier plays a vital role in maintaining the microenvironment stability of the spinal cord. When the spinal cord is subjected to ischemia/reperfusion (I/R) injury, the structure and function of the BSCB is disrupted, further destroying the spinal cord homeostasis and ultimately leading to neurological deficit. Remote ischemic preconditioning (RIPC) is an approach in which interspersed cycles of preconditioning ischemia is followed by reperfusion to tissues/organs to protect the distant target tissues/organs against subsequent lethal ischemic injuries. RIPC is an innovation of the treatment strategies that protect the organ from I/R injury. In this study, we review the morphological structure and function of the BSCB, the injury mechanism of BSCB resulting from spinal cord I/R, and the effect of RIPC on it.

  15. Electroacupuncture increased cerebral blood flow and reduced ischemic brain injury: dependence on stimulation intensity and frequency

    PubMed Central

    Zhou, Fei; Guo, Jingchun; Cheng, Jieshi; Wu, Gencheng

    2011-01-01

    Stroke causes ischemic brain injury and is a leading cause of neurological disability and death. There is, however, no promising therapy to protect the brain from ischemic stress to date. Here we show an exciting finding that optimal electroacupuncture (EA) effectively protects the brain from ischemic injury. The experiments were performed on rats subjected to middle cerebral artery occlusion (MCAO) with continuous monitoring of cerebral blood flow. EA was delivered to acupoints of “Shuigou” (Du 26) and “Baihui” (Du 20) with different intensities and frequencies to optimize the stimulation parameters. The results showed that 1) EA at 1.0–1.2 mA and 5–20 Hz remarkably reduced ischemic infarction, neurological deficit, and death rate; 2) the EA treatment increased the blood flow by >100%, which appeared immediately after the initiation of EA and disappeared after the cessation of EA; 3) the EA treatment promoted the recovery of the blood flow after MCAO; 4) “nonoptimal” parameters of EA (e.g., <0.6 mA or >40 Hz) could not improve the blood flow or reduce ischemic injury; and 5) the same EA treatment with optimal parameters could not increase the blood flow in naive brains. These novel observations suggest that appropriate EA treatment protects the brain from cerebral ischemia by increasing blood flow to the ischemic brain region via a rapid regulation. Our findings have far-reaching impacts on the prevention and treatment of ischemic encephalopathy, and the optimized EA parameters may potentially be a useful clue for the clinical application of EA. PMID:21836043

  16. Radon inhalation protects against transient global cerebral ischemic injury in gerbils.

    PubMed

    Kataoka, Takahiro; Etani, Reo; Takata, Yuji; Nishiyama, Yuichi; Kawabe, Atsushi; Kumashiro, Masayuki; Taguchi, Takehito; Yamaoka, Kiyonori

    2014-10-01

    Although brain disorders are not the main indication for radon therapy, our previous study suggested that radon inhalation therapy might mitigate brain disorders. In this study, we assessed whether radon inhalation protects against transient global cerebral ischemic injury in gerbils. Gerbils were treated with inhaled radon at a concentration of 2,000 Bq/m(3) for 24 h. After radon inhalation, transient global cerebral ischemia was induced by bilateral occlusion of the common carotid artery. Results showed that transient global cerebral ischemia induced neuronal damage in hippocampal CA1, and the number of damaged neurons was significantly increased compared with control. However, radon treatment inhibited ischemic damage. Superoxide dismutase (SOD) activity in the radon-treated gerbil brain was significantly higher than that in sham-operated gerbils. These findings suggested that radon inhalation activates antioxidative function, especially SOD, thereby inhibiting transient global cerebral ischemic injury in gerbils.

  17. Detection of renal brush border membrane enzymes for evaluation of renal injury in neonatal scleredema

    PubMed Central

    Ren, Qing; Zhang, Yongjun; Yang, Jinying; Wei, Lixia; Zhao, Lili; Yang, Qiaozhi

    2015-01-01

    Objective: To evaluate renal brush border membrane enzymes in urine as an indicator for renal injury in neonatal scleredema (NS). Methods: Sixty nine NS patients in our hospital were enrolled and divided into mild group and moderate/severe group. Patients were further randomly divided into therapy and control subgroups for 7 days ligustrazine administration. Urine samples were collected to detect renal brush border membrane enzymes (RBBME) by ELISA and β2-microglobulin (β2-MG) by radioimmunoassay (RIA). The results were compared with those of 30 normal neonates. Data were statistically analyzed using SPSS13.0 software. Results: Both RBBME and β2-MG were found to be higher in urine in NS patients than normal controls (P < 0.01). Level of RBBME increased with the severity of NS (P <0.05), while urinary β2-MG did not (P >0.05). After being treated with ligustrazine, a medicine for renal function recovery, both RBBME and β2-MG were similarly significantly decreased comparing to untreated groups (P < 0.05). 79.7% of NS patients showed abnormal RBBME while only 52.2% had an abnormal urinary β2-MG (χ2=11.65,P < 0.01). Conclusion: RBBME was more sensitive than β2-MG in reflecting the renal injury in NS. Examination of RBBME effectively reflected the recovery of renal injury after treatment with ligustrazine. PMID:25878616

  18. Radiofrequency Renal Denervation Protects the Ischemic Heart via Inhibition of GRK2 and Increased Nitric Oxide Signaling

    PubMed Central

    Polhemus, David J.; Gao, Juan; Scarborough, Amy L.; Trivedi, Rishi; McDonough, Kathleen H.; Goodchild, Traci T.; Smart, Frank

    2016-01-01

    Rationale: Catheter-based renal denervation (RDN) is currently under development for the treatment of resistant hypertension and is thought to reduce blood pressure via interruption of sympathetic pathways that modulate cardiovascular function. The sympathetic nervous system also plays a critical role in the pathogenesis of acute myocardial infarction and heart failure. Objective: We examined whether treatment with radiofrequency (RF)-RDN would protect the heart against subsequent myocardial ischemia/reperfusion injury via direct effects on the myocardium. Methods and Results: Spontaneously hypertensive rats received either bilateral RF-RDN or sham-RDN. At 4 weeks after RF-RDN (n=14) or sham-RDN (n=14) treatment, spontaneously hypertensive rats were subjected to 30 minutes of transient coronary artery occlusion and 24 hours –7 days reperfusion. Four weeks after RF-RDN, myocardial oxidative stress was markedly attenuated, and transcription and translation of antioxidants, superoxide dismutase 1 and glutathione peroxidase-1, were significantly upregulated compared with sham-RDN spontaneously hypertensive rats. RF-RDN also inhibited myocardial G protein–coupled receptor kinase 2 pathological signaling and enhanced myocardial endothelial nitric oxide synthase function and nitric oxide signaling. RF-RDN therapy resulted in a significant reduction in myocardial infarct size per area at risk compared with sham-RDN (26.8 versus 43.9%; P<0.01) at 24 hours postreperfusion and significantly improved left ventricular function at 7 days after myocardial ischemia/reperfusion. Conclusions: RF-RDN reduced oxidative stress, inhibited G protein–coupled receptor kinase 2 signaling, increased nitric oxide bioavailability, and ameliorated myocardial reperfusion injury in the setting of severe hypertension. These findings provide new insights into the remote cardioprotective effects of RF-RDN acting directly on cardiac myocytes to attenuate cell death and protect against ischemic

  19. Arterial Embolization for the Treatment of Renal Masses and Traumatic Renal Injuries.

    PubMed

    Ramaswamy, Raja S; Darcy, Michael D

    2016-09-01

    Renal artery embolization (RAE) for a variety of indications has been performed for several decades. RAE techniques have been refined over time for clinical efficacy and a more favorable safety profile. Owing to improved catheters, embolic agents for precise delivery, and clinical experience, RAE is increasingly used as an adjunct to, or as the preferred alternative to surgical interventions. The indications for RAE are expanding for many urologic and medical conditions. In this article, we focus on the role and technical aspects of RAE in the treatment of renal masses and traumatic renal injuries. PMID:27641454

  20. Experiences of Conflict Zone-Related Ballistic Renal Injury.

    PubMed

    Taş, Huseyin; Şenocak, Rahman; Kaymak, Şahin; Lapsekili, Emin

    2016-08-01

    To analyze our approaches and experiences in patients with renal injuries accompanying penetrating abdominal injuries admitted to the hospital due to high kinetic energy weapons. Patients including renal injuries associated with penetrating abdominal injuries due to gunshot wounds and fragments of shell treated at our institution between February 2002 and May 2013 were retrospectively analyzed. Total 21 patients were included in this study, 20 of whom (86.2 %) were male and 1 (13.8 %) female. Renal injury was scaled in 2 patients as grade 1, 4 patients as grade 2, 4 patients as grade 3, 8 patients as grade 4, and 3 patients as grade 5. While conservative treatment was applied to patients with grade 1 and 2 injuries, 2 patients with grade 3 injury underwent renal repair and the other 13 patients underwent nephrectomy. The amount of blood transfused in all cases was determined to be mean 8.28 (6-16) units for red blood cells (ES) and 9 (6-17) units for fresh frozen plasma. When patients were assessed according to the Penetrating Abdominal Trauma Index (PATI) scores, the median score and average PATI score were 35 and 37.6 (10-70), respectively. A physical examination along with a quick assessment of vital signs should be made, and unnecessary and time-consuming investigations such as abdominal tomography and angiographic intervention should be avoided. Conservative and organ preservation should be considered absolutely for appropriately selected patients, namely in stable patients in whom kinetic energy transfer is less and who have bullet path away from midline. However, the majority of these patients are considered to be hemodynamically unstable condition, possible complications of the procedure to be applied, and selection of patients should be carefully evaluated. PMID:27574348

  1. Cardiovascular risk factors cause premature rarefaction of the collateral circulation and greater ischemic tissue injury

    PubMed Central

    Moore, Scott M.; Zhang, Hua; Maeda, Nobuyo; Doerschuk, Claire M.; Faber, James E.

    2015-01-01

    Rationale Collaterals lessen tissue injury in occlusive disease. However, aging causes progressive decline in their number and smaller diameters in those that remain (collateral rarefaction), beginning at 16 months-age in mice (ie, middle age), and worse ischemic injury—effects that are accelerated in even 3 months-old eNOS−/− mice. These findings have found indirect support in recent human studies. Objective We sought to determine if other cardiovascular risk factors (CVRFs) associated with endothelial dysfunction cause collateral rarefaction, investigate possible mechanisms, and test strategies for prevention. Methods and Results Mice with nine different models of CVRFs of 4–12 months-age were assessed for number and diameter of native collaterals in skeletal muscle and brain, and for collateral-dependent perfusion and ischemic injury after arterial occlusion. Hypertension caused collateral rarefaction whose severity increased with duration and level of hypertension, accompanied by greater hindlimb ischemia and cerebral infarct volume. Chronic treatment of wildtype mice with L-NG-nitro-arginine methylester caused similar rarefaction and worse ischemic injury that were not prevented by lowering arterial pressure with hydralazine. Metabolic syndrome, hypercholesterolemia, diabetes mellitus, and obesity also caused collateral rarefaction. Neither chronic statin treatment nor exercise training lessened hypertension-induced rarefaction. Conclusion Chronic CVRF presence caused collateral rarefaction and worse ischemic injury, even at relatively young ages. Rarefaction was associated with increased proliferation rate of collateral endothelial cells, effects that may promote accelerated endothelial cell senescence. PMID:25862671

  2. ADVANCES IN THE CELL-BASED TREATMENT OF NEONATAL HYPOXIC-ISCHEMIC BRAIN INJURY

    PubMed Central

    Pabon, Mibel M.; Borlongan, Cesar V.

    2012-01-01

    Stem cell therapy for adult stroke has reached limited clinical trials. Here, we provide translational research guidance on stem cell therapy for neonatal hypoxic-ischemic brain injury requiring a careful consideration of clinically relevant animal models, feasible stem cell sources, and validated safety and efficacy endpoint assays, as well as a general understanding of modes of action of this cellular therapy. To this end, we refer to existing translational guidelines, in particular the recommendations outlined in the consortium of academicians, industry partners and regulators called Stem cell Therapeutics as an Emerging Paradigm for Stroke or STEPS. Although the STEPS guidelines are directed at enhancing the successful outcome of cell therapy in adult stroke, we highlight overlapping pathologies between adult stroke and neonatal hypoxic-ischemic brain injury. We are, however, cognizant that the neonatal hypoxic-ischemic brain injury displays disease symptoms distinct from adult stroke in need of an innovative translational approach that facilitates the entry of cell therapy in the clinic. Finally, insights into combination therapy are provided with the vision that stem cell therapy may benefit from available treatments, such as hypothermia, already being tested in children diagnosed with hypoxic-ischemic brain injury. PMID:23565051

  3. Automated Detection of Brain Abnormalities in Neonatal Hypoxia Ischemic Injury from MR Images

    PubMed Central

    Ghosh, Nirmalya; Sun, Yu; Bhanu, Bir; Ashwal, Stephen; Obenaus, Andre

    2014-01-01

    We compared the efficacy of three automated brain injury detection methods, namely symmetry-integrated region growing (SIRG), hierarchical region splitting (HRS) and modified watershed segmentation (MWS) in human and animal magnetic resonance imaging (MRI) datasets for the detection of hypoxic ischemic injuries (HII). Diffusion weighted imaging (DWI, 1.5T) data from neonatal arterial ischemic stroke (AIS) patients, as well as T2-weighted imaging (T2WI, 11.7T, 4.7T) at seven different time-points (1, 4, 7, 10, 17, 24 and 31 days post HII) in rat-pup model of hypoxic ischemic injury were used to check the temporal efficacy of our computational approaches. Sensitivity, specificity, similarity were used as performance metrics based on manual (‘gold standard’) injury detection to quantify comparisons. When compared to the manual gold standard, automated injury location results from SIRG performed the best in 62% of the data, while 29% for HRS and 9% for MWS. Injury severity detection revealed that SIRG performed the best in 67% cases while HRS for 33% data. Prior information is required by HRS and MWS, but not by SIRG. However, SIRG is sensitive to parameter-tuning, while HRS and MWS are not. Among these methods, SIRG performs the best in detecting lesion volumes; HRS is the most robust, while MWS lags behind in both respects. PMID:25000294

  4. Unilateral Renal Ischemia-Reperfusion as a Robust Model for Acute to Chronic Kidney Injury in Mice

    PubMed Central

    Le Clef, Nathalie; Verhulst, Anja; D’Haese, Patrick C.; Vervaet, Benjamin A.

    2016-01-01

    Acute kidney injury (AKI) is an underestimated, yet important risk factor for development of chronic kidney disease (CKD). Even after initial total recovery of renal function, some patients develop progressive and persistent deterioration of renal function and these patients are more likely to progress to end-stage renal disease (ESRD). Animal models are indispensable for unravelling the mechanisms underlying this progression towards CKD and ESRD and for the development of new therapeutic strategies in its prevention or treatment. Ischemia (i.e. hypoperfusion after surgery, bleeding, dehydration, shock, or sepsis) is a major aetiology in human AKI, yet unilateral ischemia-reperfusion is a rarely used animal model for research on CKD and fibrosis. Here, we demonstrate in C57Bl/6J mice, by both histology and gene expression, that unilateral ischemia-reperfusion without contralateral nephrectomy is a very robust model to study the progression from acute renal injury to long-term tubulo-interstitial fibrosis, i.e. the histopathological hallmark of CKD. Furthermore, we report that the extent of renal fibrosis, in terms of Col I, TGFβ, CCN2 and CCN3 expression and collagen I immunostaining, increases with increasing body temperature during ischemia and ischemia-time. Thus, varying these two main determinants of ischemic injury allows tuning the extent of the long-term fibrotic outcome in this model. Finally, in order to cover the whole practical finesse of ischemia-reperfusion and allow model and data transfer, we provide a referenced overview on crucial technical issues (incl. anaesthesia, analgesia, and pre- and post-operative care) with the specific aim of putting starters in the right direction of implementing ischemia in their research and stimulate them, as well as the community, to have a critical view on ischemic literature data. PMID:27007127

  5. Unilateral Renal Ischemia-Reperfusion as a Robust Model for Acute to Chronic Kidney Injury in Mice.

    PubMed

    Le Clef, Nathalie; Verhulst, Anja; D'Haese, Patrick C; Vervaet, Benjamin A

    2016-01-01

    Acute kidney injury (AKI) is an underestimated, yet important risk factor for development of chronic kidney disease (CKD). Even after initial total recovery of renal function, some patients develop progressive and persistent deterioration of renal function and these patients are more likely to progress to end-stage renal disease (ESRD). Animal models are indispensable for unravelling the mechanisms underlying this progression towards CKD and ESRD and for the development of new therapeutic strategies in its prevention or treatment. Ischemia (i.e. hypoperfusion after surgery, bleeding, dehydration, shock, or sepsis) is a major aetiology in human AKI, yet unilateral ischemia-reperfusion is a rarely used animal model for research on CKD and fibrosis. Here, we demonstrate in C57Bl/6J mice, by both histology and gene expression, that unilateral ischemia-reperfusion without contralateral nephrectomy is a very robust model to study the progression from acute renal injury to long-term tubulo-interstitial fibrosis, i.e. the histopathological hallmark of CKD. Furthermore, we report that the extent of renal fibrosis, in terms of Col I, TGFβ, CCN2 and CCN3 expression and collagen I immunostaining, increases with increasing body temperature during ischemia and ischemia-time. Thus, varying these two main determinants of ischemic injury allows tuning the extent of the long-term fibrotic outcome in this model. Finally, in order to cover the whole practical finesse of ischemia-reperfusion and allow model and data transfer, we provide a referenced overview on crucial technical issues (incl. anaesthesia, analgesia, and pre- and post-operative care) with the specific aim of putting starters in the right direction of implementing ischemia in their research and stimulate them, as well as the community, to have a critical view on ischemic literature data. PMID:27007127

  6. SALT SENSITIVITY IN RESPONSE TO RENAL INJURY REQUIRES RENAL ANGIOTENSIN-CONVERTING ENZYME

    PubMed Central

    Giani, Jorge F.; Bernstein, Kenneth E.; Janjulia, Tea; Han, Jiyang; Toblli, Jorge E.; Shen, Xiao Z.; Rodriguez-Iturbe, Bernardo; McDonough, Alicia A.; Gonzalez-Villalobos, Romer A.

    2015-01-01

    Recent evidence indicates that salt-sensitive hypertension can result from a subclinical injury that impairs the kidneys’ capacity to properly respond to a high salt diet. However, how this occurs is not well understood. Here, we showed that while previously salt resistant wild-type mice became salt-sensitive after the induction of renal injury with the nitric oxide synthase inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME); mice lacking renal angiotensin-converting enzyme, exposed to the same insult, did not become hypertensive when faced with a sodium load. This is because the activity of renal angiotensin-converting enzyme plays a critical role in: 1) augmenting the local pool of angiotensin II and, 2) the establishment of the anti-natriuretic state via modulation of glomerular filtration rate and sodium tubular transport. Thus, this study demonstrates that the presence of renal angiotensin-converting enzyme plays a pivotal role in the development of salt sensitivity in response to renal injury. PMID:26150439

  7. Neuroinflammation and Neuroimmune Dysregulation after Acute Hypoxic-Ischemic Injury of Developing Brain

    PubMed Central

    Bhalala, Utpal S.; Koehler, Raymond C.; Kannan, Sujatha

    2015-01-01

    Hypoxic-ischemic (HI) injury to developing brain results from birth asphyxia in neonates and from cardiac arrest in infants and children. It is associated with varying degrees of neurologic sequelae, depending upon the severity and length of HI. Global HI triggers a series of cellular and biochemical pathways that lead to neuronal injury. One of the key cellular pathways of neuronal injury is inflammation. The inflammatory cascade comprises activation and migration of microglia – the so-called “brain macrophages,” infiltration of peripheral macrophages into the brain, and release of cytotoxic and proinflammatory cytokines. In this article, we review the inflammatory and immune mechanisms of secondary neuronal injury after global HI injury to developing brain. Specifically, we highlight the current literature on microglial activation in relation to neuronal injury, proinflammatory and anti-inflammatory/restorative pathways, the role of peripheral immune cells, and the potential use of immunomodulators as neuroprotective compounds. PMID:25642419

  8. Regulation of the proteasome by ATP: implications for ischemic myocardial injury and donor heart preservation.

    PubMed

    Majetschak, Matthias

    2013-08-01

    Several lines of evidence suggest that proteasomes are involved in multiple aspects of myocardial physiology and pathology, including myocardial ischemia-reperfusion injury. It is well established that the 26S proteasome is an ATP-dependent enzyme and that ischemic heart disease is associated with changes in the ATP content of the cardiomyocyte. A functional link between the 26S proteasome, myocardial ATP concentrations, and ischemic cardiac injury, however, has been suggested only recently. This review discusses the currently available data on the pathophysiological role of the cardiac proteasome during ischemia and reperfusion in the context of the cellular ATP content. Depletion of the myocardial ATP content during ischemia appears to activate the 26S proteasome via direct regulatory effects of ATP on 26S proteasome stability and activity. This implies pathological degradation of target proteins by the proteasome and could provide a pathophysiological basis for beneficial effects of proteasome inhibitors in various models of myocardial ischemia. In contrast to that in the ischemic heart, reduced and impaired proteasome activity is detectable in the postischemic heart. The paradoxical findings that proteasome inhibitors showed beneficial effects when administered during reperfusion in some studies could be explained by their anti-inflammatory and immune suppressive actions, leading to reduction of leukocyte-mediated myocardial reperfusion injury. The direct regulatory effects of ATP on the 26S proteasome have implications for the understanding of the contribution of the 26S proteasome to the pathophysiology of the ischemic heart and its possible role as a therapeutic target.

  9. Early prediction of renal parenchymal injury with serum procalcitonin

    PubMed Central

    Barati, Leila; Safaeian, Baranak; Mehrjerdian, Mahshid; Vakili, Mohammad-Ali

    2016-01-01

    Introduction: Urinary tract infection (UTI) is one of the most common bacterial infections in children that can be associated with renal parenchymal injuries and late scars. Dimercaptosuccinic acid (DMSA) renal scan is known as golden standard for detecting acute pyelonephritis (APN) that has a lot of difficulties and limitations. Objectives: we designed this study the accuracy of one inflammatory marker, serum procalcitonin (PCT) to identify as an early predictor of renal injuries. Patients and Methods: A prospective study was carried out in 95 patients who admitted in the hospital with the first febrile UTI. Serum PCT of all patients was measured; sensitivity, specificity, positive and negative predictive value (PPV and NPV) of this marker was analyzed compared to DMSA scan. P value <0.05 was taken as significant. Results: In total, 79 females and 16 males were investigated. There are 42 cases in group 1 with normal DMSA scan and 53 patients in group two with renal parenchymal injuries in their scans. Mann-Whitney test showed a meaningful relation between the two groups regarding PCT level (P<0.0001). Sensitivity, specificity, PPV and NPV of PCT reported in optimum cut off were 70%, 88.1%, 88.1% and 70%, respectively. The positive likelihood ratio (PLR) of PCT test was 5.8. Conclusion: In the current survey, PCT was the eligible inflammatory marker to predict renal parenchymal injuries in children with proper sensitivity, specificity, PPV and NPV that play also a pivotal role in the children aged less than 24 months, although, more studies should be undertaken to confirm. PMID:27689104

  10. Early prediction of renal parenchymal injury with serum procalcitonin

    PubMed Central

    Barati, Leila; Safaeian, Baranak; Mehrjerdian, Mahshid; Vakili, Mohammad-Ali

    2016-01-01

    Introduction: Urinary tract infection (UTI) is one of the most common bacterial infections in children that can be associated with renal parenchymal injuries and late scars. Dimercaptosuccinic acid (DMSA) renal scan is known as golden standard for detecting acute pyelonephritis (APN) that has a lot of difficulties and limitations. Objectives: we designed this study the accuracy of one inflammatory marker, serum procalcitonin (PCT) to identify as an early predictor of renal injuries. Patients and Methods: A prospective study was carried out in 95 patients who admitted in the hospital with the first febrile UTI. Serum PCT of all patients was measured; sensitivity, specificity, positive and negative predictive value (PPV and NPV) of this marker was analyzed compared to DMSA scan. P value <0.05 was taken as significant. Results: In total, 79 females and 16 males were investigated. There are 42 cases in group 1 with normal DMSA scan and 53 patients in group two with renal parenchymal injuries in their scans. Mann-Whitney test showed a meaningful relation between the two groups regarding PCT level (P<0.0001). Sensitivity, specificity, PPV and NPV of PCT reported in optimum cut off were 70%, 88.1%, 88.1% and 70%, respectively. The positive likelihood ratio (PLR) of PCT test was 5.8. Conclusion: In the current survey, PCT was the eligible inflammatory marker to predict renal parenchymal injuries in children with proper sensitivity, specificity, PPV and NPV that play also a pivotal role in the children aged less than 24 months, although, more studies should be undertaken to confirm.

  11. SUR1-Associated Mechanisms Are Not Involved in Ischemic Optic Neuropathy 1 Day Post-Injury

    PubMed Central

    Nicholson, James D.; Guo, Yan; Bernstein, Steven L.

    2016-01-01

    Ischemia-reperfusion injury after central nervous system (CNS) injury presents a major health care challenge with few promising treatments. Recently, it has become possible to reduce edema after CNS injury by antagonizing a sulfonylurea receptor 1 (SUR1) regulated ion channel expressed after injury. SUR1 upregulation after injury is a necessary precondition for the formation of this channel, and has been implicated in white matter injury after clinical spinal cord trauma. Glibenclamide, an SUR1 antagonist, appears to have neuroprotective effect against cerebral stroke in an open-label small clinical trial and great effectiveness in reducing damage after varied experimental CNS injury models. Despite its importance in CNS injuries, SUR1 upregulation appears to play no part in rodent anterior ischemic optic neuropathy (rAION) injury as tested by real-time PCR and immunohistochemical staining of rAION-injured rat optic nerve (ON). Furthermore, the SUR1 antagonist glibenclamide administered immediately after rAION injury provided no protection to proximal ON microvasculature 1 day post-injury but may reduce optic nerve head edema in a manner unrelated to ON SUR1 expression. Our results suggest that there may be fundamental differences between rAION optic nerve ischemia and other CNS white matter injuries where SUR1 appears to play a role. PMID:27560494

  12. SUR1-Associated Mechanisms Are Not Involved in Ischemic Optic Neuropathy 1 Day Post-Injury.

    PubMed

    Nicholson, James D; Guo, Yan; Bernstein, Steven L

    2016-01-01

    Ischemia-reperfusion injury after central nervous system (CNS) injury presents a major health care challenge with few promising treatments. Recently, it has become possible to reduce edema after CNS injury by antagonizing a sulfonylurea receptor 1 (SUR1) regulated ion channel expressed after injury. SUR1 upregulation after injury is a necessary precondition for the formation of this channel, and has been implicated in white matter injury after clinical spinal cord trauma. Glibenclamide, an SUR1 antagonist, appears to have neuroprotective effect against cerebral stroke in an open-label small clinical trial and great effectiveness in reducing damage after varied experimental CNS injury models. Despite its importance in CNS injuries, SUR1 upregulation appears to play no part in rodent anterior ischemic optic neuropathy (rAION) injury as tested by real-time PCR and immunohistochemical staining of rAION-injured rat optic nerve (ON). Furthermore, the SUR1 antagonist glibenclamide administered immediately after rAION injury provided no protection to proximal ON microvasculature 1 day post-injury but may reduce optic nerve head edema in a manner unrelated to ON SUR1 expression. Our results suggest that there may be fundamental differences between rAION optic nerve ischemia and other CNS white matter injuries where SUR1 appears to play a role.

  13. SUR1-Associated Mechanisms Are Not Involved in Ischemic Optic Neuropathy 1 Day Post-Injury.

    PubMed

    Nicholson, James D; Guo, Yan; Bernstein, Steven L

    2016-01-01

    Ischemia-reperfusion injury after central nervous system (CNS) injury presents a major health care challenge with few promising treatments. Recently, it has become possible to reduce edema after CNS injury by antagonizing a sulfonylurea receptor 1 (SUR1) regulated ion channel expressed after injury. SUR1 upregulation after injury is a necessary precondition for the formation of this channel, and has been implicated in white matter injury after clinical spinal cord trauma. Glibenclamide, an SUR1 antagonist, appears to have neuroprotective effect against cerebral stroke in an open-label small clinical trial and great effectiveness in reducing damage after varied experimental CNS injury models. Despite its importance in CNS injuries, SUR1 upregulation appears to play no part in rodent anterior ischemic optic neuropathy (rAION) injury as tested by real-time PCR and immunohistochemical staining of rAION-injured rat optic nerve (ON). Furthermore, the SUR1 antagonist glibenclamide administered immediately after rAION injury provided no protection to proximal ON microvasculature 1 day post-injury but may reduce optic nerve head edema in a manner unrelated to ON SUR1 expression. Our results suggest that there may be fundamental differences between rAION optic nerve ischemia and other CNS white matter injuries where SUR1 appears to play a role. PMID:27560494

  14. Hypomagnesemia is a risk factor for nonrecovery of renal function and mortality in AIDS patients with acute kidney injury.

    PubMed

    Santos, M S Biagioni; Seguro, A C; Andrade, L

    2010-03-01

    The objective of the present study was to determine the prevalence of electrolyte disturbances in AIDS patients developing acute kidney injury in the hospital setting, as well as to determine whether such disturbances constitute a risk factor for nephrotoxic and ischemic injury. A prospective, observational cohort study was carried out. Hospitalized AIDS patients were evaluated for age; gender; coinfection with hepatitis; diabetes mellitus; hypertension; time since HIV seroconversion; CD4 count; HIV viral load; proteinuria; serum levels of creatinine, urea, sodium, potassium and magnesium; antiretroviral use; nephrotoxic drug use; sepsis; intensive care unit (ICU) admission, and the need for dialysis. Each of these characteristics was correlated with the development of acute kidney injury, with recovery of renal function and with survival. Fifty-four patients developed acute kidney injury: 72% were males, 59% had been HIV-infected for >5 years, 72% had CD4 counts <200 cells/mm(3), 87% developed electrolyte disturbances, 33% recovered renal function, and 56% survived. ICU admission, dialysis, sepsis and hypomagnesemia were all significantly associated with nonrecovery of renal function and with mortality. Nonrecovery of renal function was significantly associated with hypomagnesemia, as was mortality in the multivariate analysis. The risks for nonrecovery of renal function and for death were 6.94 and 6.92 times greater, respectively, for patients with hypomagnesemia. In hospitalized AIDS patients, hypomagnesemia is a risk factor for nonrecovery of renal function and for in-hospital mortality. To determine whether hypomagnesemia is a determinant or simply a marker of critical illness, further studies involving magnesium supplementation in AIDS patients are warranted.

  15. MicroRNA-378 Alleviates Cerebral Ischemic Injury by Negatively Regulating Apoptosis Executioner Caspase-3

    PubMed Central

    Zhang, Nan; Zhong, Jie; Han, Song; Li, Yun; Yin, Yanling; Li, Junfa

    2016-01-01

    miRNAs have been linked to many human diseases, including ischemic stroke, and are being pursued as clinical diagnostics and therapeutic targets. Among the aberrantly expressed miRNAs in our previous report using large-scale microarray screening, the downregulation of miR-378 in the peri-infarct region of middle cerebral artery occluded (MCAO) mice can be reversed by hypoxic preconditioning (HPC). In this study, the role of miR-378 in the ischemic injury was further explored. We found that miR-378 levels significantly decreased in N2A cells following oxygen-glucose deprivation (OGD) treatment. Overexpression of miR-378 significantly enhanced cell viability, decreased TUNEL-positive cells and the immunoreactivity of cleaved-caspase-3. Conversely, downregulation of miR-378 aggravated OGD-induced apoptosis and ischemic injury. By using bioinformatic algorithms, we discovered that miR-378 may directly bind to the predicted 3′-untranslated region (UTR) of Caspase-3 gene. The protein level of caspase-3 increased significantly upon OGD treatment, and can be downregulated by pri-miR-378 transfection. The luciferase reporter assay confirmed the binding of miR-378 to the 3′-UTR of Caspase-3 mRNA and repressed its translation. In addition, miR-378 agomir decreased cleaved-caspase-3 ratio, reduced infarct volume and neural cell death induced by MCAO. Furthermore, caspase-3 knockdown could reverse anti-miR-378 mediated neuronal injury. Taken together, our data demonstrated that miR-378 attenuated ischemic injury by negatively regulating the apoptosis executioner, caspase-3, providing a potential therapeutic target for ischemic stroke. PMID:27598143

  16. MicroRNA-378 Alleviates Cerebral Ischemic Injury by Negatively Regulating Apoptosis Executioner Caspase-3.

    PubMed

    Zhang, Nan; Zhong, Jie; Han, Song; Li, Yun; Yin, Yanling; Li, Junfa

    2016-01-01

    miRNAs have been linked to many human diseases, including ischemic stroke, and are being pursued as clinical diagnostics and therapeutic targets. Among the aberrantly expressed miRNAs in our previous report using large-scale microarray screening, the downregulation of miR-378 in the peri-infarct region of middle cerebral artery occluded (MCAO) mice can be reversed by hypoxic preconditioning (HPC). In this study, the role of miR-378 in the ischemic injury was further explored. We found that miR-378 levels significantly decreased in N2A cells following oxygen-glucose deprivation (OGD) treatment. Overexpression of miR-378 significantly enhanced cell viability, decreased TUNEL-positive cells and the immunoreactivity of cleaved-caspase-3. Conversely, downregulation of miR-378 aggravated OGD-induced apoptosis and ischemic injury. By using bioinformatic algorithms, we discovered that miR-378 may directly bind to the predicted 3'-untranslated region (UTR) of Caspase-3 gene. The protein level of caspase-3 increased significantly upon OGD treatment, and can be downregulated by pri-miR-378 transfection. The luciferase reporter assay confirmed the binding of miR-378 to the 3'-UTR of Caspase-3 mRNA and repressed its translation. In addition, miR-378 agomir decreased cleaved-caspase-3 ratio, reduced infarct volume and neural cell death induced by MCAO. Furthermore, caspase-3 knockdown could reverse anti-miR-378 mediated neuronal injury. Taken together, our data demonstrated that miR-378 attenuated ischemic injury by negatively regulating the apoptosis executioner, caspase-3, providing a potential therapeutic target for ischemic stroke. PMID:27598143

  17. MG53 permeates through blood-brain barrier to protect ischemic brain injury

    PubMed Central

    Li, Haichang; Han, Yu; Chen, Ken; Wang, Zhen; Zeng, Jing; Liu, Yukai; Wang, Xinquan; Li, Yu; He, Duofen; Lin, Peihui; Zhou, Xinyu; Park, Ki Ho; Bian, Zehua; Chen, Zhishui; Gong, Nianqiao; Tan, Tao; Zhou, Jingsong; Zhang, Meng; Ma, Jianjie; Zeng, Chunyu

    2016-01-01

    Ischemic injury to neurons represents the underlying cause of stroke to the brain. Our previous studies identified MG53 as an essential component of the cell membrane repair machinery. Here we show that the recombinant human (rh)MG53 protein facilitates repair of ischemia-reperfusion (IR) injury to the brain. MG53 rapidly moves to acute injury sites on neuronal cells to form a membrane repair patch. IR-induced brain injury increases permeability of the blood-brain-barrier, providing access of MG53 from blood circulation to target the injured brain tissues. Exogenous rhMG53 protein can protect cultured neurons against hypoxia/reoxygenation-induced damages. Transgenic mice with increased levels of MG53 in the bloodstream are resistant to IR-induced brain injury. Intravenous administration of rhMG53, either prior to or after ischemia, can effectively alleviate brain injuries in rats. rhMG53-mediated neuroprotection involves suppression of apoptotic neuronal cell death, as well as activation of the pro-survival RISK signaling pathway. Our data indicate a physiological function for MG53 in the brain and suggest that targeting membrane repair or RISK signaling may be an effective means to treat ischemic brain injury. PMID:26967557

  18. Estetrol attenuates neonatal hypoxic-ischemic brain injury.

    PubMed

    Tskitishvili, Ekaterine; Nisolle, Michelle; Munaut, Carine; Pequeux, Christel; Gerard, Celine; Noel, Agnes; Foidart, Jean-Michel

    2014-11-01

    Estetrol (E4) is a recently described natural estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. It has important antioxidative activity. The aim of the present study was to define the importance of E4 in the attenuation of neonatal hypoxic-ischemic encephalopathy. Antioxidative effect of 650μM, 3.25mM and 6.5mM E4 on primary hippocampal cell cultures was studied before/after H202-induced oxidative stress. To examine oxidative stress and cell viability, lactate dehydrogenase activity and cell proliferation colorimetric assays were performed. To study the neuroprotective and therapeutic effects of E4 in vivo neonatal hypoxic-ischemic encephalopathy model of 7-day-old newborn rat pups was used. The neuroprotective and therapeutic effects of estetrol before/after hypoxic-ischemic insult was studied in 1mg/kg/day, 5mg/kg/day, 10mg/kg/day, 50mg/kg/day E4 pretreated/treated groups and compared with the sham and the vehicle treated groups. The body temperature of the rat pups was examined along with their body and brain weights. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of microtubule-associated protein-2, doublecortin and vascular-endothelial growth factor were evaluated by histo- and immunohistochemistry. ELISAs were performed on blood samples to detect concentrations of S100B and glial fibrillary acidic protein as brain damage markers. This work reveals for the first time that E4 significantly decreases LDH activity and enhances cell proliferation in primary hippocampal neuronal cell cultures in vitro, and decreases the early gray matter loss and promotes neuro- and angiogenesis in vivo. PMID:25079370

  19. Renal dysfunction and thrombolytic therapy in patients with acute ischemic stroke: a systematic review and meta-analysis.

    PubMed

    Hao, Zilong; Yang, Chunsong; Liu, Ming; Wu, Bo

    2014-12-01

    Renal dysfunction is a prevalent comorbidity in acute ischemic stroke patients requiring thrombolytic therapy. However, the effect of renal dysfunction on the clinical outcome of this population remains controversial. This study aimed to evaluate the safety and effectiveness of thrombolytic therapy in acute stroke patients with renal dysfunction using a meta-analysis. We systematically searched PubMed and EMBASE for studies that evaluated the relationship between renal dysfunction and intravenous tissue plasminogen activator (tPA) in patients with acute ischemic stroke. Poor outcome (modified Rankin Scale≥2), mortality, and symptomatic intracranial hemorrhage (ICH) and any ICH were analyzed. Fourteen studies were included (N=53,553 patients). The mean age ranged from 66 to 75 years. The proportion of male participants was 49% to 74%. The proportion of renal dysfunction varied from 21.9% to 83% according to different definitions. Based on 9 studies with a total of 7796 patients, the meta-analysis did not identify a significant difference in the odds of poor outcome (odds ratio [OR]=1.06; 95% confidence interval [CI]: 0.96-1.16; I=44.5) between patients with renal dysfunction and those without renal dysfunction. Patients with renal dysfunction were more likely to die after intravenous thrombolysis (OR=1.13; 95% CI: 1.05-1.21; I=70.3). No association was observed between symptomatic ICH (OR=1.02; 95% CI: 0.94-1.10; I=0) and any ICH (OR=1.07; 95% CI: 0.96-1.18; I=25.8). Renal dysfunction does not increase the risk of poor outcome and ICH after stroke thrombolysis. Renal dysfunction should not be a contraindication for administration of intravenous thrombolysis to eligible patients. PMID:25526464

  20. Amelioration of myocardial ischemic reperfusion injury with Calendula officinalis.

    PubMed

    Ray, Diptarka; Mukherjee, Subhendu; Falchi, Mario; Bertelli, Aldo; Das, Dipak K

    2010-12-01

    Calendula officinalis of family Asteraceae, also known as marigold, has been widely used from time immemorial in Indian and Arabic cultures as an anti-inflammatory agent to treat minor skin wound and infections, burns, bee stings, sunburn and cancer. At a relatively high dose, calendula can lower blood pressure and cholesterol. Since inflammatory responses are behind many cardiac diseases, we sought to evaluate if calendula could be cardioprotective against ischemic heart disease Two groups of hearts were used: the treated rat hearts were perfused with calendula solution at 50 mM in KHB buffer (in mM: sodium chloride 118, potassium chloride 4.7, calcium chloride 1.7, sodium bicarbonate 25, potassium biphosphate 0.36, magnesium sulfate 1.2, and glucose 10) for 15 min prior to subjecting the heart to ischemia, while the control group was perfused with the buffer only. Calendula achieved cardioprotection by stimulating left ventricular developed pressure and aortic flow as well as by reducing myocardial infarct size and cardiomyocyte apoptosis. Cardioprotection appears to be achieved by changing ischemia reperfusion-mediated death signal into a survival signal by modulating antioxidant and anti-inflammatory pathways as evidenced by the activation of Akt and Bcl2 and depression of TNFα. The results further strengthen the concept of using natural products in degeneration diseases like ischemic heart disease.

  1. Sex-dependent effects of sleep deprivation on myocardial sensitivity to ischemic injury.

    PubMed

    Zoladz, Phillip R; Krivenko, Anna; Eisenmann, Eric D; Bui, Albert D; Seeley, Sarah L; Fry, Megan E; Johnson, Brandon L; Rorabaugh, Boyd R

    2016-01-01

    Sleep deprivation is associated with increased risk of myocardial infarction. However, it is unknown whether the effects of sleep deprivation are limited to increasing the likelihood of experiencing a myocardial infarction or if sleep deprivation also increases the extent of myocardial injury. In this study, rats were deprived of paradoxical sleep for 96 h using the platform-over-water method. Control rats were subjected to the same condition except the control platform was large enough for the rats to sleep. Hearts from sleep deprived and control rats were subjected to 20 min ischemia on a Langendorff isolated heart system. Infarct size and post ischemic recovery of contractile function were unaffected by sleep deprivation in male hearts. In contrast, hearts from sleep-deprived females exhibited significantly larger infarcts than hearts from control females. Post ischemic recovery of rate pressure product and + dP/dT were significantly attenuated by sleep deprivation in female hearts, and post ischemic recovery of end diastolic pressure was significantly elevated in hearts from sleep deprived females compared to control females, indicating that post ischemic recovery of both systolic and diastolic function were worsened by sleep deprivation. These data provide evidence that sleep deprivation increases the extent of ischemia-induced injury in a sex-dependent manner. PMID:26953626

  2. Treatment with Isorhamnetin Protects the Brain Against Ischemic Injury in Mice.

    PubMed

    Zhao, Jin-Jing; Song, Jin-Qing; Pan, Shu-Yi; Wang, Kai

    2016-08-01

    Ischemic stroke is a major cause of morbidity and mortality, yet lacks effective neuroprotective treatments. The aim of this work was to investigate whether treatment with isorhamnetin protected the brain against ischemic injury in mice. Experimental stroke mice underwent the filament model of middle cerebral artery occlusion with reperfusion. Treatment with isorhamnetin or vehicle was initiated immediately at the onset of reperfusion. It was found that treatment of experimental stroke mice with isorhamnetin reduced infarct volume and caspase-3 activity (a biomarker of apoptosis), and improved neurological function recovery. Treatment of experimental stroke mice with isorhamnetin attenuated cerebral edema, improved blood-brain barrier function, and upregulated gene expression of tight junction proteins including occludin, ZO-1, and claudin-5. Treatment of experimental stroke mice with isorhamnetin activated Nrf2/HO-1, suppressed iNOS/NO, and led to reduced formation of MDA and 3-NT in ipsilateral cortex. In addition, treatment of experimental stroke mice with isorhamnetin suppressed activity of MPO (a biomarker of neutrophil infiltration) and reduced protein levels of IL-1β, IL-6, and TNF-α in ipsilateral cortex. Furthermore, it was found that treatment of experimental stroke mice with isorhamnetin reduced mRNA and protein expression of NMDA receptor subunit NR1 in ipsilateral cortex. In conclusion, treatment with isorhamnetin protected the brain against ischemic injury in mice. Isorhamnetin could thus be envisaged as a countermeasure for ischemic stroke but remains to be tested in humans. PMID:27161367

  3. Demonstration of early ischemic injury in porcine right ventricular myocardium.

    PubMed Central

    Spinale, F. G.; Schulte, B. A.; Crawford, F. A.

    1989-01-01

    Past studies of acute canine right ventricular (RV) ischemia have failed to demonstrate early irreversible injury or decreased function; however, the dog has extensive collateral circulation that may attenuate RV myocardial injury. The aim of this study was to measure RV function using contrast ventriculography and assess myocardial injury by immunohistochemical evaluation of creatine kinase (CK), lactate dehydrogenase (LDH), and tropomyosin (TROP) as well as by electron microscopy after right coronary occlusion in 14 closed-chest pigs. Significant depression in RV ejection fraction and stroke volume index after 10 minutes and was observed (P less than 0.05). CK, LDH, and TROP were positive in control tissue with a diminution of CK and LDH staining along the subendocardium after 15 minutes of ischemia. Irreversible ultrastructural injury in conjunction with large losses of CK and LDH became evident after 30 minutes. Thus, in the pig, which has a coronary anatomy similar to humans, significant RV dysfunction and irreversible myocardial injury can be demonstrated after 15 to 30 minutes of ischemia. Images Figure 2 Figure 3 Figure 4 Figure 5 PMID:2923187

  4. Association of systemic hypertension with renal injury in dogs with induced renal failure.

    PubMed

    Finco, Delmar R

    2004-01-01

    Systemic hypertension is hypothesized to cause renal injury to dogs. This study was performed on dogs with surgically induced renal failure to determine whether hypertension was associated with altered renal function or morphology. Mean arterial pressure (MAP), heart rate (HR), systolic arterial pressure (SAP), and diastolic arterial pressure (DAP) were measured before and after surgery. Glomerular filtration rate (GFR) and urine protein:creatinine ratios (UPC) were measured at 1, 12, 24, 36, and 56-69 weeks after surgery, and renal histology was evaluated terminally. The mean of weekly MAP, SAP, and DAP measurements for each dog over the 1st 26 weeks was used to rank dogs on the basis of MAP, SAP, or DAP values. A statistically significant association was found between systemic arterial pressure ranking and ranked measures of adverse renal responses. When dogs were divided into higher pressure and lower pressure groups on the basis of SAP, group 1 (higher pressure, n = 9) compared with group 2 (lower pressure, n = 10) had significantly lower GFR values at 36 and 56-69 weeks; higher UPC values at 12 and 56-69 weeks; and higher kidney lesion scores for mesangial matrix, tubule damage, and fibrosis. When dogs were divided on MAP and DAP values, group 1 compared with group 2 had significantly lower GFR values at 12, 24, 36, and 56-69 weeks; higher UPC values at 12 and 56-69 weeks; and higher kidney lesion scores for mesangial matrix, tubule damage, fibrosis, and cell infiltrate. These results demonstrate an association between increased systemic arterial pressure and renal injury. Results from this study might apply to dogs with some types of naturally occurring renal failure.

  5. GM-CSF Promotes Macrophage Alternative Activation after Renal Ischemia/Reperfusion Injury

    PubMed Central

    Huynh, Larry; Marlier, Arnaud; Lee, Yashang; Moeckel, Gilbert W.; Cantley, Lloyd G.

    2015-01-01

    After kidney ischemia/reperfusion (I/R) injury, monocytes home to the kidney and differentiate into activated macrophages. Whereas proinflammatory macrophages contribute to the initial kidney damage, an alternatively activated phenotype can promote normal renal repair. The microenvironment of the kidney during the repair phase mediates the transition of macrophage activation from a proinflammatory to a reparative phenotype. In this study, we show that macrophages isolated from murine kidneys during the tubular repair phase after I/R exhibit an alternative activation gene profile that differs from the canonical alternative activation induced by IL-4–stimulated STAT6 signaling. This unique activation profile can be reproduced in vitro by stimulation of bone marrow-derived macrophages with conditioned media from serum-starved mouse proximal tubule cells. Secreted tubular factors were found to activate macrophage STAT3 and STAT5 but not STAT6, leading to induction of the unique alternative activation pattern. Using STAT3-deficient bone marrow-derived macrophages and pharmacologic inhibition of STAT5, we found that tubular cell-mediated macrophage alternative activation is regulated by STAT5 activation. Both in vitro and after renal I/R, tubular cells expressed GM-CSF, a known STAT5 activator, and this pathway was required for in vitro alternative activation of macrophages by tubular cells. Furthermore, administration of a neutralizing antibody against GM-CSF after renal I/R attenuated kidney macrophage alternative activation and suppressed tubular proliferation. Taken together, these data show that tubular cells can instruct macrophage activation by secreting GM-CSF, leading to a unique macrophage reparative phenotype that supports tubular proliferation after sterile ischemic injury. PMID:25388222

  6. Dichotomous effects of chronic intermittent hypoxia on focal cerebral ischemic injury

    PubMed Central

    Jackman, Katherine A.; Zhou, Ping; Faraco, Giuseppe; Peixoto, Pablo M.; Coleman, Christal; Voss, Henning U.; Pickel, Virginia; Manfredi, Giovanni; Iadecola, Costantino

    2014-01-01

    Background and purpose Obstructive sleep apnea (OSA), a condition associated with chronic intermittent hypoxia (CIH), carries an increased risk of stroke. However, CIH has been reported to either increase or decrease brain injury in models of focal cerebral ischemia. The factors determining the differential effects of CIH on ischemic injury and their mechanisms remain unclear. Here, we tested the hypothesis that the intensity of the hypoxic challenge determines the protective or destructive nature of CIH by modulating mitochondrial resistance to injury. Methods Male C57Bl/6J mice were exposed to CIH with 10% or 6% O2 for up to 35 days and subjected to transient middle cerebral artery occlusion (MCAO). Motor deficits and infarct volume were assessed 3 days later. Intra-ischemic CBF was measured by laser-Doppler flowmetry and resting CBF by arterial spin labeling MRI. Ca2+-induced mitochondrial depolarization and reactive oxygen species (ROS) production were evaluated in isolated brain mitochondria. Results We found that 10% CIH is neuroprotective, while 6% CIH exacerbates tissue damage. No differences in resting or intra-ischemic CBF were observed between 6% and 10% CIH. However, 10% CIH reduced, while 6% CIH increases mitochondrial ROS production and susceptibility to Ca2+-induced depolarizations. Conclusions The influence of CIH on the ischemic brain is dichotomous and can be attributed in part to changes in the mitochondrial susceptibility to injury. The findings highlight a previously unappreciated complexity in the effect of CIH on the brain, which needs to be considered in evaluating the neurological impact of conditions associated with cyclic hypoxia. PMID:24713530

  7. Prenatal methamphetamine differentially alters myocardial sensitivity to ischemic injury in male and female adult hearts.

    PubMed

    Rorabaugh, Boyd R; Seeley, Sarah L; Bui, Albert D; Sprague, Lisanne; D'Souza, Manoranjan S

    2016-02-15

    Methamphetamine is one of the most common illicit drugs abused during pregnancy. The neurological effects of prenatal methamphetamine are well known. However, few studies have investigated the potential effects of prenatal methamphetamine on adult cardiovascular function. Previous work demonstrated that prenatal cocaine exposure increases sensitivity of the adult heart to ischemic injury. Methamphetamine and cocaine have different mechanisms of action, but both drugs exert their effects by increasing dopaminergic and adrenergic receptor stimulation. Thus the goal of this study was to determine whether prenatal methamphetamine also worsens ischemic injury in the adult heart. Pregnant rats were injected with methamphetamine (5 mg·kg(-1)·day(-1)) or saline throughout pregnancy. When pups reached 8 wk of age, their hearts were subjected to ischemia and reperfusion by means of a Langendorff isolated heart system. Prenatal methamphetamine had no significant effect on infarct size, preischemic contractile function, or postischemic recovery of contractile function in male hearts. However, methamphetamine-treated female hearts exhibited significantly larger infarcts and significantly elevated end-diastolic pressure during recovery from ischemia. Methamphetamine significantly reduced protein kinase Cε expression and Akt phosphorylation in female hearts but had no effect on these cardioprotective proteins in male hearts. These data indicate that prenatal methamphetamine differentially affects male and female sensitivity to myocardial ischemic injury and alters cardioprotective signaling proteins in the adult heart.

  8. Vitamin D deficiency contributes to vascular damage in sustained ischemic acute kidney injury.

    PubMed

    de Bragança, Ana C; Volpini, Rildo A; Mehrotra, Purvi; Andrade, Lúcia; Basile, David P

    2016-07-01

    Reductions in renal microvasculature density and increased lymphocyte activity may play critical roles in the progression of chronic kidney disease (CKD) following acute kidney injury (AKI) induced by ischemia/reperfusion injury (IRI). Vitamin D deficiency is associated with tubulointerstitial damage and fibrosis progression following IRI-AKI We evaluated the effect of vitamin D deficiency in sustained IRI-AKI, hypothesizing that such deficiency contributes to the early reduction in renal capillary density or alters the lymphocyte response to IRI Wistar rats were fed vitamin D-free or standard diets for 35 days. On day 28, rats were randomized into four groups: control, vitamin D deficient (VDD), bilateral IRI, and VDD+IRI Indices of renal injury and recovery were evaluated for up to 7 days following the surgical procedures. VDD rats showed reduced capillary density (by cablin staining), even in the absence of renal I/R. In comparison with VDD and IRI rats, VDD+IRI rats manifested a significant exacerbation of capillary rarefaction as well as higher urinary volume, kidney weight/body weight ratio, tissue injury scores, fibroblast-specific protein-1, and alpha-smooth muscle actin. VDD+IRI rats also had higher numbers of infiltrating activated CD4(+) and CD8(+) cells staining for interferon gamma and interleukin-17, with a significant elevation in the Th17/T-regulatory cell ratio. These data suggest that vitamin D deficiency impairs renal repair responses to I/R injury, exacerbates changes in renal capillary density, as well as promoting fibrosis and inflammation, which may contribute to the transition from AKI to CKD.

  9. Stromal cell-derived factor-1 (SDF1)-dependent recruitment of bone marrow-derived renal endothelium-like cells in a mouse model of acute kidney injury

    PubMed Central

    OHNISHI, Hiroyuki; MIZUNO, Shinya; MIZUNO-HORIKAWA, Yoko; KATO, Takashi

    2015-01-01

    Ischemic acute kidney injury (AKI) is the most key pathological event for accelerating progression to chronic kidney disease through vascular endothelial injury or dysfunction. Thus, it is critical to elucidate the molecular mechanism of endothelial protection and regeneration. Emerging evidence indicates that bone marrow-derived cells (BMCs) contribute to tissue reconstitution in several types of organs post-injury, but little is known whether and how BMCs contribute to renal endothelial reconstitution, especially in an early-stage of AKI. Using a mouse model of ischemic AKI, we provide evidence that incorporation of BMCs in vascular components (such as endothelial and smooth muscle cells) becomes evident within four days after renal ischemia and reperfusion, associated with an increase in stromal cell-derived factor-1 (SDF1) in endothelium and that in CXCR4/SDF1-receptor in BMCs. Notably, anti-CXCR4 antibody decreased the numbers of infiltrated BMCs and BMC-derived endothelium-like cells, but not of BMC-derived smooth muscle cell-like cells. These results suggest that reconstitution of renal endothelium post-ischemia partially depends on a paracrine loop of SDF1-CXCR4 between resident endothelium and BMCs. Such a chemokine ligand-receptor system may be attributable for selecting a cellular lineage (s), required for renal vascular protection, repair and homeostasis, even in an earlier phase of AKI. PMID:25833353

  10. Differential renal function in unilateral renal injury: possible effects of radiopharmaceutical choice. [Rats

    SciTech Connect

    Taylor, A. Jr.; Lallone, R.

    1985-01-01

    An abnormal filtration fraction or a significant divergence between a kidney's ability to extract Tc-99m dimercaptosuccinic acid (DMSA) and other function parameters, such as the glomerular filtration rate (GFR) or the effective renal plasma flow (ERPF, could lead to different estimates of relative or absolute renal function, depending on the radiopharmaceutical administered. To evaluate this possible divergence, the authors measured the relative GFR (I-125 iothalamate), ERPF (I-131 hippurate), and Tc-99m DMSA accumulation in adult male Sprague-Dawley rats with unilateral ureteral obstruction or unilateral ischemia at various times after renal injury. The relative ERPF of the obstructed kidney was significantly greater than the relative GFR at all time periods studied; significant but less dramatic differences were noted comparing DMSA with GFR in obstruction and DMSA and ERPF with GRF in ischemia.

  11. VEGF-121 preserves renal microvessel structure and ameliorates secondary renal disease following acute kidney injury

    PubMed Central

    Leonard, Ellen C.; Friedrich, Jessica L.; Basile, David P.

    2008-01-01

    Acute kidney injury induced by renal ischemia-reperfusion (I/R) compromises microvascular density and predisposes to chronic kidney disease (CKD) and sodium-dependent hypertension. VEGF-121 was administered to rats fed a standard (0.4%) sodium diet at various times following recovery from I/R injury for up to 35 days. VEGF-121 had no effect on the initial loss of renal function, as indicated by serum creatinine levels measured 24 h after injury. Serum creatinine levels declined thereafter, indicative of renal repair. Rats were then switched to an elevated (4.0%) sodium diet for an additional 28 days to induce CKD. The 4.0% sodium diet enhanced renal hypertrophy, interstitial volume, albuminuria, and cardiac hypertrophy relative to postischemic animals maintained on the 0.4% sodium diet. Administration of VEGF-121 from day 0 to 14, day 0 to 35, or day 3 to 35 after I/R suppressed the effects of sodium diet on CKD development, while delayed administration of VEGF-121 from day 21 to 35 had no effect. Endothelial nitric oxide synthase protein levels were upregulated in postischemic animals, and this effect was significantly increased by the 4.0% sodium diet but was not influenced by prior treatment with VEGF. Conversely, microvascular density was preserved in postischemic animals treated with VEGF-121 relative to vehicle-treated postischemic animals. These data suggest that early, but not delayed, treatment with VEGF-121 can preserve vascular structure after ischemia and influence chronic renal function in response to elevated sodium intake. PMID:18799550

  12. Catestatin improves post-ischemic left ventricular function and decreases ischemia/reperfusion injury in heart.

    PubMed

    Penna, Claudia; Alloatti, Giuseppe; Gallo, Maria Pia; Cerra, Maria Carmela; Levi, Renzo; Tullio, Francesca; Bassino, Eleonora; Dolgetta, Serena; Mahata, Sushil K; Tota, Bruno; Pagliaro, Pasquale

    2010-11-01

    The Chromogranin A (CgA)-derived anti-hypertensive peptide catestatin (CST) antagonizes catecholamine secretion, and is a negative myocardial inotrope acting via a nitric oxide-dependent mechanism. It is not known whether CST contributes to ischemia/reperfusion injury or is a component of a cardioprotective response to limit injury. Here, we tested whether CST by virtue of its negative inotropic activity improves post-ischemic cardiac function and cardiomyocyte survival. Three groups of isolated perfused hearts from adult Wistar rats underwent 30-min ischemia and 120-min reperfusion (I/R, Group 1), or were post-conditioned by brief ischemic episodes (PostC, 5-cycles of 10-s I/R at the beginning of 120-min reperfusion, Group 2), or with exogenous CST (75 nM for 20 min, CST-Post, Group-3) at the onset of reperfusion. Perfusion pressure and left ventricular pressure (LVP) were monitored. Infarct size was evaluated with nitroblue-tetrazolium staining. The CST (5 nM) effects were also tested in simulated ischemia/reperfusion experiments on cardiomyocytes isolated from young-adult rats, evaluating cell survival with propidium iodide labeling. Infarct size was 61 ± 6% of risk area in hearts subjected to I/R only. PostC reduced infarct size to 34 ± 5%. Infarct size in CST-Post was 36 ± 3% of risk area (P < 0.05 respect to I/R). CST-Post reduced post-ischemic rise of diastolic LVP, an index of contracture, and significantly improved post-ischemic recovery of developed LVP. In isolated cardiomyocytes, CST increased the cell viability rate by about 65% after simulated ischemia/reperfusion. These results suggest a novel cardioprotective role for CST, which appears mainly due to a direct reduction of post-ischemic myocardial damages and dysfunction, rather than to an involvement of adrenergic terminals and/or endothelium.

  13. Cardioprotection by systemic dosing of thymosin beta four following ischemic myocardial injury

    PubMed Central

    Bao, Weike; Ballard, Victoria L.; Needle, Saul; Hoang, Bao; Lenhard, Stephen C.; Tunstead, James R.; Jucker, Beat M.; Willette, Robert N.; Pipes, G. Teg

    2013-01-01

    Thymosin beta 4 (Tβ4) was previously shown to reduce infarct size and improve contractile performance in chronic myocardial ischemic injury via two phases of action: an acute phase, just after injury, when Tβ4 preserves ischemic myocardium via antiapoptotic or anti-inflammatory mechanisms; and a chronic phase, when Tβ4 activates the growth of vascular or cardiac progenitor cells. In order to differentiate between the effects of Tβ4 during the acute and during the chronic phases, and also in order to obtain detailed hemodynamic and biomarker data on the effects of Tβ4 treatment suitable for use in clinical studies, we tested Tβ4 in a rat model of chronic myocardial ischemia using two dosing regimens: short term dosing (Tβ4 administered only during the first 3 days following injury), and long term dosing (Tβ4 administered during the first 3 days following injury and also every third day until the end of the study). Tβ4 administered throughout the study reduced infarct size and resulted in significant improvements in hemodynamic performance; however, chamber volumes and ejection fractions were not significantly improved. Tβ4 administered only during the first 3 days following injury tended to reduce infarct size, chamber volumes and improve hemodynamic performance. Plasma biomarkers of myocyte injury were significantly reduced by Tβ4 treatment during the acute injury period, and plasma ANP levels were significantly reduced in both dosing groups. Surprisingly, neither acute nor chronic Tβ4 treatment significantly increased blood vessel density in peri-infarct regions. These results suggest the following: repeated dosing may be required to achieve clinically measureable improvements in cardiac function post-myocardial infarction (MI); improvement in cardiac function may be observed in the absence of a high degree of angiogenesis; and that plasma biomarkers of cardiac function and myocardial injury are sensitive pharmacodynamic biomarkers of the effects of T

  14. Study on the Mechanism of mTOR-Mediated Autophagy during Electroacupuncture Pretreatment against Cerebral Ischemic Injury

    PubMed Central

    Wu, Zhou-Quan; Cui, Su-yang; Zhu, Liang

    2016-01-01

    This study is aimed at investigating the association between the electroacupuncture (EA) pretreatment-induced protective effect against early cerebral ischemic injury and autophagy. EA pretreatment can protect cerebral ischemic and reperfusion injuries, but whether the attenuation of early cerebral ischemic injury by EA pretreatment was associated with autophagy is not yet clear. This study used the middle cerebral artery occlusion model to monitor the process of ischemic injury. For rats in the EA pretreatment group, EA pretreatment was conducted at Baihui acupoint before ischemia for 30 min for 5 consecutive days. The results suggested that EA pretreatment significantly increased the expression of autophagy in the cerebral cortical area on the ischemic side of rats. But the EA pretreatment-induced protective effects on the brain could be reversed by the specific inhibitor 3-methyladenine of autophagy. Additionally, the Pearson correlation analysis indicated that the impact of EA pretreatment on p-mTOR (2481) was negatively correlated with its impact on autophagy. In conclusion, the mechanism of EA pretreatment at Baihui acupoint against cerebral ischemic injury is mainly associated with the upregulation of autophagy expression, and its regulation of autophagy may depend on mTOR-mediated signaling pathways. PMID:27547233

  15. PPARα agonist, fenofibrate, ameliorates age-related renal injury.

    PubMed

    Kim, Eun Nim; Lim, Ji Hee; Kim, Min Young; Kim, Hyung Wook; Park, Cheol Whee; Chang, Yoon Sik; Choi, Bum Soon

    2016-08-01

    The kidney ages quickly compared with other organs. Expression of senescence markers reflects changes in the energy metabolism in the kidney. Two important issues in aging are mitochondrial dysfunction and oxidative stress. Peroxisome proliferator-activated receptor α (PPARα) is a member of the ligand-activated nuclear receptor superfamily. PPARα plays a major role as a transcription factor that regulates the expression of genes involved in various processes. In this study, 18-month-old male C57BL/6 mice were divided into two groups, the control group (n=7) and the fenofibrate-treated group (n=7) was fed the normal chow plus fenofibrate for 6months. The PPARα agonist, fenofibrate, improved renal function, proteinuria, histological change (glomerulosclerosis and tubular interstitial fibrosis), inflammation, and apoptosis in aging mice. This protective effect against age-related renal injury occurred through the activation of AMPK and SIRT1 signaling. The activation of AMPK and SIRT1 allowed for the concurrent deacetylation and phosphorylation of their target molecules and decreased the kidney's susceptibility to age-related changes. Activation of the AMPK-FOXO3a and AMPK-PGC-1α signaling pathways ameliorated oxidative stress and mitochondrial dysfunction. Our results suggest that activation of PPARα and AMPK-SIRT1 signaling may have protective effects against age-related renal injury. Pharmacological targeting of PPARα and AMPK-SIRT1 signaling molecules may prevent or attenuate age-related pathological changes in the kidney. PMID:27130813

  16. Acute Kidney Injury Associated with Renal Cell Carcinoma Complicated by Renal Vein and Inferior Vena Cava Involvement.

    PubMed

    Sugase, Taro; Akimoto, Tetsu; Kubo, Taro; Imai, Toshimi; Otani-Takei, Naoko; Miki, Takuya; Takeda, Shin-Ichi; Nukui, Akinori; Muto, Shigeaki; Morita, Tatsuo; Nagata, Daisuke

    2016-01-01

    Acute kidney injury (AKI) is caused by diverse pathologies, although it may occasionally result from concurrent renal efflux disturbances. We herein describe a case of AKI in a patient complicated by renal cell carcinoma (RCC) with renal vein and inferior vena cava (IVC) involvement. A neoplastic thrombus which disrupted the blood flow in the renal vein appeared to play a role in the rapid decline in the renal function. Such a scenario has rarely been mentioned in the previous literature describing the cases of RCC complicated by AKI. Concerns regarding the diagnostic and therapeutic strategies for RCC are also discussed. PMID:27580548

  17. Severe hypertriglyceridemia does not protect from ischemic brain injury in gene-modified hypertriglyceridemic mice.

    PubMed

    Chen, Yong; Liu, Ping; Qi, Rong; Wang, Yu-Hui; Liu, George; Wang, Chun

    2016-05-15

    Hypertriglyceridemia (HTG) is a weak risk factor in primary ischemic stroke prevention. However, clinical studies have found a counterintuitive association between a good prognosis after ischemic stroke and HTG. This "HTG paradox" requires confirmation and further explanation. The aim of this study was to experimentally assess this paradox relationship using the gene-modified mice model of extreme HTG. We first used the human Apolipoprotein CIII transgenic (Tg-ApoCIII) mice and non-transgenic (Non-Tg) littermates to examine the effect of HTG on stroke. To our surprise, infarct size, neurological deficits, brain edema, BBB permeability, neuron density and lipid peroxidation were the same in Tg-ApoCIII mice and Non-Tg mice after temporary middle cerebral artery occlusion (tMCAO). In the late phase (21 days after surgery), no differences were found in brain atrophy, neurological dysfunctions, weight and mortality between the two groups. To confirm the results in Tg-ApoCIII mice, Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1(GPIHBP1) knockout mice, another severe HTG mouse model, were used and yielded similar results. Our study demonstrates for the first time that extreme HTG does not affect ischemic brain injuries in the tMCAO mouse model, indicating that the association between HTG and good outcomes after ischemic stroke probably represents residual unmeasured confounding. Further clinical and prospective population-based studies are needed to explore variables that contribute to the paradox. PMID:26970521

  18. Pharmacological Neuroprotection after Perinatal Hypoxic-Ischemic Brain Injury

    PubMed Central

    Fan, Xiyong; Kavelaars, Annemieke; Heijnen, Cobi J; Groenendaal, Floris; van Bel, Frank

    2010-01-01

    Perinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury. Recent progress in the search for neuroprotective compounds has provided us with several promising drugs to reduce perinatal HI-induced brain injury. In the early stage (first 6 hours after birth) therapies are concentrated on prevention of the production of reactive oxygen species or free radicals (xanthine-oxidase-, nitric oxide synthase-, and prostaglandin inhibition), anti-inflammatory effects (erythropoietin, melatonin, Xenon) and anti-apoptotic interventions (nuclear factor kappa B- and c-jun N-terminal kinase inhibition); in a later stage stimulation of neurotrophic properties in the neonatal brain (erythropoietin, growth factors) can be targeted to promote neuronal and oligodendrocyte regeneration. Combination of pharmacological means of treatment with moderate hypothermia, which is accepted now as a meaningful therapy, is probably the next step in clinical treatment to fight post-asphyxial brain damage. Further studies should be directed at a more rational use of therapies by determining the optimal time and dose to inhibit the different potentially destructive molecular pathways or to enhance endogenous repair while at the same time avoiding adverse effects of the drugs used. PMID:21629441

  19. Aluminum Citrate Prevents Renal Injury from Calcium Oxalate Crystal Deposition

    PubMed Central

    Besenhofer, Lauren M.; Cain, Marie C.; Dunning, Cody

    2012-01-01

    Calcium oxalate monohydrate crystals are responsible for the kidney injury associated with exposure to ethylene glycol or severe hyperoxaluria. Current treatment strategies target the formation of calcium oxalate but not its interaction with kidney tissue. Because aluminum citrate blocks calcium oxalate binding and toxicity in human kidney cells, it may provide a different therapeutic approach to calcium oxalate-induced injury. Here, we tested the effects of aluminum citrate and sodium citrate in a Wistar rat model of acute high-dose ethylene glycol exposure. Aluminum citrate, but not sodium citrate, attenuated increases in urea nitrogen, creatinine, and the ratio of kidney to body weight in ethylene glycol–treated rats. Compared with ethylene glycol alone, the addition of aluminum citrate significantly increased the urinary excretion of both crystalline calcium and crystalline oxalate and decreased the deposition of crystals in renal tissue. In vitro, aluminum citrate interacted directly with oxalate crystals to inhibit their uptake by proximal tubule cells. These results suggest that treating with aluminum citrate attenuates renal injury in rats with severe ethylene glycol toxicity, apparently by inhibiting calcium oxalate’s interaction with, and retention by, the kidney epithelium. PMID:23138489

  20. The feasibility of imaging myocardial ischemic/reperfusion injury using 99mTc-labeled duramycin in a porcine model

    PubMed Central

    Wang, Lei; Wang, Feng; Fang, Wei; Johnson, Steven E.; Audi, Said; Zimmer, Michael; Holly, Thomas A; Lee, Daniel; Zhu, Bao; Zhu, Haibo; Zhao, Ming

    2015-01-01

    When pathologically externalized, phosphatidylethanolamine (PE) is a potential surrogate marker for detecting tissue injuries. 99mTc-labeled duramycin is a peptide-based imaging agent that binds PE with high affinity and specificity. The goal of the current study was to investigate the clearance kinetics of 99mTc-labeled duramycin in a large animal model (normal pigs) and to assess its uptake in the heart using a pig model of myocardial ischemia-reperfusion injury. Methods The clearance and distribution of intravenously injected 99mTc-duramycin were characterized in sham-operated animals (n = 5). In a closed chest model of myocardial ischemia, coronary occlusion was induced by balloon angioplasty (n = 9). 99mTc-duramycin (10-15 mCi) was injected intravenously at 1 hour after reperfusion. SPECT/CT was acquired at 1 and 3 hours after injection. Cardiac tissues were analyzed for changes associated with acute cellular injuries. Autoradiography and gamma counting was used to determine radioactivity uptake. For the remaining animals, 99mTc-tetrafosamin scan was performed on the second day to identify the infarct site. Results Intravenously injected 99mTc-duramycin cleared from circulation predominantly via the renal/urinary tract with an α-phase half-life of 3.6 ± 0.3 minutes and β-phase half-life of 179.9 ± 64.7 minutes. In control animals, the ratios between normal heart and lung were 1.76 ± 0.21, 1.66 ± 0.22, 1.50 ± 0.20 and 1.75 ± 0.31 at 0.5, 1, 2 and 3 hours post injection, respectively. The ratios between normal heart and liver were 0.88 ± 0.13, 0.80 ± 0.13, 0.82 ± 0.19 and 0.88 ± 0.14. In vivo visualization of focal radioactivity uptake in the ischemic heart was attainable as early as 30 min post injection. The in vivo ischemic-to-normal uptake ratios were 3.57 ± 0.74 and 3.69 ± 0.91 at 1 and 3 hours post injection, respectively. Ischemic-to-lung ratios were 4.89 ± 0.85 and 4.93 ± 0.57; and ischemic-to-liver ratios were 2.05 ± 0.30 to 3.23 ± 0

  1. Spino-renal fistula due to gunshot injury.

    PubMed

    Alsharef, M M; Christopher, N; Fourie, T

    2011-07-01

    A 22-year-old female patient was treated for spino-renal fistula as a result of a high-velocity gunshot injury to her abdomen. The patient presented with meningeal signs, a headache and right monoparesis. A CT scan of her abdomen revealed a leak of contrast from the right kidney into the perirenal space and tracking further into the thecal sac. An MRI scan showed a stable fracture of L3 with slight compression of the thecal sac and features of cord contusion caused by the shockwave of the bullet. To the best of our knowledge a spino-renal fistula of traumatic origin has not previously been reported in the English language literature.

  2. Ischemic postconditioning provides protection against ischemia-reperfusion injury in intestines of rats.

    PubMed

    Chu, Weiwei; Li, Sheng; Wang, Shanwei; Yan, Aili; Nie, Lei

    2015-01-01

    In the present study, we investigated the protective role of ischemic postconditioning (IPOST) against intestine ischemia-reperfusion (I/R) injury in rats. Male Sprague-Dawley rats were divided into sham-operation group (S), I/R group (I/R), ischemic preconditioning group (IPC), ischemic postconditioning group (IPOST). After reperfusion, small intestines were resected for histopathologic evaluations. To evaluate DNA fragmentation, resolving agarose gel electrophoresis was performed. To measure cellular apoptotic rates in intestine tissues, we performed TUNEL staining. To examine lipid peroxidation, production of superoxide radicals and tissue neutrophil infiltration, we tested the content of malondialdehyde and activities of superoxidase dismutase and myeloperoxidase in intestine tissues, respectively. Under light microscope, intestinal mucosal impairment in IPOST and IPC groups was found milder than that in I/R group (P < 0.05). The number of apoptosis cells in I/R group was significantly higher than that in IPOST and IPC groups (P < 0.05). The content of malondialdehyde and activity of myeloperoxidase were significantly reduced in IPOST group and IPC group compared with I/R group, but the activity of superoxidase dismutase in IPOST group and IPC group was enhanced compared with I/R group (P < 0.05). These results suggest that IPOST results in protection against intestine I/R injury, which may be related to reduced production of reactive oxygen species, enhanced activities of antioxidant systems and inhibited apoptosis of intestinal mucosal cells.

  3. Renal cortical pyruvate as a potentially critical mediator of acute kidney injury.

    PubMed

    Johnson, Ali C M; Zager, Richard A

    2014-01-01

    Pyruvate is a key intermediary in both aerobic and anaerobic energy metabolisms. In addition, a burgeoning body of experimental literature indicates that it can also dramatically impact oxidant, proinflammatory, and cytoprotective pathways. In sum, these actions can confer protection against diverse forms of tissue damage. However, the fate of pyruvate during the evolution of acute kidney injury (AKI) has remained ill defined. Recent experimental studies have indicated that following either ischemic or nephrotoxic renal injury, marked and sustained pyruvate depletion results. While multiple potential mechanisms for this pyruvate loss may be involved, experimental data suggest that a loss of lactate (a dominant pyruvate precursor) and enhanced gluconeogenesis (i.e. pyruvate utilization) are involved. The importance of pyruvate depletion for AKI pathogenesis is underscored by observations that pyruvate therapy can attenuate diverse forms of experimental AKI. This protection may stem from reductions in tissue inflammation, improved anti-inflammatory defenses, and an enhanced cellular energy metabolism. The pieces of information that give rise to these conclusions are discussed in this brief report. PMID:25343836

  4. Protective effects of amlodipine on mitochondrial injury in ischemic reperfused rat heart.

    PubMed

    Khan, Najam Ali; Chattopadhyay, Pronobesh; Abid, Mohammad; Pawdey, Abhijeet; Kishore, Kamal; Wahi, Arun Kumar

    2012-05-01

    The most significant finding of the present study was the release of nitric oxide (NO). The effect of amlodipine on NO production associated with ischemic reperfused (IR) injury was investigated in rat heart model. Cardiac tissues from animal groups were processed for biochemical, histopathological and electron microscopic studies. There was a significant increase in myocardial catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH) enzymes in amlodipine treated group (1.37, 10.27, 6.39) when compared to IR injured group (0.81, 6.87, 4.53). Histopathology studies showed amlodipine reduce cardiocyte damage in cardiac injury during the cardiac IR. Transmission electron microscopic (TEM) study confirmed the cardioprotective role of amlodipine against IR induced cardiac injury. On the basis of findings, it is hypothesized that a portion of the beneficial actions of amlodipine may involve the release or action of NO and probably by its antioxidant properties.

  5. Impaired cerebral autoregulation and brain injury in newborns with hypoxic-ischemic encephalopathy treated with hypothermia.

    PubMed

    Massaro, An N; Govindan, R B; Vezina, Gilbert; Chang, Taeun; Andescavage, Nickie N; Wang, Yunfei; Al-Shargabi, Tareq; Metzler, Marina; Harris, Kari; du Plessis, Adre J

    2015-08-01

    Impaired cerebral autoregulation may contribute to secondary injury in newborns with hypoxic-ischemic encephalopathy (HIE). Continuous, noninvasive assessment of cerebral pressure autoregulation can be achieved with bedside near-infrared spectroscopy (NIRS) and systemic mean arterial blood pressure (MAP) monitoring. This study aimed to evaluate whether impaired cerebral autoregulation measured by NIRS-MAP monitoring during therapeutic hypothermia and rewarming relates to outcome in 36 newborns with HIE. Spectral coherence analysis between NIRS and MAP was used to quantify changes in the duration [pressure passivity index (PPI)] and magnitude (gain) of cerebral autoregulatory impairment. Higher PPI in both cerebral hemispheres and gain in the right hemisphere were associated with neonatal adverse outcomes [death or detectable brain injury by magnetic resonance imaging (MRI), P < 0.001]. NIRS-MAP monitoring of cerebral autoregulation can provide an ongoing physiological biomarker that may help direct care in perinatal brain injury.

  6. Impaired cerebral autoregulation and brain injury in newborns with hypoxic-ischemic encephalopathy treated with hypothermia.

    PubMed

    Massaro, An N; Govindan, R B; Vezina, Gilbert; Chang, Taeun; Andescavage, Nickie N; Wang, Yunfei; Al-Shargabi, Tareq; Metzler, Marina; Harris, Kari; du Plessis, Adre J

    2015-08-01

    Impaired cerebral autoregulation may contribute to secondary injury in newborns with hypoxic-ischemic encephalopathy (HIE). Continuous, noninvasive assessment of cerebral pressure autoregulation can be achieved with bedside near-infrared spectroscopy (NIRS) and systemic mean arterial blood pressure (MAP) monitoring. This study aimed to evaluate whether impaired cerebral autoregulation measured by NIRS-MAP monitoring during therapeutic hypothermia and rewarming relates to outcome in 36 newborns with HIE. Spectral coherence analysis between NIRS and MAP was used to quantify changes in the duration [pressure passivity index (PPI)] and magnitude (gain) of cerebral autoregulatory impairment. Higher PPI in both cerebral hemispheres and gain in the right hemisphere were associated with neonatal adverse outcomes [death or detectable brain injury by magnetic resonance imaging (MRI), P < 0.001]. NIRS-MAP monitoring of cerebral autoregulation can provide an ongoing physiological biomarker that may help direct care in perinatal brain injury. PMID:26063779

  7. Ischemic brain injury in hemodialysis patients: which is more dangerous, hypertension or intradialytic hypotension?

    PubMed

    McIntyre, Christopher W; Goldsmith, David J

    2015-06-01

    Abnormalities of cognitive function and high levels of depression incidence are characteristic of hemodialysis patients. Although previously attributed to the humoral effects of uremia, it is becoming increasingly appreciated that many elements of the overall disease state in CKD patients contribute to functional disturbances and physical brain injury. These factors range from those associated with the underlying primary diseases (cardiovascular, diabetes etc.) to those specifically associated with the requirement for dialysis (including consequences of the hemodialysis process itself). They are, however, predominantly ischemic threats to the integrity of brain tissue. These evolving insights are starting to allow nephrologists to appreciate the potential biological basis of dependency and depression in our patients, as well as develop and test new therapeutic approaches to this increasingly prevalent and important issue. This review aims to summarize the current understanding of brain injury in this setting, as well as examine recent advances being made in the modification of dialysis-associated brain injury. PMID:25853331

  8. Post-injury administration of allicin attenuates ischemic brain injury through sphingosine kinase 2: In vivo and in vitro studies.

    PubMed

    Lin, Jia-Ji; Chang, Ting; Cai, Wen-Ke; Zhang, Zhuo; Yang, Yong-Xiang; Sun, Chao; Li, Zhu-Yi; Li, Wei-Xin

    2015-10-01

    Allicin, one of the main biologically active compounds derived from garlic, has been shown to exert various pharmacological activities and is considered to have therapeutic potential for many pathologic conditions. In the present study, we investigated the potential post-ischemic neuroprotective effects of allicin and its underlying mechanisms. Using a rat middle cerebral artery occlusion (MCAO) model, we found that intraperitoneal treatment with 50 mg/kg allicin significantly reduced brain infarct volume, attenuated cerebral edema and decreased the neurological deficit score. Allicin treatment also diminished TUNEL positive cells and inhibited the activation of caspase-3 after MCAO. These protective effects could be observed even if the administration was delayed to 6 h after injury. In addition, we evaluated the in vitro protective effects of allicin against oxygen glucose deprivation (OGD) induced neuronal injury in primary cultured cortical neurons. Allicin (50 μM) increased neuronal viability, decreased lactate dehydrogenase (LDH) release and inhibited apoptotic neuronal death after OGD. These protective effects could be observed even if the administration was delayed to 4 h after injury. Furthermore, allicin significantly increased the expression of sphingosine kinases 2 (Sphk2) both in vivo and in vitro. Pretreatment with the Sphk2 inhibitor ABC294640 partially reversed the protective effects of allicin against MCAO and OGD injury, indicating that an Sphk2-mediated mechanism was involved in allicin-induced protection in our models. The combination of findings suggests that post-injury administration of allicin has potential as a neuroprotective strategy for ischemic stroke. PMID:26275594

  9. Obstructive renal injury: from fluid mechanics to molecular cell biology.

    PubMed

    Ucero, Alvaro C; Gonçalves, Sara; Benito-Martin, Alberto; Santamaría, Beatriz; Ramos, Adrian M; Berzal, Sergio; Ruiz-Ortega, Marta; Egido, Jesus; Ortiz, Alberto

    2010-04-22

    Urinary tract obstruction is a frequent cause of renal impairment. The physiopathology of obstructive nephropathy has long been viewed as a mere mechanical problem. However, recent advances in cell and systems biology have disclosed a complex physiopathology involving a high number of molecular mediators of injury that lead to cellular processes of apoptotic cell death, cell injury leading to inflammation and resultant fibrosis. Functional studies in animal models of ureteral obstruction using a variety of techniques that include genetically modified animals have disclosed an important role for the renin-angiotensin system, transforming growth factor-β1 (TGF-β1) and other mediators of inflammation in this process. In addition, high throughput techniques such as proteomics and transcriptomics have identified potential biomarkers that may guide clinical decision-making.

  10. Peroxiredoxin 2 battles PARP1- and p53-dependent pro-death pathways following ischemic injury

    PubMed Central

    Leak, Rehana K.; Zhang, Lili; Luo, Yumin; Li, Peiying; Zhao, Haiping; Liu, Xiangrong; Ling, Feng; Jia, Jianping; Chen, Jun; Ji, Xunming

    2013-01-01

    Background and Purpose Ischemic/reperfusion neuronal injury is characterized by accumulation of reactive oxygen species (ROS) and oxidative DNA damage, which can trigger cell death by various signaling pathways. Two of these modes of death include poly(ADP-ribose) polymerase 1 (PARP1)-mediated death or p53- and Bax-mediated apoptosis. The present study tested the hypothesis that peroxiredoxin2 (PRX2) attenuates DNA damage-mediated pro-death signaling using in vitro and in vivo models of ischemic injury. The impact of this peroxide scavenger on p53- and PARP1-mediated ischemic death is unknown. Methods Neuronal PRX2 overexpression in primary cortical cultures and transgenic mice was combined with the PARP1 inhibitor AG14361. AG14361 was also applied to p53 and Bax knockout cultures and mice and combined with the JNK inhibitor SP600125. DCF fluorescence, AP sites, single-strand breaks, Comet tail-length, NAD+ depletion, and viability were assessed in response to oxygen-glucose deprivation in cultures or transient focal cerebral ischemia in mice. Results PRX2 attenuated ROS, DNA damage, NAD+ depletion, and cell death. PRX2 knockdown exacerbated neuronal death following OGD. PRX2 ameliorated PARP1, p53, Bax, and caspase activation following ischemia. AG14361 reduced ischemic cell death in wild-type and p53 or Bax knockout cultures and animals but had no additional effect in PRX2-overexpressing mice. AG14361 and p53 knockout elicited additive effects with SP600125 on viability in vitro. Our findings support the existence of multiple parallel pro-death pathways with some crosstalk. Conclusions The promising therapeutic candidate PRX2 can clamp upstream DNA damage and efficiently inhibit multiple pro-death cascades operating in both parallel and interactive fashions. PMID:23429506

  11. Galectin-1-secreting neural stem cells elicit long-term neuroprotection against ischemic brain injury

    PubMed Central

    Wang, Jiayin; Xia, Jinchao; Zhang, Feng; Shi, Yejie; Wu, Yun; Pu, Hongjian; Liou, Anthony K. F.; Leak, Rehana K.; Yu, Xinguang; Chen, Ling; Chen, Jun

    2015-01-01

    Galectin-1 (gal-1), a special lectin with high affinity to β-galactosides, is implicated in protection against ischemic brain injury. The present study investigated transplantation of gal-1-secreting neural stem cell (s-NSC) into ischemic brains and identified the mechanisms underlying protection. To accomplish this goal, secretory gal-1 was stably overexpressed in NE-4C neural stem cells. Transient cerebral ischemia was induced in mice by middle cerebral artery occlusion for 60 minutes and s-NSCs were injected into the striatum and cortex within 2 hours post-ischemia. Brain infarct volume and neurological performance were assessed up to 28 days post-ischemia. s-NSC transplantation reduced infarct volume, improved sensorimotor and cognitive functions, and provided more robust neuroprotection than non-engineered NSCs or gal-1-overexpressing (but non-secreting) NSCs. White matter injury was also ameliorated in s-NSC-treated stroke mice. Gal-1 modulated microglial function in vitro, by attenuating secretion of pro-inflammatory cytokines (TNF-α and nitric oxide) in response to LPS stimulation and enhancing production of anti-inflammatory cytokines (IL-10 and TGF-β). Gal-1 also shifted microglia/macrophage polarization toward the beneficial M2 phenotype in vivo by reducing CD16 expression and increasing CD206 expression. In sum, s-NSC transplantation confers robust neuroprotection against cerebral ischemia, probably by alleviating white matter injury and modulating microglial/macrophage function. PMID:25858671

  12. Multi-parametric imaging of cerebral hemodynamic and metabolic response followed by ischemic injury

    NASA Astrophysics Data System (ADS)

    Qin, Jia; Shi, Lei; Dziennis, Suzan; Wang, Ruikang K.

    2014-02-01

    We use rodent parietal cortex as a model system and utilize a synchronized dual wavelength laser speckle imaging (SDW-LSCI) technique to explore the hemodynamic response of infarct and penumbra to a brain injury (middle cerebral artery occlusion (MCAO) model). The SDW-LSCI system is able to take snapshots rapidly (maximum 500 Hz) over the entire brain surface, providing key information about the hemodynamic response, in terms of which it may be used to elucidate evolution of penumbra region from onsite to 90 min of MCAO. Changes in flow are quantified as to the flow experiencing physical occlusions of the MCA normalized to that of baseline. Furthermore, the system is capable of providing information as to the changes of the concentration of oxygenated, (HbO) deoxygenated (Hb), and total hemoglobin (HbT) in the cortex based on the spectral characteristics of HbO and Hb. We observe that the oxygenation variations in the four regions are detectable and distinct. Combining the useful information, four regions of interest (ROI), infarct, penumbra, reduced flow and contralateral portions in the brain upon ischemic injury may be differentiated. Implications of our results are discussed with respect to current understanding of the mechanisms underlying MCAO. We anticipate that SDW-LSCI holds promise for rapid and large field of view localization of ischemic injury.

  13. GSPE Inhibits HMGB1 Release, Attenuating Renal IR-Induced Acute Renal Injury and Chronic Renal Fibrosis

    PubMed Central

    Zhan, Juan; Wang, Kun; Zhang, Conghui; Zhang, Chunxiu; Li, Yueqiang; Zhang, Ying; Chang, Xiaoyan; Zhou, Qiaodan; Yao, Ying; Liu, Yanyan; Xu, Gang

    2016-01-01

    Grape seed proanthocyanindin extract (GSPE) is a polyphenolic bioflavonoid derived from grape seeds and has been widely studied for its potent antioxidant, anti-inflammatory and antitumor activities. HMGB1 is a newly discovered danger-associated molecular pattern (DAMP) that has potent proinflammatory effects once released by necrotic cells. However, the effect of GSPE on the HMGB1, and the relationship of those two with acute kidney injury and chronic kidney fibrosis are unknown. This study aimed to investigate the impact of GSPE on acute kidney injury and chronic fibrosis. C57bl/6 mice were subjected to bilateral ischemia/reperfusion (I/R) and unilateral I/R with or without GSPE administration. After bilateral I/R, mice administered GSPE had a marked improvement in renal function (BUN and Cr), decreased pathological damage and reduced inflammation. In unilateral I/R, mice subjected GSPE showed reduced tubulointerstitial fibrosis and decreased inflammatory reaction. The renoprotection of GSPE on both models was associated with the inhibition of HMGB1 nucleocytoplasmic shuttling and release, which can amplify the inflammation through binding to its downstream receptor TLR4 and facilitated P65 transcription. Thus, we have reason to believe that GSPE could be a good alternative therapy for the prevention and treatment of IR-induced renal injury and fibrosis in clinical practice. PMID:27690015

  14. Eriodictyol-7-O-glucoside activates Nrf2 and protects against cerebral ischemic injury

    SciTech Connect

    Jing, Xu; Ren, Dongmei; Wei, Xinbing; Shi, Huanying; Zhang, Xiumei; Perez, Ruth G.; Lou, Haiyan; Lou, Hongxiang

    2013-12-15

    Stroke is a complex disease that may involve oxidative stress-related pathways in its pathogenesis. The nuclear factor erythroid-2-related factor 2/antioxidant response element (Nrf2/ARE) pathway plays an important role in inducing phase II detoxifying enzymes and antioxidant proteins and thus has been considered a potential target for neuroprotection in stroke. The aim of the present study was to determine whether eriodictyol-7-O-glucoside (E7G), a novel Nrf2 activator, can protect against cerebral ischemic injury and to understand the role of the Nrf2/ARE pathway in neuroprotection. In primary cultured astrocytes, E7G increased the nuclear localization of Nrf2 and induced the expression of the Nrf2/ARE-dependent genes. Exposure of astrocytes to E7G provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insult. The protective effect of E7G was abolished by RNA interference-mediated knockdown of Nrf2 expression. In vivo administration of E7G in a rat model of focal cerebral ischemia significantly reduced the amount of brain damage and ameliorated neurological deficits. These data demonstrate that activation of Nrf2/ARE signaling by E7G is directly associated with its neuroprotection against oxidative stress-induced ischemic injury and suggest that targeting the Nrf2/ARE pathway may be a promising approach for therapeutic intervention in stroke. - Highlights: • E7G activates Nrf2 in astrocytes. • E7G stimulates expression of Nrf2-mediated cytoprotective proteins in astrocytes. • E7G protects astrocytes against OGD-induced cell death and apoptosis. • The neuroprotective effect of E7G involves the Nrf2/ARE pathway. • E7G protects rats against cerebral ischemic injury.

  15. Retinal ischemic injury rescued by sodium 4-phenylbutyrate in a rat model.

    PubMed

    Jeng, Yung-Yue; Lin, Nien-Ting; Chang, Pen-Heng; Huang, Yuan-Ping; Pang, Victor Fei; Liu, Chen-Hsuan; Lin, Chung-Tien

    2007-03-01

    Retinal ischemia is a common cause of visual impairment for humans and animals. Herein, the neuroprotective effects of phenylbutyrate (PBA) upon retinal ischemic injury were investigated using a rat model. Retinal ganglion cells (RGCs) were retrograde labeled with the fluorescent tracer fluorogold (FG) applied to the superior collicoli of test Sprague-Dawley rats. High intraocular pressure and retinal ischemia were induced seven days subsequent to such FG labeling. A dose of either 100 or 400 mg/kg PBA was administered intraperitoneally to test rats at two time points, namely 30 min prior to the induction of retinal ischemia and 1 h subsequent to the cessation of the procedure inducing retinal ischemia. The test-rat retinas were collected seven days subsequent to the induction of retinal ischemia, and densities of surviving RGCs were estimated by counting FG-labeled RGCs within the retina. Histological analysis revealed that ischemic injury caused the loss of retinal RGCs and a net decrease in retinal thickness. For PBA-treated groups, almost 100% of the RGCs were preserved by a pre-ischemia treatment with PBA (at a dose of either 100 or 400 mg/kg), while post-ischemia treatment of RGCs with PBA did not lead to the preservation of RGCs from ischemic injury by PBA as determined by the counting of whole-mount retinas. Pre-ischemia treatment of RGCs with PBA (at a dose of either 100 or 400 mg/kg) significantly reduced the level of ischemia-associated loss of thickness of the total retina, especially the inner retina, and the inner plexiform layer of retina. Besides, PBA treatment significantly reduced the ischemia-induced loss of cells in the ganglion-cell layer of the retina. Taken together, these results suggest that PBA demonstrates a marked neuroprotective effect upon high intraocular pressure-induced retinal ischemia when the PBA is administered prior to ischemia induction. PMID:17178414

  16. Olmesartan restores the protective effect of remote ischemic perconditioning against myocardial ischemia/reperfusion injury in spontaneously hypertensive rats

    PubMed Central

    Lu, Xin; Bi, Yan-Wen; Chen, Ke-Biao

    2015-01-01

    OBJECTIVES: Remote ischemic perconditioning is the newest technique used to lessen ischemia/reperfusion injury. However, its effect in hypertensive animals has not been investigated. This study aimed to examine the effect of remote ischemic perconditioning in spontaneously hypertensive rats and determine whether chronic treatment with Olmesartan could influence the effect of remote ischemic perconditioning. METHODS: Sixty rats were randomly divided into six groups: vehicle-sham, vehicle-ischemia/reperfusion injury, vehicle-remote ischemic perconditioning, olmesartan-sham, olmesartan-ischemia/reperfusion and olmesartan-remote ischemic perconditioning. The left ventricular mass index, creatine kinase concentration, infarct size, arrhythmia scores, HIF–1α mRNA expression, miR-21 expression and miR-210 expression were measured. RESULTS: Olmesartan significantly reduced the left ventricular mass index, decreased the creatine kinase concentration, limited the infarct size and reduced the arrhythmia score. The infarct size, creatine kinase concentration and arrhythmia score during reperfusion were similar for the vehicle-ischemia/reperfusion group and vehicle-remote ischemic perconditioning group. However, these values were significantly decreased in the olmesartan-remote ischemic perconditioning group compared to the olmesartan-ischemia/reperfusion injury group. HIF–1α, miR-21 and miR-210 expression were markedly down-regulated in the Olmesartan-sham group compared to the vehicle-sham group and significantly up-regulated in the olmesartan-remote ischemic perconditioning group compared to the olmesartan-ischemia/reperfusion injury group. CONCLUSION: The results indicate that 1 the protective effect of remote ischemic perconditioning is lost in vehicle-treated rats and that chronic treatment with Olmesartan restores the protective effect of remote ischemic perconditioning; 2 chronic treatment with Olmesartan down-regulates HIF–1α, miR-21 and miR-210 expression and

  17. Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model

    PubMed Central

    Ishida, Tokiko; Kotani, Hirokazu; Miyao, Masashi; Kawai, Chihiro; Jemail, Leila; Abiru, Hitoshi; Tamaki, Keiji

    2016-01-01

    The pathogenesis of renal impairment in chronic liver diseases (CLDs) has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy), autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet–fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the pathophysiological mechanisms

  18. The Transcription Factor Interferon Regulatory Factor 1 Is Expressed after Cerebral Ischemia and Contributes to Ischemic Brain Injury

    PubMed Central

    Iadecola, Costantino; Salkowski, Cindy A.; Zhang, Fangyi; Aber, Tracy; Nagayama, Masao; Vogel, Stefanie N.; Elizabeth Ross, M.

    1999-01-01

    The transcription factor interferon regulatory factor 1 (IRF-1) is involved in the molecular mechanisms of inflammation and apoptosis, processes that contribute to ischemic brain injury. In this study, the induction of IRF-1 in response to cerebral ischemia and its role in ischemic brain injury were investigated. IRF-1 gene expression was markedly upregulated within 12 h of occlusion of the middle cerebral artery in C57BL/6 mice. The expression reached a peak 4 d after ischemia (6.0 ± 1.8-fold; P < 0.001) and was restricted to the ischemic regions of the brain. The volume of ischemic injury was reduced by 23 ± 3% in IRF-1+/− and by 46 ± 9% in IRF-1−/− mice (P < 0.05). The reduction in infarct volume was paralleled by a substantial attenuation in neurological deficits. Thus, IRF-1 is the first nuclear transacting factor demonstrated to contribute directly to cerebral ischemic damage and may be a novel therapeutic target in ischemic stroke. PMID:9989987

  19. Ischemic stroke secondary to aortic dissection following rifle butt recoil chest injury: a case report.

    PubMed

    Rao, Mamatha; Panduranga, Prashanth; Al-Mukhaini, Mohammed; Al-Jufaili, Mahmood; Valiath, John

    2011-11-01

    Ischemic stroke secondary to aortic dissection is not uncommon. We present a patient with left hemiplegia secondary to Stanford type A aortic dissection extending to the supra-aortic vessels, which was precipitated by rifle butt recoil chest injury. The diagnosis of aortic dissection was delayed due to various factors. Finally, the patient underwent successful Bentall procedure with complete resolution of symptoms. This case emphasizes the need for caution in the use of firearms for recreation and to take precautions in preventing such incidents. In addition, this case illustrates the need for prompt cardiovascular physical examination in patients presenting with stroke.

  20. Ischemic Stroke Secondary to Aortic Dissection Following Rifle Butt Recoil Chest Injury: A Case Report

    PubMed Central

    Rao, Mamatha; Panduranga, Prashanth; Al-Mukhaini, Mohammed; Al-Jufaili, Mahmood; Valiath, John

    2011-01-01

    Ischemic stroke secondary to aortic dissection is not uncommon. We present a patient with left hemiplegia secondary to Stanford type A aortic dissection extending to the supra-aortic vessels, which was precipitated by rifle butt recoil chest injury. The diagnosis of aortic dissection was delayed due to various factors. Finally, the patient underwent successful Bentall procedure with complete resolution of symptoms. This case emphasizes the need for caution in the use of firearms for recreation and to take precautions in preventing such incidents. In addition, this case illustrates the need for prompt cardiovascular physical examination in patients presenting with stroke. PMID:22253955

  1. Treatment with polyamine oxidase inhibitor reduces microglial activation and limits vascular injury in ischemic retinopathy.

    PubMed

    Patel, C; Xu, Z; Shosha, E; Xing, J; Lucas, R; Caldwell, R W; Caldwell, R B; Narayanan, S P

    2016-09-01

    Retinal vascular injury is a major cause of vision impairment in ischemic retinopathies. Insults such as hyperoxia, oxidative stress and inflammation contribute to this pathology. Previously, we showed that hyperoxia-induced retinal neurodegeneration is associated with increased polyamine oxidation. Here, we are studying the involvement of polyamine oxidases in hyperoxia-induced injury and death of retinal vascular endothelial cells. New-born C57BL6/J mice were exposed to hyperoxia (70% O2) from postnatal day (P) 7 to 12 and were treated with the polyamine oxidase inhibitor MDL 72527 or vehicle starting at P6. Mice were sacrificed after different durations of hyperoxia and their retinas were analyzed to determine the effects on vascular injury, microglial cell activation, and inflammatory cytokine profiling. The results of this analysis showed that MDL 72527 treatment significantly reduced hyperoxia-induced retinal vascular injury and enhanced vascular sprouting as compared with the vehicle controls. These protective effects were correlated with significant decreases in microglial activation as well as levels of inflammatory cytokines and chemokines. In order to model the effects of polyamine oxidation in causing microglial activation in vitro, studies were performed using rat brain microvascular endothelial cells treated with conditioned-medium from rat retinal microglia stimulated with hydrogen peroxide. Conditioned-medium from activated microglial cultures induced cell stress signals and cell death in microvascular endothelial cells. These studies demonstrate the involvement of polyamine oxidases in hyperoxia-induced retinal vascular injury and retinal inflammation in ischemic retinopathy, through mechanisms involving cross-talk between endothelial cells and resident retinal microglia. PMID:27239699

  2. Treatment with polyamine oxidase inhibitor reduces microglial activation and limits vascular injury in ischemic retinopathy

    PubMed Central

    Patel, C.; Xu, Z.; Shosha, E.; Xing, J.; Lucas, R.; Caldwell, R.W.; Caldwell, R.B.; Narayanan, S.P.

    2016-01-01

    Retinal vascular injury is a major cause of vision impairment in ischemic retinopathies. Insults such as hyperoxia, oxidative stress and inflammation contribute to this pathology. Previously, we showed that hyperoxia-induced retinal neurodegeneration is associated with increased polyamine oxidation. Here, we are studying the involvement of polyamine oxidases in hyperoxia-induced injury and death of retinal vascular endothelial cells. Newborn C57BL6/J mice were exposed to hyperoxia (70% O2) from postnatal day (P) 7 to 12 and were treated with the polyamine oxidase inhibitor MDL 72527 or vehicle starting at P6. Mice were sacrificed after different durations of hyperoxia and their retinas were analyzed to determine the effects on vascular injury, microglial cell activation, and inflammatory cytokine profiling. The results of this analysis showed that MDL 72527 treatment significantly reduced hyperoxia-induced retinal vascular injury and enhanced vascular sprouting as compared with the vehicle controls. These protective effects were correlated with significant decreases in microglial activation as well as levels of inflammatory cytokines and chemokines. In order to model the effects of polyamine oxidation in causing microglial activation in vitro, studies were performed using rat brain microvascular endothelial cells treated with conditioned-medium from rat retinal microglia stimulated with hydrogen peroxide. Conditioned-medium from activated microglial cultures induced cell stress signals and cell death in microvascular endothelial cells. These studies demonstrate the involvement of polyamine oxidases in hyperoxia-induced retinal vascular injury and retinal inflammation in ischemic retinopathy, through mechanisms involving cross-talk between endothelial cells and resident retinal microglia. PMID:27239699

  3. Hypothermia inhibits the propagation of acute ischemic injury by inhibiting HMGB1.

    PubMed

    Lee, Jung Ho; Yoon, Eun Jang; Seo, Jeho; Kavoussi, Adriana; Chung, Yong Eun; Chung, Sung Phil; Park, Incheol; Kim, Chul Hoon; You, Je Sung

    2016-01-01

    Acute ischemic stroke causes significant chronic disability worldwide. We designed this study to clarify the mechanism by which hypothermia helps alleviate acute ischemic stroke. In a middle cerebral artery occlusion model (4 h ischemia without reperfusion), hypothermia effectively reduces mean infarct volume. Hypothermia also prevents neurons in the infarct area from releasing high mobility group box 1 (HMGB1), the most well-studied damage-associated molecular pattern protein. By preventing its release, hypothermia also prevents the typical middle cerebral artery occlusion-induced increase in serum HMGB1. We also found that both glycyrrhizin-mediated inhibition of HMGB1 and intracerebroventricular neutralizing antibody treatments before middle cerebral artery occlusion onset diminish infarct volume. This suggests a clear neuroprotective effect of HMGB1 inhibition by hypothermia in the brain. We next used real-time polymerase chain reaction to measure the levels of pro-inflammatory cytokines in peri-infarct regions. Although middle cerebral artery occlusion increases the expression of interleukin-1β and tissue necrosis factor-α, this elevation is suppressed by both hypothermia and glycyrrhizin treatment. We show that hypothermia reduces the production of inflammatory cytokines and helps salvage peri-infarct regions from the propagation of ischemic injury via HMGB1 blockade. In addition to suggesting a potential mechanism for hypothermia's therapeutic effects, our results suggest HMGB1 modulation may lengthen the therapeutic window for stroke treatments. PMID:27544687

  4. A procyanidin type A trimer from cinnamon extract attenuates glial cell swelling and the reduction in glutamate uptake following ischemic injury in vitro

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dietary polyphenols exert neuroprotective effects in ischemic injury. The protective effects of a procyanidin type A trimer (trimer 1) isolated from a water soluble cinnamon extract (CE) were investigated on key features of ischemic injury including cell swelling, increased free radical production, ...

  5. Unawareness of deficits in ischemic injury: role of the cingulate cortex.

    PubMed

    Palermo, S; Leotta, D; Bongioanni, M R; Amanzio, M

    2014-01-01

    Reduced awareness of illness is a well-known phenomenon that has been studied in patients with vascular disease, but the precise nature of their executive dysfunction is an intriguing question that still has to be resolved. It would be particularly interesting to study patients with reduced awareness of disease possibly related to vascular lesions of the prefrontal cortex. Due to the clinical importance of the case, here we present a patient with a selective right anterior cingulate ischemic injury and impaired awareness of deficits. We suggest that the cingulo-frontal area dysfunction may represent one of the corresponding neurobiological substrates of his persistent unawareness, which has not yet been evaluated in the literature on patients with acquired brain injury (ABI). PMID:23962086

  6. Protection from ischemic heart injury by a vigilant heme oxygenase-1 plasmid system.

    PubMed

    Tang, Yao Liang; Tang, Yi; Zhang, Y Clare; Qian, Keping; Shen, Leping; Phillips, M Ian

    2004-04-01

    Although human heme oxygenase-1 (hHO-1) could provide a useful approach for cellular protection in the ischemic heart, constitutive overexpression of hHO-1 may lead to unwanted side effects. To avoid this, we designed a hypoxia-regulated hHO-1 gene therapy system that can be switched on and off. This vigilant plasmid system is composed of myosin light chain-2v promoter and a gene switch that is based on an oxygen-dependent degradation domain from the hypoxia inducible factor-1-alpha. The vector can sense ischemia and switch on the hHO-1 gene system, specifically in the heart. In an in vivo experiment, the vigilant hHO-1 plasmid or saline was injected intramyocardially into myocardial infarction mice or sham operation mice. After gene transfer, expression of hHO-1 was only detected in the ischemic heart treated with vigilant hHO-1 plasmids. Masson trichrome staining showed significantly fewer fibrotic areas in vigilant hHO-1 plasmids-treated mice compared with saline control (43.0%+/-4.8% versus 62.5%+/-3.3%, P<0.01). The reduction of interstitial fibrosis is accompanied by an increase in myocardial hHO-1 expression in peri-infarct border areas, concomitant with higher Bcl-2 levels and lower Bax, Bak, and caspase 3 levels in the ischemic myocardium compared with saline control. By use of a cardiac catheter, heart from vigilant hHO-1 plasmids-treated mice showed improved recovery of contractile and diastolic performance after myocardial infarction compared with saline control. This study documents the beneficial regulation and therapeutic potential of vigilant plasmid-mediated hHO-1 gene transfer. This novel gene transfer strategy can provide cardiac-specific protection from future repeated bouts of ischemic injury.

  7. Lipopolysaccharide Pretreatment Protects from Renal Ischemia/Reperfusion Injury

    PubMed Central

    Heemann, Uwe; Szabo, Attila; Hamar, Peter; Müller, Veronika; Witzke, Oliver; Lutz, Jens; Philipp, Thomas

    2000-01-01

    In vivo administration of low doses of lipopolysaccharide (LPS) to rodents can protect these animals from subsequently administrated, usually lethal doses of endotoxin or LPS. In this study we tested the effects of LPS pretreatment on ischemia/reperfusion injury in the kidney. Male C57/B1 mice were pretreated with different doses of LPS or phosphate-buffered saline on days −4 and −3. The right kidney was removed, and the vessels of the left kidney were clamped for 30 or 45 minutes on day 0. Creatinine levels and survival of animals were monitored. To test the involvement of cytokines, additional animals were harvested before (“time 0”) and 15 minutes, 1, 2, 8, and 16 hours after reperfusion for histology, immunohistochemistry, terminal deoxynucleotidyltransferase-mediated UTP end-labeling assay, and reverse transcriptase-polymerase chain reaction analysis (including tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, inducible nitric oxide synthase (iNOS), and interferon (IFN)-γ messenger RNA (mRNA)). In controls, renal ischemia of 30 minutes was nonlethal, whereas 73% of the animals died within 48 ± 18 hours, after 45 minutes of ischemia. All different doses of LPS protected the animals from lethal renal ischemia/reperfusion injury. Starting at similar levels, serum creatinine increased significantly in controls but not in LPS-pretreated animals over time. As early as 2 hours after reperfusion, tubular cell damage was significantly more pronounced in controls than in LPS-treated mice. In controls, tubules deteriorated progressively until 8 hours of reperfusion. At this time, more than 50% of tubular cells were destroyed. This destruction was accompanied by a pronounced leukocytic infiltration, predominantly by macrophages. In contrast, LPS pretreatment prevented the destruction of kidney tissue and infiltration by leukocytes. The terminal deoxynucleotidyltransferase-mediated UTP end-labeling assay revealed significantly more apoptotic cells in

  8. The effect of Euryale ferox (Makhana), an herb of aquatic origin, on myocardial ischemic reperfusion injury.

    PubMed

    Das, Samarjit; Der, Peter; Raychaudhuri, Utpal; Maulik, Nilanjana; Das, Dipak K

    2006-09-01

    Fox nut or gorgon nut (Euryale ferox--Family Nymphaeaceae), popularly known as Makhana, has been widely used in traditional oriental medicine to cure a variety of diseases including kidney problems, chronic diarrhea, excessive leucorrhea and hypofunction of the spleen. Based on the recent studies revealing antioxidant activities of Euryale ferox and its glucosides composition, we sought to determine if Euryale ferox seeds (Makhana) could reduce myocardial ischemic reperfusion injury. Two different models were used: acute model, where isolated rat hearts were preperfused for 15 min with Krebs Henseleit bicarbonate (KHB) buffer containing three different doses of makhana (25, 125 or 250 microg/ml) followed by 30 min of ischemia and 2 h of reperfusion; and chronic model, where rats were given two different doses of makhana (250 and 500 mg/kg/day) for 21 days, after which isolated hearts were subjected to 30 min of ischemia followed by 2 h of reperfusion. In both cases, the hearts of the Makhana treated rats were resistant to ischemic reperfusion injury as evidenced by their improved post-ischemic ventricular function and reduced myocardial infarct size. Antibody array technique was used to identify the cardioprotective proteins. The Makhana-treated hearts had increased amounts of thioredoxin-1 (Trx-1) and thioredoxin-related protein-32 (TRP32) compared to the control hearts. Western blot analysis confirmed increased expression of TRP32 and thioredoxin proteins. In vitro studies revealed that Makhana extracts had potent reactive oxygen species scavenging activities. Taken together, the results of this study demonstrate cardioprotective properties of Makhana and suggest that such cardioprotective properties may be linked with the ability of makhana to induce TRP32 and Trx-1 proteins and to scavenge ROS.

  9. Sex-dependent effects of chronic psychosocial stress on myocardial sensitivity to ischemic injury.

    PubMed

    Rorabaugh, Boyd R; Krivenko, Anna; Eisenmann, Eric D; Bui, Albert D; Seeley, Sarah; Fry, Megan E; Lawson, Joseph D; Stoner, Lauren E; Johnson, Brandon L; Zoladz, Phillip R

    2015-01-01

    Individuals with post-traumatic stress disorder (PTSD) experience many debilitating symptoms, including intrusive memories, persistent anxiety and avoidance of trauma-related cues. PTSD also results in numerous physiological complications, including increased risk for cardiovascular disease (CVD). However, characterization of PTSD-induced cardiovascular alterations is lacking, especially in preclinical models of the disorder. Thus, we examined the impact of a psychosocial predator-based animal model of PTSD on myocardial sensitivity to ischemic injury. Male and female Sprague-Dawley rats were exposed to psychosocial stress or control conditions for 31 days. Stressed rats were given two cat exposures, separated by a period of 10 days, and were subjected to daily social instability throughout the paradigm. Control rats were handled daily for the duration of the experiment. Rats were tested on the elevated plus maze (EPM) on day 32, and hearts were isolated on day 33 and subjected to 20 min ischemia and 2 h reperfusion on a Langendorff isolated heart system. Stressed male and female rats gained less body weight relative to controls, but only stressed males exhibited increased anxiety on the EPM. Male, but not female, rats exposed to psychosocial stress exhibited significantly larger infarcts and attenuated post-ischemic recovery of contractile function compared to controls. Our data demonstrate that predator stress combined with daily social instability sex-dependently increases myocardial sensitivity to ischemic injury. Thus, this manipulation may be useful for studying potential mechanisms underlying cardiovascular alterations in PTSD, as well as sex differences in the cardiovascular stress response. PMID:26458179

  10. Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury

    PubMed Central

    Zhang, Xiangnan; Yuan, Yang; Jiang, Lei; Zhang, Jingying; Gao, Jieqiong; Shen, Zhe; Zheng, Yanrong; Deng, Tian; Yan, Haijing; Li, Wenlu; Hou, Wei-Wei; Lu, Jianxin; Shen, Yao; Dai, Haibing; Hu, Wei-Wei; Zhang, Zhuohua; Chen, Zhong

    2014-01-01

    Transient cerebral ischemia leads to endoplasmic reticulum (ER) stress. However, the contributions of ER stress to cerebral ischemia are not clear. To address this issue, the ER stress activators tunicamycin (TM) and thapsigargin (TG) were administered to transient middle cerebral artery occluded (tMCAO) mice and oxygen-glucose deprivation-reperfusion (OGD-Rep.)-treated neurons. Both TM and TG showed significant protection against ischemia-induced brain injury, as revealed by reduced brain infarct volume and increased glucose uptake rate in ischemic tissue. In OGD-Rep.-treated neurons, 4-PBA, the ER stress releasing mechanism, counteracted the neuronal protection of TM and TG, which also supports a protective role of ER stress in transient brain ischemia. Knocking down the ER stress sensor Eif2s1, which is further activated by TM and TG, reduced the OGD-Rep.-induced neuronal cell death. In addition, both TM and TG prevented PARK2 loss, promoted its recruitment to mitochondria, and activated mitophagy during reperfusion after ischemia. The neuroprotection of TM and TG was reversed by autophagy inhibition (3-methyladenine and Atg7 knockdown) as well as Park2 silencing. The neuroprotection was also diminished in Park2+/− mice. Moreover, Eif2s1 and downstream Atf4 silencing reduced PARK2 expression, impaired mitophagy induction, and counteracted the neuroprotection. Taken together, the present investigation demonstrates that the ER stress induced by TM and TG protects against the transient ischemic brain injury. The PARK2-mediated mitophagy may be underlying the protection of ER stress. These findings may provide a new strategy to rescue ischemic brains by inducing mitophagy through ER stress activation. PMID:25126734

  11. Sex-dependent effects of chronic psychosocial stress on myocardial sensitivity to ischemic injury.

    PubMed

    Rorabaugh, Boyd R; Krivenko, Anna; Eisenmann, Eric D; Bui, Albert D; Seeley, Sarah; Fry, Megan E; Lawson, Joseph D; Stoner, Lauren E; Johnson, Brandon L; Zoladz, Phillip R

    2015-01-01

    Individuals with post-traumatic stress disorder (PTSD) experience many debilitating symptoms, including intrusive memories, persistent anxiety and avoidance of trauma-related cues. PTSD also results in numerous physiological complications, including increased risk for cardiovascular disease (CVD). However, characterization of PTSD-induced cardiovascular alterations is lacking, especially in preclinical models of the disorder. Thus, we examined the impact of a psychosocial predator-based animal model of PTSD on myocardial sensitivity to ischemic injury. Male and female Sprague-Dawley rats were exposed to psychosocial stress or control conditions for 31 days. Stressed rats were given two cat exposures, separated by a period of 10 days, and were subjected to daily social instability throughout the paradigm. Control rats were handled daily for the duration of the experiment. Rats were tested on the elevated plus maze (EPM) on day 32, and hearts were isolated on day 33 and subjected to 20 min ischemia and 2 h reperfusion on a Langendorff isolated heart system. Stressed male and female rats gained less body weight relative to controls, but only stressed males exhibited increased anxiety on the EPM. Male, but not female, rats exposed to psychosocial stress exhibited significantly larger infarcts and attenuated post-ischemic recovery of contractile function compared to controls. Our data demonstrate that predator stress combined with daily social instability sex-dependently increases myocardial sensitivity to ischemic injury. Thus, this manipulation may be useful for studying potential mechanisms underlying cardiovascular alterations in PTSD, as well as sex differences in the cardiovascular stress response.

  12. Ischemic post-conditioning to counteract intestinal ischemia/reperfusion injury

    PubMed Central

    Guan, Yan-Fang; Pritts, Timothy A; Montrose, Marshall H

    2010-01-01

    Intestinal ischemia is a severe disorder with a variety of causes. Reperfusion is a common occurrence during treatment of acute intestinal ischemia but the injury resulting from ischemia/reperfusion (IR) may lead to even more serious complications from intestinal atrophy to multiple organ failure and death. The susceptibility of the intestine to IR-induced injury (IRI) appears from various experimental studies and clinical settings such as cardiac and major vascular surgery and organ transplantation. Whereas oxygen free radicals, activation of leukocytes, failure of microvascular perfusion, cellular acidosis and disturbance of intracellular homeostasis have been implicated as important factors in the pathogenesis of intestinal IRI, the mechanisms underlying this disorder are not well known. To date, increasing attention is being paid in animal studies to potential pre- and post-ischemia treatments that protect against intestinal IRI such as drug interference with IR-induced apoptosis and inflammation processes and ischemic pre-conditioning. However, better insight is needed into the molecular and cellular events associated with reperfusion-induced damage to develop effective clinical protection protocols to combat this disorder. In this respect, the use of ischemic post-conditioning in combination with experimentally prolonged acidosis blocking deleterious reperfusion actions may turn out to have particular clinical relevance. PMID:21607154

  13. Resveratrol attenuates peripheral and brain inflammation and reduces ischemic brain injury in aged female mice.

    PubMed

    Jeong, Sae Im; Shin, Jin A; Cho, Sunghee; Kim, Hye Won; Lee, Ji Yoon; Kang, Jihee Lee; Park, Eun-Mi

    2016-08-01

    Resveratrol is known to improve metabolic dysfunction associated with obesity. Visceral obesity is a sign of aging and is considered a risk factor for ischemic stroke. In this study, we investigated the effects of resveratrol on inflammation in visceral adipose tissue and the brain and its effects on ischemic brain injury in aged female mice. Mice treated with resveratrol (0.1 mg/kg, p.o.) for 10 days showed reduced levels of interleukin-1β and tumor necrosis factor-α, as well as a reduction in the size of adipocytes in visceral adipose tissue. Resveratrol also reduced interleukin-1β and tumor necrosis factor-α protein levels and immunoglobulin G extravasation in the brain. Mice treated with resveratrol demonstrated smaller infarct size, improved neurological function, and blunted peripheral inflammation at 3 days postischemic stroke. These results showed that resveratrol counteracted inflammation in visceral adipose tissue and in the brain and reduced stroke-induced brain injury and peripheral inflammation in aged female mice. Therefore, resveratrol administration can be a valuable strategy for the prevention of age-associated and disease-provoked inflammation in postmenopausal women.

  14. ATTENUATION OF ISCHEMIC LIVER INJURY BY AUGMENTATION OF ENDOGENOUS ADENOSINE1,2

    PubMed Central

    Todo, Satoru; Zhu, Yue; Zhang, Shimin; Jin, Maeng Bong; Ishizaki, Naoki; Tanaka, Hiromu; Subbotin, Vladimir; Starzl, Thomas E.

    2010-01-01

    Hepatic grafts from non-heartbeating donors may alleviate the organ shortage, but they inherently suffer from warm ischemia. In the present study, we tested our hypothesis that augmentation of endogenous adenosine by inhibition of nucleoside transport with R75231 attenuates ischemic liver injury. Adult female beagle dogs underwent 2-hr hepatic vascular exclusion with venovenous bypass. R75231 was given to the animals by continuous intravenous infusion for 30 min before ischemia at a dose of 0.1 mg/kg (Group 2, n=6), 0.05 mg/kg (Group 3, n=6), or 0.025 mg/kg (Group 4, n=6). Nontreated animals were used as the control (Group 1, n=10). Animal survival, hepatic tissue blood flow, liver function, and histopathology were analyzed. Two-week animal survival was 30% in Group 1, 88% in Group 2, 100% in Group 3, and 100% in Group 4. Postreperfusion hepatic tissue blood flow was markedly improved by the treatment. Treatment significantly attenuated liver enzyme release, lipid peroxidation, and changes in adenine nucleotides and purine catabolites. Structural abnormality of the liver after reperfusion was markedly improved by R75231 treatment, showing better architecture and less neutrophil infiltration. Preischemic administration of a nucleoside transport inhibitor ameliorated ischemic liver injury due to the positive effects of augmented endogenous adenosine, and is applicable clinically when the liver is procured from a controlled non-heartbeating donor. PMID:9020320

  15. CITED4 induces physiologic hypertrophy and promotes functional recovery after ischemic injury

    PubMed Central

    Bezzerides, Vassilios J.; Platt, Colin; Paruchuri, Kaavya; Oh, Nul Loren; Xiao, Chunyang; Cao, Yunshan; Mann, Nina; Spiegelman, Bruce M.

    2016-01-01

    The mechanisms by which exercise mediates its multiple cardiac benefits are only partly understood. Prior comprehensive analyses of the cardiac transcriptional components and microRNAs dynamically regulated by exercise suggest that the CBP/p300-interacting protein CITED4 is a downstream effector in both networks. While CITED4 has documented functional consequences in neonatal cardiomyocytes in vitro, nothing is known about its effects in the adult heart. To investigate the impact of cardiac CITED4 expression in adult animals, we generated transgenic mice with regulated, cardiomyocyte-specific CITED4 expression. Cardiac CITED4 expression in adult mice was sufficient to induce an increase in heart weight and cardiomyocyte size with normal systolic function, similar to the effects of endurance exercise training. After ischemia-reperfusion, CITED4 expression did not change initial infarct size but mediated substantial functional recovery while reducing ventricular dilation and fibrosis. Forced cardiac expression of CITED4 also induced robust activation of the mTORC1 pathway after ischemic injury. Moreover, pharmacological inhibition of mTORC1 abrogated CITED4’s effects in vitro and in vivo. Together, these data establish CITED4 as a regulator of mTOR signaling that is sufficient to induce physiologic hypertrophy at baseline and mitigate adverse ventricular remodeling after ischemic injury. PMID:27430023

  16. Mixed Organic Solvents Induce Renal Injury in Rats

    PubMed Central

    Qin, Weisong; Xu, Zhongxiu; Lu, Yizhou; Zeng, Caihong; Zheng, Chunxia; Wang, Shengyu; Liu, Zhihong

    2012-01-01

    To investigate the injury effects of organic solvents on kidney, an animal model of Sprague-Dawley (SD) rats treated with mixed organic solvents via inhalation was generated and characterized. The mixed organic solvents consisted of gasoline, dimethylbenzene and formaldehyde (GDF) in the ratio of 2∶2:1, and were used at 12,000 PPM to treat the rats twice a day, each for 3 hours. Proteinuria appeared in the rats after exposure for 5–6 weeks. The incidences of proteinuria in male and female rats after exposure for 12 weeks were 43.8% (7/16) and 25% (4/16), respectively. Urinary N-Acetyl-β-(D)-Glucosaminidase (NAG) activity was increased significantly after exposure for 4 weeks. Histological examination revealed remarkable injuries in the proximal renal tubules, including tubular epithelial cell detachment, cloud swelling and vacuole formation in the proximal tubular cells, as well as proliferation of parietal epithelium and tubular reflux in glomeruli. Ultrastructural examination found that brush border and cytoplasm of tubular epithelial cell were dropped, that tubular epithelial cells were partially disintegrated, and that the mitochondria of tubular epithelial cells were degenerated and lost. In addition to tubular lesions, glomerular damages were also observed, including segmental foot process fusion and loss of foot process covering on glomerular basement membrane (GBM). Immunofluorescence staining indicated that the expression of nephrin and podocin were both decreased after exposure of GDF. In contrast, increased expression of desmin, a marker of podocyte injury, was found in some areas of a glomerulus. TUNEL staining showed that GDF induced apoptosis in tubular cells and glomerular cells. These studies demonstrate that GDF can induce both severe proximal tubular damage and podocyte injury in rats, and the tubular lesions appear earlier than that of glomeruli. PMID:23029287

  17. Remote Ischemic Preconditioning Reduces Perioperative Cardiac and Renal Events in Patients Undergoing Elective Coronary Intervention: A Meta-Analysis of 11 Randomized Trials

    PubMed Central

    Pei, Hanjun; Wu, Yongjian; Wei, Yingjie; Yang, Yuejin; Teng, Siyong; Zhang, Haitao

    2014-01-01

    Background Results from randomized controlled trials (RCT) concerning cardiac and renal effect of remote ischemic preconditioning(RIPC) in patients with stable coronary artery disease(CAD) are inconsistent. The aim of this study was to explore whether RIPC reduce cardiac and renal events after elective percutaneous coronary intervention (PCI). Methods and Results RCTs with data on cardiac or renal effect of RIPC in PCI were searched from Pubmed, EMBase, and Cochrane library (up to July 2014). Meta-regression and subgroup analysis were performed to identify the potential sources of significant heterogeneity(I2≥40%). Eleven RCTs enrolling a total of 1713 study subjects with stable CAD were selected. Compared with controls, RIPC significantly reduced perioperative incidence of myocardial infarction (MI) [odds ratio(OR)  = 0.68; 95% CI, 0.51 to 0.91; P = 0.01; I2 = 41.0%] and contrast-induced acute kidney injury(AKI) (OR = 0.61; 95% CI, 0.38 to 0.98; P = 0.04; I2 = 39.0%). Meta-regression and subgroup analyses confirmed that the major source of heterogeneity for the incidence of MI was male proportion (coefficient  = −0.049; P = 0.047; adjusted R2 = 0.988; P = 0.02 for subgroup difference). Conclusions The present meta-analysis of RCTs suggests that RIPC may offer cardiorenal protection by reducing the incidence of MI and AKI in patients undergoing elective PCI. Moreover, this effect on MI is more pronounced in male subjects. Future high-quality, large-scale clinical trials should focus on the long-term clinical effect of RIPC. PMID:25551671

  18. Astragaloside IV ameliorates renal injury in db/db mice

    PubMed Central

    Sun, Huili; Wang, Wenjing; Han, Pengxun; Shao, Mumin; Song, Gaofeng; Du, Heng; Yi, Tiegang; Li, Shunmin

    2016-01-01

    Diabetic nephropathy is a lethal complication of diabetes mellitus and a major type of chronic kidney disease. Dysregulation of the Akt pathway and its downstream cascades, including mTOR, NFκB, and Erk1/2, play a critical role in the development of diabetic nephropathy. Astragaloside IV is a major component of Huangqi and exerts renal protection in a mouse model of type 1 diabetes. The current study was undertaken to investigate the protective effects of diet supplementation of AS-IV on renal injury in db/db mice, a type 2 diabetic mouse model. Results showed that administration of AS-IV reduced albuminuria, ameliorated changes in the glomerular and tubular pathology, and decreased urinary NAG, NGAL, and TGF-β1 in db/db mice. AS-IV also attenuated the diabetes-related activation of Akt/mTOR, NFκB, and Erk1/2 signaling pathways without causing any detectable hepatotoxicity. Collectively, these findings showed AS-IV to be beneficial to type 2 diabetic nephropathy, which might be associated with the inhibition of Akt/mTOR, NFκB and Erk1/2 signaling pathways. PMID:27585918

  19. Tanshinone IIA pretreatment attenuates ischemia/reperfusion-induced renal injury

    PubMed Central

    Xu, Yan-Mei; Ding, Guo-Hua; Huang, Jie; Xiong, Yan

    2016-01-01

    Tanshinone IIA is a chemical compound extracted from the root of traditional Chinese herb Salvia miltiorrhiza Bunge. Tanshinone IIA has been suggested to possess anti-inflammatory activity and antioxidizing capability. Recently, accumulating results have indicated the antitumor activity of tanshinone IIA; thus, it has attracted increasing attention. In addition, tanshinone IIA has been indicated to attenuate ischemia/reperfusion induced renal injury (I/RIRI); however, little is known regarding the underlying mechanisms involved in this process. In the present study an I/RIRI rat model was used to analyze the effects of tanshinone IIA on myeloperoxidase (MPO), TNF-α and IL-6 activities using ELISA kits. Furthermore, macrophage migration inhibitory factor (MIF), cleaved caspase-3, B-cell lymphoma 2 (Bcl-2) and p38 mitogen-activated protein kinase (MAPK) protein expression levels were evaluated using western blot analysis. The results indicated that tanshinone IIA protected renal function in I/RIRI rats. ELISA demonstrated that tanshinone IIA significantly reduced MIF, TNF-α and IL-6 activities in I/RIRI rats. Western blot analysis showed that tanshinone IIA significantly suppressed MIF, cleaved caspase-3 and p38 MAPK protein expression levels in I/RIRI rats. The present results suggest that tanshinone IIA pretreatment attenuates I/RIRI via the downregulation of MPO expression, inflammation, MIF, cleaved caspase-3 and p38 MAPK. PMID:27698779

  20. Astragaloside IV ameliorates renal injury in db/db mice

    NASA Astrophysics Data System (ADS)

    Sun, Huili; Wang, Wenjing; Han, Pengxun; Shao, Mumin; Song, Gaofeng; Du, Heng; Yi, Tiegang; Li, Shunmin

    2016-09-01

    Diabetic nephropathy is a lethal complication of diabetes mellitus and a major type of chronic kidney disease. Dysregulation of the Akt pathway and its downstream cascades, including mTOR, NFκB, and Erk1/2, play a critical role in the development of diabetic nephropathy. Astragaloside IV is a major component of Huangqi and exerts renal protection in a mouse model of type 1 diabetes. The current study was undertaken to investigate the protective effects of diet supplementation of AS-IV on renal injury in db/db mice, a type 2 diabetic mouse model. Results showed that administration of AS-IV reduced albuminuria, ameliorated changes in the glomerular and tubular pathology, and decreased urinary NAG, NGAL, and TGF-β1 in db/db mice. AS-IV also attenuated the diabetes-related activation of Akt/mTOR, NFκB, and Erk1/2 signaling pathways without causing any detectable hepatotoxicity. Collectively, these findings showed AS-IV to be beneficial to type 2 diabetic nephropathy, which might be associated with the inhibition of Akt/mTOR, NFκB and Erk1/2 signaling pathways.

  1. Tanshinone IIA pretreatment attenuates ischemia/reperfusion-induced renal injury

    PubMed Central

    Xu, Yan-Mei; Ding, Guo-Hua; Huang, Jie; Xiong, Yan

    2016-01-01

    Tanshinone IIA is a chemical compound extracted from the root of traditional Chinese herb Salvia miltiorrhiza Bunge. Tanshinone IIA has been suggested to possess anti-inflammatory activity and antioxidizing capability. Recently, accumulating results have indicated the antitumor activity of tanshinone IIA; thus, it has attracted increasing attention. In addition, tanshinone IIA has been indicated to attenuate ischemia/reperfusion induced renal injury (I/RIRI); however, little is known regarding the underlying mechanisms involved in this process. In the present study an I/RIRI rat model was used to analyze the effects of tanshinone IIA on myeloperoxidase (MPO), TNF-α and IL-6 activities using ELISA kits. Furthermore, macrophage migration inhibitory factor (MIF), cleaved caspase-3, B-cell lymphoma 2 (Bcl-2) and p38 mitogen-activated protein kinase (MAPK) protein expression levels were evaluated using western blot analysis. The results indicated that tanshinone IIA protected renal function in I/RIRI rats. ELISA demonstrated that tanshinone IIA significantly reduced MIF, TNF-α and IL-6 activities in I/RIRI rats. Western blot analysis showed that tanshinone IIA significantly suppressed MIF, cleaved caspase-3 and p38 MAPK protein expression levels in I/RIRI rats. The present results suggest that tanshinone IIA pretreatment attenuates I/RIRI via the downregulation of MPO expression, inflammation, MIF, cleaved caspase-3 and p38 MAPK.

  2. Astragaloside IV ameliorates renal injury in db/db mice.

    PubMed

    Sun, Huili; Wang, Wenjing; Han, Pengxun; Shao, Mumin; Song, Gaofeng; Du, Heng; Yi, Tiegang; Li, Shunmin

    2016-01-01

    Diabetic nephropathy is a lethal complication of diabetes mellitus and a major type of chronic kidney disease. Dysregulation of the Akt pathway and its downstream cascades, including mTOR, NFκB, and Erk1/2, play a critical role in the development of diabetic nephropathy. Astragaloside IV is a major component of Huangqi and exerts renal protection in a mouse model of type 1 diabetes. The current study was undertaken to investigate the protective effects of diet supplementation of AS-IV on renal injury in db/db mice, a type 2 diabetic mouse model. Results showed that administration of AS-IV reduced albuminuria, ameliorated changes in the glomerular and tubular pathology, and decreased urinary NAG, NGAL, and TGF-β1 in db/db mice. AS-IV also attenuated the diabetes-related activation of Akt/mTOR, NFκB, and Erk1/2 signaling pathways without causing any detectable hepatotoxicity. Collectively, these findings showed AS-IV to be beneficial to type 2 diabetic nephropathy, which might be associated with the inhibition of Akt/mTOR, NFκB and Erk1/2 signaling pathways. PMID:27585918

  3. Simvastatin Reduces Lipopolysaccharides-Accelerated Cerebral Ischemic Injury via Inhibition of Nuclear Factor-kappa B Activity

    PubMed Central

    Anthony Jalin, Angela M. A.; Lee, Jae-Chul; Cho, Geum-Sil; Kim, Chunsook; Ju, Chung; Pahk, Kisoo; Song, Hwa Young; Kim, Won-Ki

    2015-01-01

    Preceding infection or inflammation such as bacterial meningitis has been associated with poor outcomes after stroke. Previously, we reported that intracorpus callosum microinjection of lipopolysaccharides (LPS) strongly accelerated the ischemia/reperfusion-evoked brain tissue damage via recruiting inflammatory cells into the ischemic lesion. Simvastatin, 3-hydroxy-3-methylgultaryl (HMG)-CoA reductase inhibitor, has been shown to reduce inflammatory responses in vascular diseases. Thus, we investigated whether simvastatin could reduce the LPS-accelerated ischemic injury. Simvastatin (20 mg/kg) was orally administered to rats prior to cerebral ischemic insults (4 times at 72, 48, 25, and 1-h pre-ischemia). LPS was microinjected into rat corpus callosum 1 day before the ischemic injury. Treatment of simvastatin reduced the LPS-accelerated infarct size by 73%, and decreased the ischemia/reperfusion-induced expressions of pro-inflammatory mediators such as iNOS, COX-2 and IL-1β in LPS-injected rat brains. However, simvastatin did not reduce the infiltration of microglial/macrophageal cells into the LPS-pretreated brain lesion. In vitro migration assay also showed that simvastatin did not inhibit the monocyte chemoattractant protein-1-evoked migration of microglial/macrophageal cells. Instead, simvastatin inhibited the nuclear translocation of NF-κB, a key signaling event in expressions of various proinflammatory mediators, by decreasing the degradation of IκB. The present results indicate that simvastatin may be beneficial particularly to the accelerated cerebral ischemic injury under inflammatory or infectious conditions. PMID:26535078

  4. Proton-sensitive cation channels and ion exchangers in ischemic brain injury: new therapeutic targets for stroke?

    PubMed Central

    Leng, Tiandong; Shi, Yejie; Xiong, Zhi-Gang; Sun, Dandan

    2014-01-01

    Ischemic brain injury results from complicated cellular mechanisms. The present therapy for acute ischemic stroke is limited to thrombolysis with the recombinant tissue plasminogen activator (rtPA) and mechanical recanalization. Therefore, a better understanding of ischemic brain injury is needed for the development of more effective therapies. Disruption of ionic homeostasis plays an important role in cell death following cerebral ischemia. Glutamate receptor-mediated ionic imbalance and neurotoxicity have been well established in cerebral ischemia after stroke. However, non-NMDA receptor-dependent mechanisms, involving acid-sensing ion channel 1a (ASIC1a), transient receptor potential melastatin 7 (TRPM7), and Na+/H+ exchanger isoform 1 (NHE1), have recently emerged as important players in the dysregulation of ionic homeostasis in the CNS under ischemic conditions. These H+-sensitive channels and/or exchangers are expressed in the majority of cell types of the neurovascular unit. Sustained activation of these proteins causes excessive influx of cations, such as Ca2+, Na+, and Zn2+, and leads to ischemic reperfusion brain injury. In this review, we summarize recent pre-clinical experimental research findings on how these channels/exchangers are regulated in both in vitro and in vivo models of cerebral ischemia. The blockade or transgenic knockdown of these proteins was shown to be neuroprotective in these ischemia models. Taken together, these non-NMDA receptor-dependent mechanisms may serve as novel therapeutic targets for stroke intervention. PMID:24467911

  5. Ischemic Preconditioning Protects against Spinal Cord Ischemia-Reperfusion Injury in Rabbits by Attenuating Blood Spinal Cord Barrier Disruption

    PubMed Central

    Fang, Bo; Li, Xiao-Man; Sun, Xi-Jia; Bao, Na-Ren; Ren, Xiao-Yan; Lv, Huang-Wei; Ma, Hong

    2013-01-01

    Ischemic preconditioning has been reported to protect against spinal cord ischemia-reperfusion (I-R) injury, but the underlying mechanisms are not fully understood. To investigate this, Japanese white rabbits underwent I-R (30 min aortic occlusion followed by reperfusion), ischemic preconditioning (three cycles of 5 min aortic occlusion plus 5 min reperfusion) followed by I-R, or sham surgery. At 4 and 24 h following reperfusion, neurological function was assessed using Tarlov scores, blood spinal cord barrier permeability was measured by Evan’s Blue extravasation, spinal cord edema was evaluated using the wet-dry method, and spinal cord expression of zonula occluden-1 (ZO-1), matrix metalloproteinase-9 (MMP-9), and tumor necrosis factor-α (TNF-α) were measured by Western blot and a real-time polymerase chain reaction. ZO-1 was also assessed using immunofluorescence. Spinal cord I-R injury reduced neurologic scores, and ischemic preconditioning treatment ameliorated this effect. Ischemic preconditioning inhibited I-R-induced increases in blood spinal cord barrier permeability and water content, increased ZO-1 mRNA and protein expression, and reduced MMP-9 and TNF-α mRNA and protein expression. These findings suggest that ischemic preconditioning attenuates the increase in blood spinal cord barrier permeability due to spinal cord I-R injury by preservation of tight junction protein ZO-1 and reducing MMP-9 and TNF-α expression. PMID:23685868

  6. Prediction of acute renal failure following soft-tissue injury using the venous bicarbonate concentration.

    PubMed

    Muckart, D J; Moodley, M; Naidu, A G; Reddy, A D; Meineke, K R

    1992-12-01

    Sixty-four patients with soft-tissue injuries were studied prospectively to determine whether an initial venous bicarbonate concentration (VBC) of less than 17 mmol/L would predict the development of myoglobin-induced acute renal failure. The VBC was > 17 mmol/L in 59 patients, seven of whom had myoglobinuria. All recovered without renal complications. The remaining five patients all had VBC < 17 mmol/L and four had myoglobinuria. Acute renal failure developed in four patients (p < 0.001). The VBC on hospital arrival was the most accurate predictor of these patients' risk for the development of acute renal failure following soft-tissue injury. PMID:1474620

  7. Preconditioning: can nature's shield be raised against surgical ischemic-reperfusion injury?

    PubMed

    Perrault, L P; Menasché, P

    1999-11-01

    Endogenous myocardial protection refers to the natural defense mechanisms available to the heart to withstand an ischemic injury. So far, these mechanisms have been shown to encompass two phenomena most likely interrelated: ischemic preconditioning and stress protein synthesis. Ischemic preconditioning can be defined as the adaptive mechanism induced by a brief period of reversible ischemia increasing the heart's resistance to a subsequent longer period of ischemia. The therapeutic exploitation of these natural adaptive mechanisms in cardiac surgery is an appealing prospect, as preconditioning could be used before aortic cross-clamping to enhance the current methods of myocardial protection. Two major conclusions emerge from the bulk of experimental data on preconditioning: First, the adaptive phenomenon reduces infarct size after regional ischemia in animal preparations across a wide variety of species but its effects on arrhythmias and on preservation of function after global ischemia are less consistent. This is relevant to cardiac surgery where postbypass pump failure is more often due to stunning than to discrete necrosis. Second, regardless of the various components of the intracellular signaling pathway elicited by the preconditioning stimulus, it seems that the major mechanisms by which this pathway leads to a cardioprotective effect are a slowing of adenosine triphosphate depletion and a limitation of acidosis during the protracted period of ischemia. If the latter is true, then it can reasonably be predicted that these energy-sparing and acidosis-limiting effects may become redundant to those of cardioplegia. From these observations, it can be inferred that preconditioning may find an elective indication in situations where the potential for suboptimal protection increases the risk of necrosis (extensive coronary artery disease, severe left ventricular hypertrophy, long ischemic time, and beating heart operations where occlusion of the target vessels

  8. Hypothermia modulates cytokine responses after neonatal rat hypoxic-ischemic injury and reduces brain damage.

    PubMed

    Yuan, Xiangpeng; Ghosh, Nirmalya; McFadden, Brian; Tone, Beatriz; Bellinger, Denise L; Obenaus, Andre; Ashwal, Stephen

    2014-01-01

    While hypothermia (HT) is the standard-of-care for neonates with hypoxic ischemic injury (HII), the mechanisms underlying its neuroprotective effect are poorly understood. We examined ischemic core/penumbra and cytokine/chemokine evolution in a 10-day-old rat pup model of HII. Pups were treated for 24 hr after HII with HT (32℃; n = 18) or normothermia (NT, 35℃; n = 15). Outcomes included magnetic resonance imaging (MRI), neurobehavioral testing, and brain cytokine/chemokine profiling (0, 24, 48, and 72 hr post-HII). Lesion volumes (24 hr) were reduced in HT pups (total 74%, p < .05; penumbra 68%, p < .05; core 85%, p = .19). Lesion volumes rebounded at 72 hr (48 hr post-HT) with no significant differences between NT and HT pups. HT reduced interleukin-1β (IL-1β) at all time points (p < .05); monocyte chemoattractant protein-1 (MCP-1) trended toward being decreased in HT pups (p = .09). The stem cell signaling molecule, stromal cell-derived factor-1 (SDF-1) was not altered by HT. Our data demonstrate that HT reduces total and penumbral lesion volumes (at 24 and 48 hr), potentially by decreasing IL-1β without affecting SDF-1. Disassociation between the increasing trend in HII volumes from 48 to 72 hr post-HII when IL-1β levels remained low suggests that after rewarming, mechanisms unrelated to IL-1β expression are likely to contribute to this delayed increase in injury. Additional studies should be considered to determine what these mechanisms might be and also to explore whether extending the duration or degree of HT might ameliorate this delayed increase in injury.

  9. Hypothermia modulates cytokine responses after neonatal rat hypoxic-ischemic injury and reduces brain damage.

    PubMed

    Yuan, Xiangpeng; Ghosh, Nirmalya; McFadden, Brian; Tone, Beatriz; Bellinger, Denise L; Obenaus, Andre; Ashwal, Stephen

    2014-01-01

    While hypothermia (HT) is the standard-of-care for neonates with hypoxic ischemic injury (HII), the mechanisms underlying its neuroprotective effect are poorly understood. We examined ischemic core/penumbra and cytokine/chemokine evolution in a 10-day-old rat pup model of HII. Pups were treated for 24 hr after HII with HT (32℃; n = 18) or normothermia (NT, 35℃; n = 15). Outcomes included magnetic resonance imaging (MRI), neurobehavioral testing, and brain cytokine/chemokine profiling (0, 24, 48, and 72 hr post-HII). Lesion volumes (24 hr) were reduced in HT pups (total 74%, p < .05; penumbra 68%, p < .05; core 85%, p = .19). Lesion volumes rebounded at 72 hr (48 hr post-HT) with no significant differences between NT and HT pups. HT reduced interleukin-1β (IL-1β) at all time points (p < .05); monocyte chemoattractant protein-1 (MCP-1) trended toward being decreased in HT pups (p = .09). The stem cell signaling molecule, stromal cell-derived factor-1 (SDF-1) was not altered by HT. Our data demonstrate that HT reduces total and penumbral lesion volumes (at 24 and 48 hr), potentially by decreasing IL-1β without affecting SDF-1. Disassociation between the increasing trend in HII volumes from 48 to 72 hr post-HII when IL-1β levels remained low suggests that after rewarming, mechanisms unrelated to IL-1β expression are likely to contribute to this delayed increase in injury. Additional studies should be considered to determine what these mechanisms might be and also to explore whether extending the duration or degree of HT might ameliorate this delayed increase in injury. PMID:25424430

  10. Effect of combined therapy with ephedrine and hyperbaric oxygen on neonatal hypoxic-ischemic brain injury.

    PubMed

    Chen, Siyuan; Xiao, Nong; Zhang, Xiaoping

    2009-11-13

    Perinatal hypoxic-ischemic (HI) is a major cause of brain injury in the newborn, and there is a lack of effective therapies to reduce injury-related disorders. The aim of the present study was to evaluate the effect of a combination of ephedrine and hyperbaric oxygen (HBO) on neonatal hypoxic-ischemic brain injury. 7-day-old Sprague-Dawley rat pups were randomly divided into sham operation, HI, ephedrine, HBO, and combined group. The ephedrine group was intraperitoneally injected with ephedrine, HBO group was treated for 2h at 2.5 absolute atmosphere (ATA) per day, the combined group received both ephedrine and HBO treatments, the sham operation and HI groups were intraperitoneally injected with normal saline. Rat brains at 7 days after HI, were collected to determine histopathological damage and the expression levels of Caspase-3 and Nogo-A. Four weeks after insult, animals were challenged with Morris water maze test. The expressions of Caspase-3 and Nogo-A were reduced in treating groups compared to those in HI group (P<0.01). Compared with the single treatment groups, the expression levels of Caspase-3 and Nogo-A were significantly reduced in the combined group (P<0.01). Compared with the single treatment groups, the average time of escape latency was significantly shorter (P<0.01) and the number of platform location crossing was more (P<0.05) in combined group. These findings indicate that the combination of ephedrine and HBO can enhance the neuroprotective effect in the neonatal rat HI model partially mediated by inhibiting Caspase-3 and Nogo-A pathways.

  11. Pathophysiology and Treatments of Oxidative Injury in Ischemic Stroke: Focus on the Phagocytic NADPH Oxidase 2

    PubMed Central

    Carbone, Federico; Teixeira, Priscila Camillo; Braunersreuther, Vincent; Mach, François; Vuilleumier, Nicolas

    2015-01-01

    Abstract Significance: Phagocytes play a key role in promoting the oxidative stress after ischemic stroke occurrence. The phagocytic NADPH oxidase (NOX) 2 is a membrane-bound enzyme complex involved in the antimicrobial respiratory burst and free radical production in these cells. Recent Advances: Different oxidants have been shown to induce opposite effects on neuronal homeostasis after a stroke. However, several experimental models support the detrimental effects of NOX activity (especially the phagocytic isoform) on brain recovery after stroke. Therapeutic strategies selectively targeting the neurotoxic ROS and increasing neuroprotective oxidants have recently produced promising results. Critical Issues: NOX2 might promote carotid plaque rupture and stroke occurrence. In addition, NOX2-derived reactive oxygen species (ROS) released by resident and recruited phagocytes enhance cerebral ischemic injury, activating the inflammatory apoptotic pathways. The aim of this review is to update evidence on phagocyte-related oxidative stress, focusing on the role of NOX2 as a potential therapeutic target to reduce ROS-related cerebral injury after stroke. Future Directions: Radical scavenger compounds (such as Ebselen and Edaravone) are under clinical investigation as a therapeutic approach against stroke. On the other hand, NOX inhibition might represent a promising strategy to prevent the stroke-related injury. Although selective NOX inhibitors are not yet available, nonselective compounds (such as apocynin and fasudil) provided encouraging results in preclinical studies. Whereas additional studies are needed to better evaluate this therapeutic potential in human beings, the development of specific NOX inhibitors (such as monoclonal antibodies, small-molecule inhibitors, or aptamers) might further improve brain recovery after stroke. Antioxid. Redox Signal. 23, 460–489. PMID:24635113

  12. Burn-induced subepicardial injury in frog heart: a simple model mimicking ST segment changes in ischemic heart disease

    PubMed Central

    KAZAMA, Itsuro

    2015-01-01

    To mimic ischemic heart disease in humans, several animal models have been created, mainly in rodents by surgically ligating their coronary arteries. In the present study, by simply inducing burn injuries on the bullfrog heart, we reproduced abnormal ST segment changes in the electrocardiogram (ECG), mimicking those observed in ischemic heart disease, such as acute myocardial infarction and angina pectoris. The “currents of injury” created by a voltage gradient between the intact and damaged areas of the myocardium, negatively deflected the ECG vector during the diastolic phase, making the ST segment appear elevated during the systolic phase. This frog model of heart injury would be suitable to explain the mechanisms of ST segment changes observed in ischemic heart disease. PMID:26346747

  13. Apelin-36, a potent peptide, protects against ischemic brain injury by activating the PI3K/Akt pathway.

    PubMed

    Gu, Qin; Zhai, Lijing; Feng, Xing; Chen, Jing; Miao, Zhigang; Ren, Liyan; Qian, Xuanchen; Yu, Jian; Li, Yan; Xu, Xingshun; Liu, Chun-Feng

    2013-11-01

    Apelin is an endogenous ligand of G protein-coupled receptor-apelin and angiotensin-1-like receptor (APJ). The biological effects of apelin-APJ system are reported in multiple systems including cardiovascular, endocrinal, and gastrointestinal system. Previous studies had shown that apelin-13 is a potential protective agent on cardiac ischemia; however, the role of apelin in the central nervous system remained unknown. In this study, we investigated therapeutic effects of apelin-36, a long form of apelin, in ischemic brain injury models. We found that apelin-36 reduced cerebral infarct volume in the middle cerebral artery occlusion (MCAO) model and the neonatal hypoxic/ischemic (H/I) injury model. Apelin-36 improved neurological deficits in the MCAO model and promoted long-term functional recovery after H/I brain injury. We further explored the protective mechanisms of apelin-36 on H/I brain injury. We clearly demonstrated that apelin-36 significantly reduced the levels of cleaved caspase-3 and Bax, two well-established apoptotic markers after H/I injury, indicating the anti-apoptotic activity of apelin-36 in ischemic injury. Since apelin-36 increased the level of phosphorylated Akt after H/I injury, we treated neonates with a specific PI3K inhibitor LY294002. We found that LY294002 decreased the phosphorylated Akt level and attenuated protective effects of apelin-36 on apoptosis. These suggested that the PI3K/Akt pathway was at least in part involved in the anti-apoptotic mechanisms of apelin-36. Our findings demonstrated that apelin-36 was a promising therapeutic agent on the treatment of ischemic brain injury.

  14. Risk of Nonarteritic Anterior Ischemic Optic Neuropathy Following End-Stage Renal Disease

    PubMed Central

    Chang, Yuh-Shin; Weng, Shih-Feng; Chang, Chun; Wang, Jhi-Joung; Su, Shih-Bin; Huang, Chien-Cheng; Wang, Jiu-Yao; Jan, Ren-Long

    2016-01-01

    Abstract To investigate the risk of nonarteritic anterior ischemic optic neuropathy (NAION) following end-stage renal disease (ESRD). A retrospective, nationwide, matched cohort study. ESRD patients identified by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 585. The study cohort included 93,804 ESRD patients registered with the Taiwan National Health Insurance Research Database between January 2000 and December 2009. An age- and sex-matched control group comprised 93,804 patients (case:control = 1:1) selected from the Taiwan Longitudinal Health Insurance Database 2000. Information for each patient was collected from the index date until December 2011. The incidence and risk of NAION were compared between the ESRD and control groups. The adjusted hazard ratio (HR) for NAION after adjustment for potential confounders was obtained by a Cox proportional hazard regression analysis. A Kaplan–Meier analysis was used to calculate the cumulative incidence rate of NAION. The incidence of NAION following ESRD. In total, 133 ESRD patients (0.14%) and 51 controls (0.05%) had NAION (P < 0.001) during the follow-up period, leading to a significantly elevated risk of NAION in the ESRD patients compared with the controls (incidence rate ratio = 3.14, 95% confidence interval [CI] = 2.11–4.67). After adjustment for potential confounders including diabetes mellitus, hypertension, hypotension, hyperlipidemia, and 2-way interaction terms between any 2 factors, ESRD patients were 3.12 times more likely to develop NAION than non-ESRD patients in the full cohort (adjusted HR = 3.12, 95% CI = 2.10–4.64). Additionally, patients with hypertension and hyperlipidemia showed higher incidence rates of NAION in the ESRD group compared with the controls: 2.31 (95% CI = 1.40–3.82) for hypertension and 2.72 (95% CI = 1.14–6.50) for hyperlipidemia. ESRD increased the risk of NAION, which is an

  15. Risk of Nonarteritic Anterior Ischemic Optic Neuropathy Following End-Stage Renal Disease.

    PubMed

    Chang, Yuh-Shin; Weng, Shih-Feng; Chang, Chun; Wang, Jhi-Joung; Su, Shih-Bin; Huang, Chien-Cheng; Wang, Jiu-Yao; Jan, Ren-Long

    2016-03-01

    To investigate the risk of nonarteritic anterior ischemic optic neuropathy (NAION) following end-stage renal disease (ESRD).A retrospective, nationwide, matched cohort study.ESRD patients identified by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 585.The study cohort included 93,804 ESRD patients registered with the Taiwan National Health Insurance Research Database between January 2000 and December 2009. An age- and sex-matched control group comprised 93,804 patients (case:control = 1:1) selected from the Taiwan Longitudinal Health Insurance Database 2000. Information for each patient was collected from the index date until December 2011. The incidence and risk of NAION were compared between the ESRD and control groups. The adjusted hazard ratio (HR) for NAION after adjustment for potential confounders was obtained by a Cox proportional hazard regression analysis. A Kaplan-Meier analysis was used to calculate the cumulative incidence rate of NAION.The incidence of NAION following ESRD.In total, 133 ESRD patients (0.14%) and 51 controls (0.05%) had NAION (P < 0.001) during the follow-up period, leading to a significantly elevated risk of NAION in the ESRD patients compared with the controls (incidence rate ratio = 3.14, 95% confidence interval [CI] = 2.11-4.67). After adjustment for potential confounders including diabetes mellitus, hypertension, hypotension, hyperlipidemia, and 2-way interaction terms between any 2 factors, ESRD patients were 3.12 times more likely to develop NAION than non-ESRD patients in the full cohort (adjusted HR = 3.12, 95% CI = 2.10-4.64). Additionally, patients with hypertension and hyperlipidemia showed higher incidence rates of NAION in the ESRD group compared with the controls: 2.31 (95% CI = 1.40-3.82) for hypertension and 2.72 (95% CI = 1.14-6.50) for hyperlipidemia.ESRD increased the risk of NAION, which is an interdisciplinary emergency. Close

  16. Hepcidin Mitigates Renal Ischemia-Reperfusion Injury by Modulating Systemic Iron Homeostasis.

    PubMed

    Scindia, Yogesh; Dey, Paromita; Thirunagari, Abhinav; Liping, Huang; Rosin, Diane L; Floris, Matteo; Okusa, Mark D; Swaminathan, Sundararaman

    2015-11-01

    Iron-mediated oxidative stress is implicated in the pathogenesis of renal ischemia-reperfusion injury. Hepcidin is an endogenous acute phase hepatic hormone that prevents iron export from cells by inducing degradation of the only known iron export protein, ferroportin. In this study, we used a mouse model to investigate the effect of renal ischemia-reperfusion injury on systemic iron homeostasis and determine if dynamic modulation of iron homeostasis with hepcidin has therapeutic benefit in the treatment of AKI. Renal ischemia-reperfusion injury induced hepatosplenic iron export through increased ferroportin expression, which resulted in hepatosplenic iron depletion and an increase in serum and kidney nonheme iron levels. Exogenous hepcidin treatment prevented renal ischemia-reperfusion-induced changes in iron homeostasis. Hepcidin also decreased kidney ferroportin expression and increased the expression of cytoprotective H-ferritin. Hepcidin-induced restoration of iron homeostasis was accompanied by a significant reduction in ischemia-reperfusion-induced tubular injury, apoptosis, renal oxidative stress, and inflammatory cell infiltration. Hepcidin -: deficient mice demonstrated increased susceptibility to ischemia-reperfusion injury compared with wild-type mice. Reconstituting hepcidin-deficient mice with exogenous hepcidin induced hepatic iron sequestration, attenuated the reduction in renal H-ferritin and reduced renal oxidative stress, apoptosis, inflammation, and tubular injury. Hepcidin-mediated protection was associated with reduced serum IL-6 levels. In summary, renal ischemia-reperfusion injury results in profound alterations in systemic iron homeostasis. Hepcidin treatment restores iron homeostasis and reduces inflammation to mediate protection in renal ischemia-reperfusion injury, suggesting that hepcidin-ferroportin pathway holds promise as a novel therapeutic target in the treatment of AKI.

  17. Low birth weight increases susceptibility to renal injury in a rat model of mild ischemia-reperfusion.

    PubMed

    Ojeda, Norma B

    2011-08-01

    Renal injury due to ischemia-reperfusion (I/R) is the major cause of acute kidney injury. Whether enhanced susceptibility to renal injury due to I/R can be programmed during fetal life is unknown. Epidemiological studies indicate that low birth weight (LBW) individuals are more susceptible to renal injury than normal birth weight (NBW) individuals. Thus, the aim of this study was to test the hypothesis that LBW is associated with an increased susceptibility to renal injury induced by mild renal I/R (15-min ischemia). Systemic and renal hemodynamic parameters were determined in NBW and LBW adult male rats after mild renal I/R; renal superoxide production and tubular injury were also assessed. A subgroup was pretreated with tempol, a superoxide dismutase mimetic, initiated 15 min before ischemia. Mild renal I/R did not alter renal hemodynamic parameters, induce tubular injury, or induce superoxide production in NBW rats. However, renal hemodynamic parameters declined, superoxide production increased, and histological indicators of tubular injury were present following mild renal I/R in LBW rats. Acute treatment with tempol prevented these alterations in LBW rats subjected to mild renal I/R. Thus, these findings suggest that adverse conditions during fetal life can compromise the renal response to subtle insults leading to an increased susceptibility to renal injury, suggesting that LBW individuals may be an "at risk" population for renal disease. Additionally, the outcome of tempol treatment proposes a possible mechanistic pathway involved in mediating enhanced susceptibility to renal injury programmed during fetal life.

  18. Renal infarction secondary to ketamine abuse.

    PubMed

    Chen, Chin-Li; Chen, Jin-Li; Cha, Tai-Lung; Wu, Sheng-Tang; Tang, Shou-Hung; Tsao, Chih-Wei; Meng, En

    2013-07-01

    Renal infarction is an uncommon condition that resulted from inadequate perfusion of the kidney and is easily missed diagnosed due to its nonspecific clinical presentations. Major risk factors for renal infarction are atrial fibrillation, previous embolism, and ischemic and valvular heart disease. Progressive decrease in renal function or even death can occur if renal infarction is not diagnosed accurately and promptly. Ketamine abuse may cause variable urinary tract injury. However, renal infarction caused by ketamine abuse has never been reported. To our knowledge, this is the first documented case of renal infarction following nasal insufflation of ketamine.

  19. Vildagliptin reduces cardiac ischemic-reperfusion injury in obese orchiectomized rats.

    PubMed

    Pongkan, Wanpitak; Pintana, Hiranya; Jaiwongkam, Thidarat; Kredphoo, Sasiwan; Sivasinprasasn, Sivaporn; Chattipakorn, Siriporn C; Chattipakorn, Nipon

    2016-10-01

    Obesity and testosterone deprivation are associated with coronary artery disease. Testosterone and vildagliptin (dipeptidyl peptidase-4 inhibitors) exert cardioprotection during ischemic-reperfusion (I/R) injury. However, the effect of these drugs on I/R heart in a testosterone-deprived, obese, insulin-resistant model is unclear. This study investigated the effects of testosterone and vildagliptin on cardiac function, arrhythmias and the infarct size in I/R heart of testosterone-deprived rats with obese insulin resistance. Orchiectomized (O) or sham operated (S) male Wistar rats were divided into 2 groups to receive normal diet (ND) or high-fat diet (HFD) for 12 weeks. Orchiectomized rats in each diet were divided to receive testosterone (2 mg/kg), vildagliptin (3 mg/kg) or the vehicle daily for 4 weeks. Then, I/R was performed by a 30-min left anterior descending coronary artery ligation, followed by a 120-min reperfusion. LV function, arrhythmia scores, infarct size and cardiac mitochondrial function were determined. HFD groups developed insulin resistance at week 12. At week 16, cardiac function was impaired in NDO, HFO and HFS rats, but was restored in all testosterone- and vildagliptin-treated rats. During I/R injury, arrhythmia scores, infarct size and cardiac mitochondrial dysfunction were prominently increased in NDO, HFO and HFS rats, compared with those in NDS rats. Treatment with either testosterone or vildagliptin similarly attenuated these impairments during I/R injury. These finding suggest that both testosterone replacement and vildagliptin share similar efficacy for cardioprotection during I/R injury by decreasing the infarct size and attenuating cardiac mitochondrial dysfunction caused by I/R injury in testosterone-deprived rats with obese insulin resistance. PMID:27543302

  20. Vildagliptin reduces cardiac ischemic-reperfusion injury in obese orchiectomized rats.

    PubMed

    Pongkan, Wanpitak; Pintana, Hiranya; Jaiwongkam, Thidarat; Kredphoo, Sasiwan; Sivasinprasasn, Sivaporn; Chattipakorn, Siriporn C; Chattipakorn, Nipon

    2016-10-01

    Obesity and testosterone deprivation are associated with coronary artery disease. Testosterone and vildagliptin (dipeptidyl peptidase-4 inhibitors) exert cardioprotection during ischemic-reperfusion (I/R) injury. However, the effect of these drugs on I/R heart in a testosterone-deprived, obese, insulin-resistant model is unclear. This study investigated the effects of testosterone and vildagliptin on cardiac function, arrhythmias and the infarct size in I/R heart of testosterone-deprived rats with obese insulin resistance. Orchiectomized (O) or sham operated (S) male Wistar rats were divided into 2 groups to receive normal diet (ND) or high-fat diet (HFD) for 12 weeks. Orchiectomized rats in each diet were divided to receive testosterone (2 mg/kg), vildagliptin (3 mg/kg) or the vehicle daily for 4 weeks. Then, I/R was performed by a 30-min left anterior descending coronary artery ligation, followed by a 120-min reperfusion. LV function, arrhythmia scores, infarct size and cardiac mitochondrial function were determined. HFD groups developed insulin resistance at week 12. At week 16, cardiac function was impaired in NDO, HFO and HFS rats, but was restored in all testosterone- and vildagliptin-treated rats. During I/R injury, arrhythmia scores, infarct size and cardiac mitochondrial dysfunction were prominently increased in NDO, HFO and HFS rats, compared with those in NDS rats. Treatment with either testosterone or vildagliptin similarly attenuated these impairments during I/R injury. These finding suggest that both testosterone replacement and vildagliptin share similar efficacy for cardioprotection during I/R injury by decreasing the infarct size and attenuating cardiac mitochondrial dysfunction caused by I/R injury in testosterone-deprived rats with obese insulin resistance.

  1. Liver free fatty acid (FFA) accumulation as an indicator of ischemic injury during cold preservation

    SciTech Connect

    Nemoto, E.M.; Kang, Y.; DeWolf, A.M.; Lin, M.R.; Bleyaert, A.L.; Winter, P.M.

    1987-05-01

    Reliable assessment of hepatic viability prior to harvest and transplant could improve graft success and aid in evaluating the efficacy of liver preservation techniques. Hepatic tissue metabolites, protein (Pr) synthesis, and ATP have been studied, but none reliably correlate with hepatic viability. Therefore, they studied changes in liver FFA relative to changes in ATP and Pr synthesis during cold ischemic preservation. Rats mechanically ventilated on 0.5% isoflurane/70% N/sub 2/O/30% O/sub 2/ were heparinized and their livers perfused with air-equilibrated Euro-Collins solution (ECS) at 0-4/sup 0/C and kept on ice. A piece of the liver was removed after 0, 2, 6, 8, 12, 24, 36 and 48 h of preservation for ATP and FFA analysis. A portion of the liver was sliced (250 ..mu..m thick) and incubated in vitro for /sup 14/C-lysine incorporation in albumin. ATP, FFA and Pr synthesis were unchanged in the first 8 h, but markedly decreased between 8 and 12 h with little change thereafter. In contrast, between 8 and 48 h, arachidonic and stearic acids increased by 5 and 2-fold, respectively. Changes in ATP and Pr synthesis correlate with the empirically derived clinical maximum of 8 to 12 h preservation. FFA accumulation appears to reflect hepatic ischemic injury and may be a means of evaluating the quality of a donor liver.

  2. Stachys sieboldii (Labiatae, Chorogi) Protects against Learning and Memory Dysfunction Associated with Ischemic Brain Injury.

    PubMed

    Harada, Shinichi; Tsujita, Tsukasa; Ono, Akiko; Miyagi, Kei; Mori, Takaharu; Tokuyama, Shogo

    2015-01-01

    Stachys sieboldii (Labiatae; Chinese artichoke, a tuber), "chorogi" in Japanese, has been extensively used in folk medicine, and has a number of pharmacological properties, including antioxidative activity. However, few studies have examined the neuroprotective effects of S. sieboldii tuber extract (chorogi extract), and it remains unknown whether the extract can alleviate learning and memory dysfunction associated with vascular dementia or Alzheimer's disease. Therefore, in this study, we investigated the neuroprotective effects of chorogi extract, and examined its protection against learning and memory dysfunction using Ginkgo biloba leaf extract (ginkgo extract) as a positive control. Mice were subjected to bilateral carotid artery occlusion (BCAO) for 30 min. Oral administration of chorogi extract or ginkgo extract significantly reduced post-ischemic glucose intolerance on day 1 and neuronal damage including memory impairment on day 3 after BCAO, compared with the vehicle-treated group. Neither herbal medicine affected locomotor activity. Furthermore, neither significantly alleviated scopolamine-induced learning and memory impairment. In primary neurons, neuronal survival rate was significantly reduced by hydrogen peroxide treatment. This hydrogen peroxide-induced neurotoxicity was significantly suppressed by chorogi extract and ginkgo extract. Taken together, our findings suggest that chorogi extract as well as ginkgo extract can protect against learning and memory dysfunction associated with ischemic brain injury through an antioxidative mechanism.

  3. Changes in Cerebral Oxidative Metabolism during Neonatal Seizures Following Hypoxic-Ischemic Brain Injury.

    PubMed

    Mitra, Subhabrata; Bale, Gemma; Mathieson, Sean; Uria-Avellanal, Cristina; Meek, Judith; Tachtsidis, Ilias; Robertson, Nicola J

    2016-01-01

    Seizures are common following hypoxic-ischemic brain injury in newborn infants. Prolonged or recurrent seizures have been shown to exacerbate neuronal damage in the developing brain; however, the precise mechanism is not fully understood. Cytochrome-c-oxidase is responsible for more than 90% of ATP production inside mitochondria. Using a novel broadband near-infrared spectroscopy system, we measured the concentration changes in the oxidation state of cerebral cytochrome-c-oxidase (Δ[oxCCO]) and hemodynamics during recurrent neonatal seizures following hypoxic-ischemic encephalopathy in a newborn infant. A rapid increase in Δ[oxCCO] was noted at the onset of seizures along with a rise in the baseline of amplitude-integrated electroencephalogram. Cerebral oxygenation and cerebral blood volume fell just prior to the seizure onset but recovered rapidly during seizures. Δ[oxCCO] during seizures correlated with changes in mean electroencephalogram voltage indicating an increase in neuronal activation and energy demand. The progressive decline in the Δ[oxCCO] baseline during seizures suggests a progressive decrease of mitochondrial oxidative metabolism. PMID:27559538

  4. Changes in Cerebral Oxidative Metabolism during Neonatal Seizures Following Hypoxic–Ischemic Brain Injury

    PubMed Central

    Mitra, Subhabrata; Bale, Gemma; Mathieson, Sean; Uria-Avellanal, Cristina; Meek, Judith; Tachtsidis, Ilias; Robertson, Nicola J.

    2016-01-01

    Seizures are common following hypoxic–ischemic brain injury in newborn infants. Prolonged or recurrent seizures have been shown to exacerbate neuronal damage in the developing brain; however, the precise mechanism is not fully understood. Cytochrome-c-oxidase is responsible for more than 90% of ATP production inside mitochondria. Using a novel broadband near-infrared spectroscopy system, we measured the concentration changes in the oxidation state of cerebral cytochrome-c-oxidase (Δ[oxCCO]) and hemodynamics during recurrent neonatal seizures following hypoxic–ischemic encephalopathy in a newborn infant. A rapid increase in Δ[oxCCO] was noted at the onset of seizures along with a rise in the baseline of amplitude-integrated electroencephalogram. Cerebral oxygenation and cerebral blood volume fell just prior to the seizure onset but recovered rapidly during seizures. Δ[oxCCO] during seizures correlated with changes in mean electroencephalogram voltage indicating an increase in neuronal activation and energy demand. The progressive decline in the Δ[oxCCO] baseline during seizures suggests a progressive decrease of mitochondrial oxidative metabolism. PMID:27559538

  5. Iptakalim protects against ischemic injury by improving neurovascular unit function in the mouse brain.

    PubMed

    Ji, Juan; Yan, Hui; Chen, Zheng-Zhen; Zhao, Zhan; Yang, Dan-Dan; Sun, Xiu-Lan; Shi, Yong-Ping

    2015-07-01

    It has been reported that the novel ATP-sensitive potassium (K-ATP) channel opener iptakalim (IPT) decreases ischemic neuronal damage in rats. However, the mechanisms underlying neuroprotection are still to be fully elucidated. The results of this study showed that mice with ischemia induced by middle cerebral artery occlusion exhibited higher mortality and more neurological deficits, as well as larger infarct volume, compared with sham mice. Moreover, it was found that ischemia activated astrocytes surrounding CA1 neurons with an increased expression of D-serine, induced greater microglial activation accompanied by higher tumor necrosis factor alpha (TNF-α) production, and caused higher expressions of matrix metalloproteinase 9 (MMP-9) in the endothelial cells of mice. Pretreatment with IPT significantly attenuated the neurological deficits and decreased the infarct volume in mice. IPT treatment could decrease MMP-9 secretion, inhibit astrocytic activation with decreasing D-serine and elevating connexin43 expression. Microglial activation was also inhibited and TNF-α production was decreased by IPT. Taken together, a K-ATP channel opener may improve the function of neurovascular unit and protect against ischemic injury. These findings suggest that targeting K-ATP channels provides a promising therapeutic approach for stroke. PMID:25998857

  6. Cystathionine β-Synthase Inhibition Is a Potential Therapeutic Approach to Treatment of Ischemic Injury

    PubMed Central

    Chan, Su Jing; Chai, Chou; Lim, Tze Wei; Yamamoto, Mie; Lo, Eng H; Lai, Mitchell Kim Peng

    2015-01-01

    Hydrogen sulfide (H2S) has been reported to exacerbate stroke outcome in experimental models. Cystathionine β-synthase (CBS) has been implicated as the predominant H2S-producing enzyme in central nervous system. When SH-SY5Y cells were transfected to overexpress CBS, these cells were able to synthesize H2S when exposed to high levels of enzyme substrates but not substrate concentrations that may reflect normal physiological conditions. At the same time, these cells demonstrated exacerbated cell death when subjected to oxygen and glucose deprivation (OGD) together with high substrate concentrations, indicating that H2S production has a detrimental effect on cell survival. This effect could be abolished by CBS inhibition. The same effect was observed with primary astrocytes exposed to OGD and high substrates or sodium hydrosulfide. In addition, CBS was upregulated and activated by truncation in primary astrocytes subjected to OGD. When rats were subjected to permanent middle cerebral artery occlusion, CBS activation was also observed. These results imply that in acute ischemic conditions, CBS is upregulated and activated by truncation causing an increased production of H2S, which exacerbate the ischemic injuries. Therefore, CBS inhibition may be a viable approach to stroke treatment. PMID:25873304

  7. Osthole decreases renal ischemia-reperfusion injury by suppressing JAK2/STAT3 signaling activation

    PubMed Central

    Luo, Lin-Na; Xie, De Qiong; Zhang, Xiao Gang; Jiang, Rong

    2016-01-01

    Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury. The pathogenetic mechanisms underlying renal I/R injury involve inflammation, oxidative stress and apoptosis. Osthole is a coumarin derivative that exhibits potential anti-inflammatory activity. The aim of the present study was to investigate the effect of osthole in renal I/R injury and its underlying mechanism. Renal I/R injury was induced by clamping the left renal artery for 45 min followed by 24 h reperfusion with the contralateral nephrectomy. A total of 70 rats were randomly assigned to seven groups (n=10 per group): Sham; IRI; and osthole (0, 5, 10, 20 and 40 mg/kg) groups. Rats were administered intraperitoneally with osthole 45 min prior to renal ischemia. Serum and renal tissue were harvested 24 h after reperfusion. Renal function and histological changes were assessed. In addition, the mRNA and protein expression of tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8) and interleukin-6 (IL-6) in renal tissue and serum were evaluated using quantitative polymerase chain reaction and ELISA assays, respectively. The protein expression levels of p65, p-p65, janus kinase 2 (JAK2), p-JAK2, signal transducer and activator of transcription 3 (STAT3) and p-STAT3 were measured using western blot analysis. The results indicate that osthole pretreatment was able to significantly attenuate the renal dysfunction in a dose-dependent manner, histological changes and the expression of TNF-α, IL-8, IL-6, p-JAK2, p-STAT3 and p-p65 induced by renal I/R injury. However, neither osthole or I/R injury affected the expression p65, JAK2 and STAT3. Osthole pretreatment is able to reduce renal I/R injury by abrogating inflammation and the mechanism is partially involved in suppressing JAK2/STAT3 activation. Thus, osthole may be a novel practical strategy for the mitigation of renal I/R injury. PMID:27698686

  8. Osthole decreases renal ischemia-reperfusion injury by suppressing JAK2/STAT3 signaling activation

    PubMed Central

    Luo, Lin-Na; Xie, De Qiong; Zhang, Xiao Gang; Jiang, Rong

    2016-01-01

    Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury. The pathogenetic mechanisms underlying renal I/R injury involve inflammation, oxidative stress and apoptosis. Osthole is a coumarin derivative that exhibits potential anti-inflammatory activity. The aim of the present study was to investigate the effect of osthole in renal I/R injury and its underlying mechanism. Renal I/R injury was induced by clamping the left renal artery for 45 min followed by 24 h reperfusion with the contralateral nephrectomy. A total of 70 rats were randomly assigned to seven groups (n=10 per group): Sham; IRI; and osthole (0, 5, 10, 20 and 40 mg/kg) groups. Rats were administered intraperitoneally with osthole 45 min prior to renal ischemia. Serum and renal tissue were harvested 24 h after reperfusion. Renal function and histological changes were assessed. In addition, the mRNA and protein expression of tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8) and interleukin-6 (IL-6) in renal tissue and serum were evaluated using quantitative polymerase chain reaction and ELISA assays, respectively. The protein expression levels of p65, p-p65, janus kinase 2 (JAK2), p-JAK2, signal transducer and activator of transcription 3 (STAT3) and p-STAT3 were measured using western blot analysis. The results indicate that osthole pretreatment was able to significantly attenuate the renal dysfunction in a dose-dependent manner, histological changes and the expression of TNF-α, IL-8, IL-6, p-JAK2, p-STAT3 and p-p65 induced by renal I/R injury. However, neither osthole or I/R injury affected the expression p65, JAK2 and STAT3. Osthole pretreatment is able to reduce renal I/R injury by abrogating inflammation and the mechanism is partially involved in suppressing JAK2/STAT3 activation. Thus, osthole may be a novel practical strategy for the mitigation of renal I/R injury.

  9. Anti-Inflammatory Effects of Traditional Chinese Medicines against Ischemic Injury in In Vivo Models of Cerebral Ischemia

    PubMed Central

    2016-01-01

    Inflammation plays a crucial role in the pathophysiology of acute ischemic stroke. In the ischemic cascade, resident microglia are rapidly activated in the brain parenchyma and subsequently trigger inflammatory mediator release, which facilitates leukocyte-endothelial cell interactions in inflammation. Activated leukocytes invade the endothelial cell junctions and destroy the blood-brain barrier integrity, leading to brain edema. Toll-like receptors (TLRs) stimulation in microglia/macrophages through the activation of intercellular signaling pathways secretes various proinflammatory cytokines and enzymes and then aggravates cerebral ischemic injury. The secreted cytokines activate the proinflammatory transcription factors, which subsequently regulate cytokine expression, leading to the amplification of the inflammatory response and exacerbation of the secondary brain injury. Traditional Chinese medicines (TCMs), including TCM-derived active compounds, Chinese herbs, and TCM formulations, exert neuroprotective effects against inflammatory responses by downregulating the following: ischemia-induced microglial activation, microglia/macrophage-mediated cytokine production, proinflammatory enzyme production, intercellular adhesion molecule-1, matrix metalloproteinases, TLR expression, and deleterious transcription factor activation. TCMs also aid in upregulating anti-inflammatory cytokine expression and neuroprotective transcription factor activation in the ischemic lesion in the inflammatory cascade during the acute phase of cerebral ischemia. Thus, TCMs exert potent anti-inflammatory properties in ischemic stroke and warrant further investigation. PMID:27703487

  10. Ultra-rapid manufacturing of engineered epicardial substitute to regenerate cardiac tissue following acute ischemic injury.

    PubMed

    Serpooshan, Vahid; Ruiz-Lozano, Pilar

    2014-01-01

    Considering the impaired regenerative capacity of adult mammalian heart tissue, cardiovascular tissue engineering aims to create functional substitutes that can restore the structure and function of the damaged cardiac tissue. The success of cardiac regenerative therapies has been limited mainly due to poor control on the structure and properties of the tissue substitute, lack of vascularization, and immunogenicity. In this study we introduce a new approach to rapidly engineer dense biomimetic scaffolds consisting of type I collagen, to protect the heart against severe ischemic injury. Scaffold biomechanical properties are adjusted to mimic embryonic epicardium which is shown to be optimal to support cardiomyocyte contractile work. Moreover, the designed patch can serve as a delivery device for targeted, controlled release of cells or therapeutic macromolecules into the lesion area.

  11. Protective effects of drag-reducing polymers on ischemic reperfusion injury of isolated rat heart.

    PubMed

    Hu, Feng; Wang, Yali; Gong, Kaizheng; Ge, Gaoyuan; Cao, Mingqiang; Zhao, Pei; Sun, Xiaoning; Zhang, Zhengang

    2016-01-01

    Drag-reducing polymers (DRPs) are blood-soluble macromolecules that can increase blood flow and reduce vascular resistance. The purpose of the present study was to observe the effect of DRPs on ischemic reperfusion (I/R) injury of isolated rat hearts. Experiments were performed on isolated rat hearts subjected to 30 min of ischemia followed by 90 min of reperfusion in Langendorff preparations. Adult Wistar rats were divided into the following five groups: control group, I/R group, group III (I/R and 2×10(-7)  g/ml PEO reperfusion), group IV (I/R and 1×10(-6)  g/ml PEO reperfusion), and group V (I/R and 5×10(-6)  g/ml PEO reperfusion). Left ventricular end-diastolic pressure (LVEDP), left ventricular systolic pressure (LVSP), maximum rate of ventricular pressure increase and decrease ( ± dp/dtmax), heart rate (HR) and coronary flow were measured. Lactate dehydrogenase (LDH) and creatine kinase (CK) activity and coronary flow, myocardial infarction size and cardiomyocytes apoptosis were also assayed. Our results showed that PEO decreased LVEDP and increased LVSP, ± dP/dtmax in group IV and group V compared with the I/R group (all P <  0.05). The coronary flow significantly increased and the activities of LDH and CK in the coronary flow significantly decreased in group IV and group V compared with those in the I/R group (all P <  0.05). Cell apoptosis and myocardial infarction size were reduced in group IV and group V compared with the I/R group (all P <  0.05). Collectively, these results suggested that DRPs had a protective effect on cardiac I/R injury of isolated rat hearts and it may offer a new potential approach for the treatment of acute ischemic heart diseases.

  12. Measuring biomarkers of acute kidney injury during renal replacement therapy: wisdom or folly?

    PubMed

    Ostermann, Marlies; Forni, Lui G

    2014-06-19

    Early data are now appearing relating to the measurement of biomarkers of acute kidney injury during renal replacement therapy. These data go some way in describing the clearance of these molecules during renal support. Understanding the potential clearance, or otherwise, of these proteins may lead to directing our therapies in the future particularly with regard to cessation of renal support. We describe a recent study which has provided data that may aid in addressing this issue.

  13. Elements of renal injury in patients with erysipelas.

    PubMed

    Velciov, Silvia; Gluhovschi, Gh; Feier, V; Curescu, Manuela; Trandafirescu, Virginia; Petrică, Ligia; Gluhovschi, Cristina; Bob, F; Bozdog, Gh; Gadalean, Florica; Florescu, Carmen; Bobu, Maria; Chiliban, Andreea

    2010-01-01

    Erysipelas is an infectious disease caused by group A beta hemolytical streptococci which may produce renal lesions, most frequently glomerular disease. Renal injury although known is less studied in practice. Rarely bioptical exams have been performed, thus the problem of the relationship erysipelas glomerular disease is practically not solved. The aim of this study was a cross-sectional analysis of renal involvement produced by erysipelas in two departments where patients with erysipelas are diagnosed and treated: Dermatology and Infectious Diseases. We investigated 166 patients (86M, 80F; mean age 61.66 +/- 18.42) with erysipelas hospitalized in the Departments of Dermatology (55 patients-33%) and Infectious Diseases (111 patients-66%) during 2005-2009. The diagnosis was established on clinical and biological data. In these patients clinical and biological exam has been performed. We assessed GFR and urinalysis (hematuria and proteinuria). The control group consisted of 110 apparently healthy persons. Of the 166 patients with erysipelas we found asymptomatic urinary abnormalities in 82 (47%), isolated proteinuria in 19 (11%) patients and proteinuria associated with hematuria in 21 (13%) patients, and isolated hematuria in 38 (23%) patients. We did not find patients with nephrotic or nephritic syndrome. In the control group we found asymptomatic urinary abnormalities in 25 (23%) of the patients. A statistically significant difference was between the two groups (p < 0.01). Asymptomatic urinary abnormalities have been more frequent in patients with erysipelas from the Infectious Diseases Department compared to those from the Dermatology Department. A statistically significant difference has been found (p < 0.03). In patients with recurrent erysipelas (43 patients-26%) we found asymptomatic urinary abnormalities in 26 (54%) of the patients compared to the presence of asymptomatic urinary abnormalities in patients with acute erysipelas in 56 out of 123 (46%). Mean

  14. Class I HDAC activity is required for renal protection and regeneration after acute kidney injury.

    PubMed

    Tang, Jinhua; Yan, Yanli; Zhao, Ting C; Gong, Rujun; Bayliss, George; Yan, Haidong; Zhuang, Shougang

    2014-08-01

    Activation of histone deacetylases (HDACs) is required for renal epithelial cell proliferation and kidney development. However, their role in renal tubular cell survival and regeneration after acute kidney injury (AKI) remains unclear. In this study, we demonstrated that all class I HDAC isoforms (1, 2, 3, and 8) were expressed in the renal epithelial cells of the mouse kidney. Inhibition of class I HDACs with MS-275, a highly selective inhibitor, resulted in more severe tubular injury in the mouse model of AKI induced by folic acid or rhabdomyolysis, as indicated by worsening renal dysfunction, increased neutrophil gelatinase-associated lipocalin expression, and enhanced apoptosis and caspase-3 activation. Blocking class I HDAC activity also impaired renal regeneration as evidenced by decreased expression of renal Pax-2, vimentin, and proliferating cell nuclear antigen. Injury to the kidney is accompanied by increased phosphorylation of epidermal growth factor receptor (EGFR), signal transducers and activators of transcription 3 (STAT3), and Akt. Inhibition of class I HDACs suppressed EGFR phosphorylation as well as reduced its expression. MS-275 was also effective in inhibiting STAT3 and Akt phosphorylation, but this treatment did not affect their expression levels. Taken together, these data suggest that the class I HDAC activity contributes to renal protection and functional recovery and is required for renal regeneration after AKI. Furthermore, renal EGFR signaling is subject to regulation by this class of HDACs.

  15. Similarities and differences of acute nonconvulsive seizures and other epileptic activities following penetrating and ischemic brain injuries in rats.

    PubMed

    Lu, Xi-Chun May; Mountney, Andrea; Chen, Zhiyong; Wei, Guo; Cao, Ying; Leung, Lai Yee; Khatri, Vivek; Cunningham, Tracy; Tortella, Frank C

    2013-04-01

    The similarities and differences between acute nonconvulsive seizures (NCS) and other epileptic events, for example, periodic epileptiform discharges (PED) and intermittent rhythmic delta activities (IRDA), were characterized in rat models of penetrating and ischemic brain injuries. The NCS were spontaneously induced by either unilateral frontal penetrating ballistic-like brain injury (PBBI) or permanent middle cerebral artery occlusion (pMCAO), and were detected by continuous electroencephalogram (EEG) monitoring begun immediately after the injury and continued for 72 h or 24 h, respectively. Analysis of NCS profiles (incidence, frequency, duration, and time distribution) revealed a high NCS incidence in both injury models. The EEG waveform expressions of NCS and PED exhibited intrinsic variations that resembled human electrographic manifestations of post-traumatic and post-ischemic ictal and inter-ictal events, but these waveform variations were not distinguishable between the two types of brain injury. However, the NCS after pMCAO occurred more acutely and intensely (latency=0.6 h, frequency=25 episodes/rat) compared with the PBBI-induced NCS (latency=24 h, frequency=10 episodes/rat), such that the most salient features differentiating post-traumatic and post-ischemic NCS were the intensity and time distribution of the NCS profiles. After pMCAO, nearly 50% of the seizures occurred within the first 2 h of injury, whereas after PBBI, NCS occurred sporadically (0-5%/h) throughout the 72 h recording period. The PED were episodically associated with NCS. By contrast, the IRDA appeared to be independent of other epileptic events. This study provided comprehensive comparisons of post-traumatic and post-ischemic epileptic profiles. The identification of the similarities and differences across a broad spectrum of epileptic events may lead to differential strategies for post-traumatic and post-stroke seizure interventions.

  16. The possible protective effects of dipyridamole on ischemic reperfusion injury of priapism

    PubMed Central

    Karaguzel, Ersagun; Bayraktar, Cemil; Kutlu, Omer; Yulug, Esin; Mentese, Ahmet; Okatan, Ali Ertan; Colak, Fatih; Ozer, Serap; O.Kazaz, Ilke

    2016-01-01

    ABSTRACT Purpose To investigate the protective effects against ischemia reperfusion injury of dipyridamole in a model of induced priapism in rats. Materials and Methods Twenty-four male Sprague-Dawley rats were divided into four groups, control, P/R, P/R+DMSO and P/R+D. 3ml blood specimens were collected from vena cava inferior in order to determine serum MDA, IMA, TAS, TOS and OSI values, and penile tissue was taken for histopathological examination in control group. Priapism was induced in P/R group. After 1h, priapism was concluded and 30 min reperfusion was performed. In P/R+DMSO group 1ml/kg DMSO was administered intraperitoneally 30 min before reperfusion, while in P/R+D group 10mg/kg dipyridamole was administered intraperitoneally 30 min before reperfusion. Blood and penis specimens were collected after the end of 30 min reperfusion period. Sinusoidal area (µm2), tears in tunica albuginea and injury parameters in sinusoidal endothelium of penis were investigated. Results Histopathological examination revealed no significant changes in term of sinusoidal area. A decrease in tears was observed in P/R+D group compared to P/R group (p<0.05). Endothelial injury decreased in P/R+D group compared to P/R group (p>0.05). There were no significant differences in MDA and IMA values between groups. A significant increase in TOS and OSI values was observed in P/R+D group compared to P/R group. A significant decrease in TAS levels was observed in P/R+D group compared to the P/R group. Conclusions The administration of dipyridamole before reperfusion in ischemic priapism model has a potential protective effect against histopathological injury of the penis. PMID:27136481

  17. Optical spectroscopy approach for the predictive assessment of kidney functional recovery following ischemic injury

    NASA Astrophysics Data System (ADS)

    Raman, Rajesh N.; Pivetti, Christopher D.; Rubenchik, Alexander M.; Matthews, Dennis L.; Troppmann, Christoph; Demos, Stavros G.

    2010-02-01

    Tissue that has undergone significant yet unknown amount of ischemic injury is frequently encountered in organ transplantation and trauma clinics. With no reliable real-time method of assessing the degree of injury incurred in tissue, surgeons generally rely on visual observation which is subjective. In this work, we investigate the use of optical spectroscopy methods as a potentially more reliable approach. Previous work by various groups was strongly suggestive that tissue autofluorescence from NADH obtained under UV excitation is sensitive to metabolic response changes. To test and expand upon this concept, we monitored autofluorescence and light scattering intensities of injured vs. uninjured rat kidneys via multimodal imaging under 355 nm, 325 nm, and 266 nm excitation as well as scattering under 500 nm illumination. 355 nm excitation was used to probe mainly NADH, a metabolite, while 266 nm excitation was used to probe mainly tryptophan to correct for non-metabolic signal artifacts. The ratio of autofluorescence intensities derived under these two excitation wavelengths was calculated and its temporal profile was fit to a relaxation model. Time constants were extracted, and longer time constants were associated with kidney dysfunction. Analysis of both the autofluorescence and light scattering images suggests that changes in microstructure tissue morphology, blood absorption spectral characteristics, and pH contribute to the behavior of the observed signal which may be used to obtain tissue functional information and offer predictive capability.

  18. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits

    PubMed Central

    Tang, Sung-Chun; Arumugam, Thiruma V.; Xu, Xiangru; Cheng, Aiwu; Mughal, Mohamed R.; Jo, Dong Gyu; Lathia, Justin D.; Siler, Dominic A.; Chigurupati, Srinivasulu; Ouyang, Xin; Magnus, Tim; Camandola, Simonetta; Mattson, Mark P.

    2007-01-01

    The innate immune system senses the invasion of pathogenic microorganisms and tissue injury through Toll-like receptors (TLR), a mechanism thought to be limited to immune cells. We now report that neurons express several TLRs, and that the levels of TLR2 and -4 are increased in neurons in response to IFN-γ stimulation and energy deprivation. Neurons from both TLR2 knockout and -4 mutant mice were protected against energy deprivation-induced cell death, which was associated with decreased activation of a proapoptotic signaling cascade involving jun N-terminal kinase and the transcription factor AP-1. TLR2 and -4 expression was increased in cerebral cortical neurons in response to ischemia/reperfusion injury, and the amount of brain damage and neurological deficits caused by a stroke were significantly less in mice deficient in TLR2 or -4 compared with WT control mice. Our findings establish a proapoptotic signaling pathway for TLR2 and -4 in neurons that may render them vulnerable to ischemic death. PMID:17693552

  19. Optical Spectroscopy Approach for the Predictive Assessment of Kidney Functional Recovery Following Ischemic Injury

    SciTech Connect

    Raman, R N; Pivetti, C D; Rubenchik, A M; Matthews, D L; Troppmann, C; Demos, S G

    2010-02-11

    Tissue that has undergone significant yet unknown amount of ischemic injury is frequently encountered in organ transplantation and trauma clinics. With no reliable real-time method of assessing the degree of injury incurred in tissue, surgeons generally rely on visual observation which is subjective. In this work, we investigate the use of optical spectroscopy methods as a potentially more reliable approach. Previous work by various groups was strongly suggestive that tissue autofluorescence from NADH obtained under UV excitation is sensitive to metabolic response changes. To test and expand upon this concept, we monitored autofluorescence and light scattering intensities of injured vs. uninjured rat kidneys via multimodal imaging under 355 nm, 325 nm, and 266 nm excitation as well as scattering under 500 nm illumination. 355 nm excitation was used to probe mainly NADH, a metabolite, while 266 nm excitation was used to probe mainly tryptophan to correct for non-metabolic signal artifacts. The ratio of autofluorescence intensities derived under these two excitation wavelengths was calculated and its temporal profile was fit to a relaxation model. Time constants were extracted, and longer time constants were associated with kidney dysfunction. Analysis of both the autofluorescence and light scattering images suggests that changes in microstructure tissue morphology, blood absorption spectral characteristics, and pH contribute to the behavior of the observed signal which may be used to obtain tissue functional information and offer predictive capability.

  20. Endoplasmic Reticulum Chaperon Tauroursodeoxycholic Acid Attenuates Aldosterone-Infused Renal Injury

    PubMed Central

    Guo, Honglei; Li, Hongmei; Ling, Lilu

    2016-01-01

    Aldosterone (Aldo) is critically involved in the development of renal injury via the production of reactive oxygen species and inflammation. Endoplasmic reticulum (ER) stress is also evoked in Aldo-induced renal injury. In the present study, we investigated the role of ER stress in inflammation-mediated renal injury in Aldo-infused mice. C57BL/6J mice were randomized to receive treatment for 4 weeks as follows: vehicle infusion, Aldo infusion, vehicle infusion plus tauroursodeoxycholic acid (TUDCA), and Aldo infusion plus TUDCA. The effect of TUDCA on the Aldo-infused inflammatory response and renal injury was investigated using periodic acid-Schiff staining, real-time PCR, Western blot, and ELISA. We demonstrate that Aldo leads to impaired renal function and inhibition of ER stress via TUDCA attenuates renal fibrosis. This was indicated by decreased collagen I, collagen IV, fibronectin, and TGF-β expression, as well as the downregulation of the expression of Nlrp3 inflammasome markers, Nlrp3, ASC, IL-1β, and IL-18. This paper presents an important role for ER stress on the renal inflammatory response to Aldo. Additionally, the inhibition of ER stress by TUDCA negatively regulates the levels of these inflammatory molecules in the context of Aldo. PMID:27721575

  1. DA-1229, a dipeptidyl peptidase IV inhibitor, protects against renal injury by preventing podocyte damage in an animal model of progressive renal injury.

    PubMed

    Eun Lee, Jee; Kim, Jung Eun; Lee, Mi Hwa; Song, Hye Kyoung; Ghee, Jung Yeon; Kang, Young Sun; Min, Hye Sook; Kim, Hyun Wook; Cha, Jin Joo; Han, Jee Young; Han, Sang Youb; Cha, Dae Ryong

    2016-05-01

    Although dipeptidyl peptidase IV (DPPIV) inhibitors are known to have renoprotective effects, the mechanism underlying these effects has remained elusive. Here we investigated the effects of DA-1229, a novel DPPIV inhibitor, in two animal models of renal injury including db/db mice and the adriamycin nephropathy rodent model of chronic renal disease characterized by podocyte injury. For both models, DA-1229 was administered at 300 mg/kg/day. DPPIV activity in the kidney was significantly higher in diabetic mice compared with their nondiabetic controls. Although DA-1229 did not affect glycemic control or insulin resistance, DA-1229 did improve lipid profiles, albuminuria and renal fibrosis. Moreover, DA-1229 treatment resulted in decreased urinary excretion of nephrin, decreased circulating and kidney DPPIV activity, and decreased macrophage infiltration in the kidney. In adriamycin-treated mice, DPPIV activity in the kidney and urinary nephrin loss were both increased, whereas glucagon-like peptide-1 concentrations were unchanged. Moreover, DA-1229 treatment significantly improved proteinuria, renal fibrosis and inflammation associated with decreased urinary nephrin loss, and kidney DPP4 activity. In cultured podocytes, DA-1229 restored the high glucose/angiotensin II-induced increase of DPPIV activity and preserved the nephrin levels in podocytes. These findings suggest that activation of DPPIV in the kidney has a role in the progression of renal disease, and that DA-1229 may exert its renoprotective effects by preventing podocyte injury.

  2. Accelerated recovery of renal mitochondrial and tubule homeostasis with SIRT1/PGC-1α activation following ischemia–reperfusion injury

    SciTech Connect

    Funk, Jason A.; Schnellmann, Rick G.

    2013-12-01

    Kidney ischemia–reperfusion (I/R) injury elicits cellular injury in the proximal tubule, and mitochondrial dysfunction is a pathological consequence of I/R. Promoting mitochondrial biogenesis (MB) as a repair mechanism after injury may offer a unique strategy to restore both mitochondrial and organ function. Rats subjected to bilateral renal pedicle ligation for 22 min were treated once daily with the SIRT1 activator SRT1720 (5 mg/kg) starting 24 h after reperfusion until 72 h–144 h. SIRT1 expression was elevated in the renal cortex of rats after I/R + vehicle treatment (IRV), but was associated with less nuclear localization. SIRT1 expression was even further augmented and nuclear localization was restored in the kidneys of rats after I/R + SRT1720 treatment (IRS). PGC-1α was elevated at 72 h–144 h in IRV and IRS kidneys; however, SRT1720 treatment induced deacetylation of PGC-1α, a marker of activation. Mitochondrial proteins ATP synthase β, COX I, and NDUFB8, as well as mitochondrial respiration, were diminished 24 h–144 h in IRV rats, but were partially or fully restored in IRS rats. Urinary kidney injury molecule-1 (KIM-1) was persistently elevated in both IRV and IRS rats; however, KIM-1 tissue expression was attenuated in IRS rats. Additionally, sustained loss of Na{sup +},K{sup +}–ATPase expression and basolateral localization and elevated vimentin in IRV rats was normalized in IRS rats, suggesting restoration of a differentiated, polarized tubule epithelium. The results suggest that SRT1720 treatment expedited recovery of mitochondrial protein expression and function by enhancing MB, which was associated with faster proximal tubule repair. Targeting MB may offer unique therapeutic strategy following ischemic injury. - Highlights: • We examined recovery of mitochondrial and renal function after ischemia–reperfusion. • SRT1720 treatment after I/R induced mitochondrial biogenesis via SIRT1/PGC-1α. • Recovery of mitochondrial function was

  3. Comprehensive renal scintillation procedures in spinal cord injury: comparison with excretory urography

    SciTech Connect

    Lloyd, L.K.; Dubovsky, E.V.; Bueschen, A.J.; Witten, D.M.; Scott, J.W.; Kuhlemeier, K.; Stover, S.L.

    1981-07-01

    A /sup 131/iodine orthoiodohippurate comprehensive renal scintillation procedure was performed and compared to results of excretory urography in 200 spinal cord injury patients. No severe urographic abnormalities were undetected by the comprehensive renal scintillation procedure. Only 1.4 per cent of renal units had greater than minimal pyelocaliectasis or ureterectasis in the presence of a normal radionuclide examination. A relatively large number of abnormalities were detected on the renal scintillation procedure when the excretory urogram was normal. Serial followup will be required to determine the significance of these findings but present data suggest that a comprehensive renal scintillation procedure and a plain film of the kidneys, ureters and bladder may be used for screening upper urinary tract abnormalities in lieu of an excretory urogram. This is particularly advantageous for the spinal cord injury population, since there have been no toxic or allergic reactions reported, no bowel preparation or dehydration is required and there is relatively low radiation exposure.

  4. Protective effects of ginsenoside Rb3 on oxygen and glucose deprivation-induced ischemic injury in PC12 cells

    PubMed Central

    Zhu, Jun-rong; Tao, Yi-fu; Lou, Shen; Wu, Zi-mei

    2010-01-01

    Aim: To investigate the protective effects of ginsenoside Rb3, a triterpenoid saponin isolated from the leaves of Panax notoginseng, on ischemic and reperfusion injury model of PC12 cells and elucidate the related mechanisms. Methods: PC12 cells exposed to oxygen and glucose deprivation (OGD) and restoration (OGD-Rep) were used as an in vitro model of ischemia and reperfusion. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) leakage were used to evaluate the protective effects of ginsenoside Rb3. Cellular apoptosis and mitochondrial membrane potential (MMP) were analyzed using flow cytometry. Intracellular calcium ion concentration ([Ca2+]i) was detected using fluorophotometer system. Caspase-3, -8, and -9 activities were measured using assay kits with an ELISA reader. Western blotting assay was used to evaluate the release of cytochrome c and expression of caspase-3, Bcl-2 and Bax proteins. Results: It was shown that ginsenoside Rb3 (0.1–10 μmol/L) significantly increased cell viability and inhibited LDH release in a dose-dependent manner on the ischemic model. In addition, ginsenoside Rb3 also significantly inhibited ischemic injury-induced apoptosis, [Ca2+]i elevation, and decrease of MMP. Meanwhile, pretreatment with ginsenoside Rb3 significantly induced an increase of Bcl-2 protein expression and a decrease of cytosolic cytochrome c, cleaved-caspase 3 and Bax protein expression, the caspase-3, -8, and -9 activity were also inhibited. Conclusion: The results indicated that ginsenoside Rb3 could markedly protected OGD-Rep induced ischemic injury and the mechanisms maybe related to its suppression of the intracellular Ca2+ elevation and inhibition of apoptosis and caspase activity. Ginsenoside Rb3 could be a promising candidate in the development of a novel class of anti-ischemic agent. PMID:20140005

  5. Selective cortical alteration after hypoxic-ischemic injury in the very immature rat brain.

    PubMed

    Sizonenko, Stephane V; Sirimanne, Ernest; Mayall, Yvette; Gluckman, Peter D; Inder, Terrie; Williams, Chris

    2003-08-01

    Distinctive cerebral lesions with disruptions to the developing white matter are found in very low birth weight (VLBW) infants. Although hypoxia-ischemia (HI) is a causal pathway, the pathogenesis of cerebral white matter injury in the VLBW infant is not fully understood. Pertinent murine models would facilitate the investigation of the processes leading to these cerebral lesions and enable the evaluation of therapeutic strategies. Postnatal d 3 (P3) rats are at a stage of cortical oligodendroglial maturation and axonal outgrowth similar to very preterm infants. Our aim was to characterize the effects of a focal hypoxic-ischemic injury at P3 on subsequent cerebral development. Three groups of P3 Wistar rats were investigated: group I underwent right carotid ligation followed by 6% hypoxia for 30 min (HI), group 2 had carotid ligation only, and group 3 had no intervention. At P21, in the HI group, the right cortical area was reduced compared with controls (p < 0.01). There were no significant alterations in the size of the dorsal hippocampus, striatum, and thalamus. The cortical myelinated area was reduced in the HI animals compared with controls (p < 0.01). There was a corresponding loss of myelinated axons extending up into the cortex, with deep cortical neuronal and axonal architecture markedly disrupted. Glial fibrillary acidic protein immunohistology showed a reactive gliosis in the deep parietal cortex (p < 0.01). Moderate HI injury in the immature rat brain compromised cortical growth and led to a selective alteration of cortical myelinated axons with persistent gliosis. These alterations induced at P3 by unilateral HI share neuropathological similarities with the diffuse white matter lesions found in VLBW infants.

  6. Insights into the role of iron in immature rat model of hypoxic-ischemic brain injury

    PubMed Central

    Wang, Zi-Wei; Yang, Li-Jun; Ding, Ying-Xue; Chang, Yan-Zhong; Cui, Hong

    2016-01-01

    This study aimed to investigate the role of iron in the occurrence and development of hypoxic-ischemic brain injury (HIBI) in immature rat models using 3-day-old Sprague Dawley rats. Normal control (NC), hypoxic-ischemic (HI), anemia, HI + ischemia, early iron treatment and late iron treatment groups were established. Rat brain tissue sections were stained with hematoxylin and eosin and pathologically evaluated. Iron content and mRNA expression levels of iron regulatory protein 2 (IRP2) and transferrin receptor in the brain tissues were measured. Ultrastructural changes in the actin, microtubules, myelin and mitochondria of oligodendrocytes and axons were examined by electron microscopy. Numbers of viable myelin sheaths and oligodendrocytes in the periventricular area were also observed. Pathological damage of brain tissue in the HI group was markedly increased compared with that in the NC group. Furthermore, there was a higher iron content and reduced number of viable oligodendrocytes in the periventricular area of the HI group compared with the NC group. No significant difference in iron content was observed between the HI + anemia and NC groups. The number of viable oligodendrocytes in the HI + anemia group was increased compared with that in the HI group, and the number in the HI + anemia group with late iron treatment was lower compared with that in the NC group and increased compared with that in the HI + anemia group. Electron microscopy revealed a significantly higher number of myelin sheaths in the HI + anemia group than in the HI group. IRP2 mRNA expression levels in the brain tissues were significantly decreased in the HI + anemia group compared with the HI group. The results suggest that anemia may reduce the rate of increase of iron content of the brain following HI. However, the early occurrence of anemia may protect against HIBI.

  7. The Neuroprotective Mechanism of Erythropoietin-TAT Fusion Protein Against Neurodegeneration from Ischemic Brain Injury.

    PubMed

    Liu, P; Liu, X; Akf Liou, Emptyyn Y; Xing, J; Jing, Z; Ji, X; Liu, X; Zhao, H; Yan, F; Chen, J; Cao, G; Luo, Y

    2013-08-27

    Aims: To compare the neuroprotection of erythropoietin (EPO) and EPO fusion protein containing transduction domain derived from HIV TAT (EPO-TAT) against ischemic brain injury, inclusive of the side effect, and explore the mechanism underlying the role of EPO-TAT in a transient focal cerebral ischemia model in rats. Methods: Transient focal ischemia was induced by middle cerebral artery occlusion (MCAO) in rats. Rats were treated, respectively, with following regimens: saline, 1000 U/kg EPO, 5000 U/kg EPO, 1000 U/kg EPO-TAT, 1000 U/kg EPO-TAT + 5 µl of 10 mM LY294002 (or/plus 5 µl of 5 mM PD98059). Neurological deficit scores, infarct volume, and hematologic side effect were assessed at 72 hours after MCAO. Apoptotic cells were determined with TUNEL staining. The expression and localization of phosphorylated AKT (pAKT) and phosphorylated ERK (pERK) were detected with Western blot, immunohistochemistry, and immunofluorescence, respectively. Results: 1000 U/kg EPO-TAT exhibited a comparable neuroprotection to 5000 U/kg EPO, as evidenced by a comparable attenuation in neurological deficit, infarct volume, and number of apoptotic cells in the rat ischemic cortex after MCAO. The pAKT and pERK levels were significantly elevated solely in neurons of rodents receiving EPO or EPO-TAT treatments, suggesting the concurrent activation of these two pathways. Specific inhibition of either AKT or ERK pathway partially abolished EPO-TAT protection, but exhibited no influence on the activation status of its counterpart, suggesting no cross-modulation between these two protective pathways. Conclusion: Our study indicates that EPO-TAT at 1000 U/kg displays neuroprotection with no detectable side effects. The mechanism for neuroprotection may be attributable to the simultaneous activation of the AKT and ERK pathways, which preserve neuronal cell viability and attenuate behavioral deficits. PMID:24040790

  8. Insights into the role of iron in immature rat model of hypoxic-ischemic brain injury

    PubMed Central

    Wang, Zi-Wei; Yang, Li-Jun; Ding, Ying-Xue; Chang, Yan-Zhong; Cui, Hong

    2016-01-01

    This study aimed to investigate the role of iron in the occurrence and development of hypoxic-ischemic brain injury (HIBI) in immature rat models using 3-day-old Sprague Dawley rats. Normal control (NC), hypoxic-ischemic (HI), anemia, HI + ischemia, early iron treatment and late iron treatment groups were established. Rat brain tissue sections were stained with hematoxylin and eosin and pathologically evaluated. Iron content and mRNA expression levels of iron regulatory protein 2 (IRP2) and transferrin receptor in the brain tissues were measured. Ultrastructural changes in the actin, microtubules, myelin and mitochondria of oligodendrocytes and axons were examined by electron microscopy. Numbers of viable myelin sheaths and oligodendrocytes in the periventricular area were also observed. Pathological damage of brain tissue in the HI group was markedly increased compared with that in the NC group. Furthermore, there was a higher iron content and reduced number of viable oligodendrocytes in the periventricular area of the HI group compared with the NC group. No significant difference in iron content was observed between the HI + anemia and NC groups. The number of viable oligodendrocytes in the HI + anemia group was increased compared with that in the HI group, and the number in the HI + anemia group with late iron treatment was lower compared with that in the NC group and increased compared with that in the HI + anemia group. Electron microscopy revealed a significantly higher number of myelin sheaths in the HI + anemia group than in the HI group. IRP2 mRNA expression levels in the brain tissues were significantly decreased in the HI + anemia group compared with the HI group. The results suggest that anemia may reduce the rate of increase of iron content of the brain following HI. However, the early occurrence of anemia may protect against HIBI. PMID:27602087

  9. Sympathetic nervous response to ischemia-reperfusion injury in humans is altered with remote ischemic preconditioning.

    PubMed

    Lambert, Elisabeth A; Thomas, Colleen J; Hemmes, Robyn; Eikelis, Nina; Pathak, Atul; Schlaich, Markus P; Lambert, Gavin W

    2016-08-01

    Sympathetic neural activation may be detrimentally involved in tissue injury caused by ischemia-reperfusion (IR). We examined the effects of experimental IR in the forearm on sympathetic nerve response, finger reactive hyperemia, and oxidative stress, and the protection afforded by applying remote ischemic preconditioning (RIPC). Ischemia was induced in the forearm for 20 min in healthy volunteers. RIPC was induced by applying two cycles, 5 min each, of ischemia and reperfusion to the upper leg immediately before IR. We examined muscle sympathetic nerve activity (MSNA) in the contralateral leg using microneurography, finger reactive hyperemia [ischemic reactive hyperemia index (RHI)], erythrocyte production of reduced gluthathione (GSH), and plasma nitric oxide (NO) concentration. In controls (no RIPC; n = 15), IR increased MSNA in the early and late phase of ischemia (70% at 5 min; 101% at 15 min). In subjects who underwent RIPC (n = 15), the increase in MSNA was delayed to the late phase of ischemia and increased only by 40%. GSH increased during ischemia in the control group (P = 0.05), but not in those who underwent RIPC. Nitrate and nitrite concentration, taken as an index of NO availability, decreased during the reperfusion period in control individuals (P < 0.05), while no change was observed in those who underwent RIPC. Experimental IR did not affect RHI in the control condition, but a significant vasodilatory response occurred in the RIPC group (P < 0.05). RIPC attenuated ischemia-induced sympathetic activation, prevented the production of an erythrocyte marker of oxidative stress and the reduction of NO availability, and ameliorated RHI. PMID:27288436

  10. Glutathione Suppresses Cerebral Infarct Volume and Cell Death after Ischemic Injury: Involvement of FOXO3 Inactivation and Bcl2 Expression

    PubMed Central

    Park, Joohyun; Oh, Yumi

    2015-01-01

    Ischemic stroke interrupts the flow of blood to the brain and subsequently results in cerebral infarction and neuronal cell death, leading to severe pathophysiology. Glutathione (GSH) is an antioxidant with cellular protective functions, including reactive oxygen species (ROS) scavenging in the brain. In addition, GSH is involved in various cellular survival pathways in response to oxidative stress. In the present study, we examined whether GSH reduces cerebral infarct size after middle cerebral artery occlusion in vivo and the signaling mechanisms involved in the promotion of cell survival after GSH treatment under ischemia/reperfusion conditions in vitro. To determine whether GSH reduces the extent of cerebral infarction, cell death after ischemia, and reperfusion injury, we measured infarct size in ischemic brain tissue and the expression of claudin-5 associated with brain infarct formation. We also examined activation of the PI3K/Akt pathway, inactivation of FOXO3, and expression of Bcl2 to assess the role of GSH in promoting cell survival in response to ischemic injury. Based on our results, we suggest that GSH might improve the pathogenesis of ischemic stroke by attenuating cerebral infarction and cell death. PMID:25722793

  11. Nephron Deficiency and Predisposition to Renal Injury in a Novel One-Kidney Genetic Model.

    PubMed

    Wang, Xuexiang; Johnson, Ashley C; Williams, Jan M; White, Tiffani; Chade, Alejandro R; Zhang, Jie; Liu, Ruisheng; Roman, Richard J; Lee, Jonathan W; Kyle, Patrick B; Solberg-Woods, Leah; Garrett, Michael R

    2015-07-01

    Some studies have reported up to 40% of patients born with a single kidney develop hypertension, proteinuria, and in some cases renal failure. The increased susceptibility to renal injury may be due, in part, to reduced nephron numbers. Notably, children who undergo nephrectomy or adults who serve as kidney donors exhibit little difference in renal function compared with persons who have two kidneys. However, the difference in risk between being born with a single kidney versus being born with two kidneys and then undergoing nephrectomy are unclear. Animal models used previously to investigate this question are not ideal because they require invasive methods to model congenital solitary kidney. In this study, we describe a new genetic animal model, the heterogeneous stock-derived model of unilateral renal agenesis (HSRA) rat, which demonstrates 50%-75% spontaneous incidence of a single kidney. The HSRA model is characterized by reduced nephron number (more than would be expected by loss of one kidney), early kidney/glomerular hypertrophy, and progressive renal injury, which culminates in reduced renal function. Long-term studies of temporal relationships among BP, renal hemodynamics, and renal function demonstrate that spontaneous single-kidney HSRA rats are more likely than uninephrectomized normal littermates to exhibit renal impairment because of the combination of reduced nephron numbers and prolonged exposure to renal compensatory mechanisms (i.e., hyperfiltration). Future studies with this novel animal model may provide additional insight into the genetic contributions to kidney development and agenesis and the factors influencing susceptibility to renal injury in individuals with congenital solitary kidney.

  12. Nephron Deficiency and Predisposition to Renal Injury in a Novel One-Kidney Genetic Model

    PubMed Central

    Wang, Xuexiang; Johnson, Ashley C.; Williams, Jan M.; White, Tiffani; Chade, Alejandro R.; Zhang, Jie; Liu, Ruisheng; Roman, Richard J.; Lee, Jonathan W.; Kyle, Patrick B.; Solberg-Woods, Leah

    2015-01-01

    Some studies have reported up to 40% of patients born with a single kidney develop hypertension, proteinuria, and in some cases renal failure. The increased susceptibility to renal injury may be due, in part, to reduced nephron numbers. Notably, children who undergo nephrectomy or adults who serve as kidney donors exhibit little difference in renal function compared with persons who have two kidneys. However, the difference in risk between being born with a single kidney versus being born with two kidneys and then undergoing nephrectomy are unclear. Animal models used previously to investigate this question are not ideal because they require invasive methods to model congenital solitary kidney. In this study, we describe a new genetic animal model, the heterogeneous stock-derived model of unilateral renal agenesis (HSRA) rat, which demonstrates 50%–75% spontaneous incidence of a single kidney. The HSRA model is characterized by reduced nephron number (more than would be expected by loss of one kidney), early kidney/glomerular hypertrophy, and progressive renal injury, which culminates in reduced renal function. Long-term studies of temporal relationships among BP, renal hemodynamics, and renal function demonstrate that spontaneous single-kidney HSRA rats are more likely than uninephrectomized normal littermates to exhibit renal impairment because of the combination of reduced nephron numbers and prolonged exposure to renal compensatory mechanisms (i.e., hyperfiltration). Future studies with this novel animal model may provide additional insight into the genetic contributions to kidney development and agenesis and the factors influencing susceptibility to renal injury in individuals with congenital solitary kidney. PMID:25349207

  13. Protective effects of alkaloid extract from Leonurus heterophyllus on cerebral ischemia reperfusion injury by middle cerebral ischemic injury (MCAO) in rats.

    PubMed

    Liang, Hao; Liu, Ping; Wang, Yunshan; Song, Shuliang; Ji, Aiguo

    2011-07-15

    The neuronal damage following cerebral ischemia is a serious risk to stroke patients. The aim of this study was to investigate the neuroprotective effects of alkaloid extract from Leonurus heterophyllus (LHAE) on cerebral ischemic injury. After 24 h of reperfusion following ischemia for 2 h induced by middle cerebral artery occlusion (MCAO), some rats were intraperitoneally administered different doses of LHAE (3.6, 7.2, 14.4 mg/kg, respectively). Neurological examination was measured in all animals. Infarct volume, myeloperoxidase (MPO) activity, levels of nitrate/nitrite metabolite (NO) and apoptosis ratio of nerve fiber in brain were determined. The results showed that LHAE at 7.2 mg/kg or 14.4 mg/kg exerted significantly decreasing neurological deficit scores and reducing the infarct volume on rats with focal cerebral ischemic injury (p<0.05). At those dose, the MPO content were significantly decreased in ischemic brain as compared with model group (p<0.05). LHAE at 14.4 mg/kg significantly decreased the NO level compared with the model group (p<0.05). In addition, LHAE significantly decreased the apoptosis ratio of nerve fiber compared with the model group (p<0.05). This study suggests that LHAE may be used for treatment of ischemic stroke as a neuroprotective agent. Further studies are warranted to assess the efficacy and safety of LHAE in patients.

  14. Protective effect of ischemic preconditioning on the jejunal graft mucosa injury during cold preservation.

    PubMed

    Jonecova, Zuzana; Toth, Stefan; Maretta, Milan; Ciccocioppo, Rachele; Varga, Jan; Rodrigo, Luis; Kruzliak, Peter

    2015-10-01

    Protection of intestinal graft mucosa during cold preservation is still an unmet need in clinical practice, thus affecting the success of transplantation. The present study investigates the ability of two ischemic preconditioning (IPC) procedures to limit cold preservation injury. Three groups of Sprague-Dawley rats were recruited (n=11 each) as follows: the short IPC (SIPC) performed through 4 cycles of mesenteric ischemia of 4 min each followed by 10 min of reperfusion, the long IPC (LIPC) obtained by 2 ischemic cycles of 12 min each followed by 10 min of reperfusion, and the control group (C) without IPC. Grafts were then stored in cold histidine-tryptophan-ketoglutarate solution and samples were taken at 0, 3, 6 and 9 h lasting preservation. Both IPC groups showed an advanced degree of preservation with delayed development of graft mucosa damage, mainly in the crypt region. At the beginning of preservation, the graft mucosa in both IPC groups showed lower degree of mucosal injury index (MII) by 50% in comparison with C group. Specifically, a significant improvement of MII was observed after 3h of preservation in the LIPC group (p<0.05) in comparison with untreated C grafts. Significant atrophy of the intestinal mucosa in C group was found after 3h of preservation (p<0.01), in SIPC group the progress of atrophy was delayed to 6 h (p<0.001), and in LIPC group only moderate decrease in that was found. A parallel increase of laminin expression with the MII rate after 6 and 9h of preservation in comparison with the level at time 0 was observed in all grafts (p<0.001 and p<0.01, respectively). In both IPC groups the apoptotic cell (AC) rate was significantly reduced at the beginning of cold preservation (p<0.05 both). Moreover, in both the SIPC and C groups, the progressive increase in MII rate connected with AC rate decrease was due to a predominance of necrosis. By contrast in the LIPC group, after an increase of nearly 50% in the AC rate at the 3rd hour, its level

  15. Paeoniflorin ameliorates acute necrotizing pancreatitis and pancreatitis-induced acute renal injury

    PubMed Central

    Wang, Peng; Wang, Weixing; Shi, Qiao; Zhao, Liang; Mei, Fangchao; Li, Chen; Zuo, Teng; He, Xiaobo

    2016-01-01

    Acute renal injury caused by acute necrotizing pancreatitis (ANP) is a common complication that is associated with a high rate of mortality. Paeoniflorin is the active ingredient of paeonia radix and exhibits a number of pharmacological effects, such as anti-inflammatory, anticancer, analgesic and immunomodulatory effects. The present study detected the potential treatment effects of paeoniflorin on acute renal injury induced by ANP in a rat model. The optimal dose of paeoniflorin for preventing acute renal injury induced by ANP was determined. Then, the possible protective mechanism of paeoniflorin was investigated. The serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were measured with enzyme-linked immunosorbent assay kits. Renal inflammation and apoptosis were measured by immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. The expression of nitric oxide in kidney tissues was also evaluated. The p38 mitogen-activated protein kinases (MAPKs) were measured by western blotting. The results shown that paeoniflorin may ameliorate acute renal injury following ANP in rats by inhibiting inflammatory responses and renal cell apoptosis. These effects may be associated with the p38MAPK and nuclear factor-κB signal pathway. PMID:27279569

  16. Kidney injury molecule-1 expression is closely associated with renal allograft damage.

    PubMed

    Song, Lianlian; Xue, Lijuan; Yu, Jinyu; Zhao, Jun; Zhang, Wenlan; Fu, Yaowen

    2013-08-01

    The aim of our study was to investigate the expression of kidney injury molecule-1 (KIM-1) in renal allograft biopsy samples and assess the clinical significance of its use as a biomarker for tissue damage. A total of 69 renal allograft biopsy samples from 17 patients with normal serum creatinine and 52 cases of increased serum creatinine were collected. They were divided into different groups according to the Banff 2007 diagnostic criteria. KIM-1 expression was detected by immunohistochemical methods and the association of KIM-1 and blood biochemical indexes was analyzed. KIM-1 expression increased as Banff 2007 classification grade increased and was positively correlated with tubular inflammation severity in the acute T-cell rejection group. Moreover, KIM-1 expression was strongly positive in the chronic active antibody-mediated rejection group. Interestingly, KIM-1 was weakly positive in the normal group without obvious acute rejection and injury of immunosuppressant toxicity. In this group, 27.3% (3/11) of the cases with normal serum creatinine level showed weakly positive KIM-1 expression in their renal tissues. KIM-1 expression level is positively correlated with renal allograft damage and tubular cell injury. KIM-1 is expressed in tubular epithelial cells before blood biochemical indexes become elevated and morphological changes occur. KIM-1 expression is an early, sensitive, and specific biomarker to determine renal tubular epithelial cell injury in renal allograft tissue.

  17. Sulfasalazine-induced renal injury in rats and the protective role of thiol-reductants.

    PubMed

    Heidari, Reza; Taheri, Vahid; Rahimi, Hamid Reza; Shirazi Yeganeh, Babak; Niknahad, Hossein; Najibi, Asma

    2016-01-01

    Sulfasalazine is widely used for inflammatory-mediated disorders in human. Renal damage is a serious adverse effect accompanied sulfasalazine administration. No specific therapeutic option is available against this complication so far. Oxidative stress seems to play a role in sulfasalazine-induced renal injury. Current investigation was designed to evaluate the effect of N-acetyl cysteine (NAC) and dithiothreitol (DTT) as thiol reductants against sulfasalazine-induced renal injury in rats. Oral administration of sulfasalazine (600 mg/kg for 14 consecutive days) caused renal injury as judged by increase in serum level of creatinine and blood urea nitrogen. Furthermore, the level of reactive oxygen species and lipid peroxidation were raised in kidney tissue after sulfasalazine administration. Additionally, it was also found that renal glutathione reservoirs were significantly depleted in sulfasalazine-treated animals. Histopathological examination of kidney endorsed organ injury in drug-treated rats. Daily intraperitoneal administration of NAC (250 and 500 mg/kg/day) and/or DTT (15 and 30 mg/kg/day) effectively alleviated renal damage induced by sulfasalazine. Data suggested that thiol reductants could serve as potential protective agents with therapeutic capabilities against sulfasalazine adverse effect toward kidney. PMID:26479898

  18. Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy.

    PubMed

    Lanaspa, Miguel A; Ishimoto, Takuji; Cicerchi, Christina; Tamura, Yoshifuru; Roncal-Jimenez, Carlos A; Chen, Wei; Tanabe, Katsuyuki; Andres-Hernando, Ana; Orlicky, David J; Finol, Esteban; Inaba, Shinichiro; Li, Nanxing; Rivard, Christopher J; Kosugi, Tomoki; Sanchez-Lozada, Laura G; Petrash, J Mark; Sautin, Yuri Y; Ejaz, A Ahsan; Kitagawa, Wataru; Garcia, Gabriela E; Bonthron, David T; Asipu, Aruna; Diggle, Christine P; Rodriguez-Iturbe, Bernardo; Nakagawa, Takahiko; Johnson, Richard J

    2014-11-01

    Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase-deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease.

  19. Endogenous Fructose Production and Fructokinase Activation Mediate Renal Injury in Diabetic Nephropathy

    PubMed Central

    Ishimoto, Takuji; Cicerchi, Christina; Tamura, Yoshifuru; Roncal-Jimenez, Carlos A.; Chen, Wei; Tanabe, Katsuyuki; Andres-Hernando, Ana; Orlicky, David J.; Finol, Esteban; Inaba, Shinichiro; Li, Nanxing; Rivard, Christopher J.; Kosugi, Tomoki; Sanchez-Lozada, Laura G.; Petrash, J. Mark; Sautin, Yuri Y.; Ejaz, A. Ahsan; Kitagawa, Wataru; Garcia, Gabriela E.; Bonthron, David T.; Asipu, Aruna; Diggle, Christine P.; Rodriguez-Iturbe, Bernardo; Nakagawa, Takahiko; Johnson, Richard J.

    2014-01-01

    Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase–deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease. PMID:24876114

  20. Differential expression of embryonic epicardial progenitor markers and localization of cardiac fibrosis in adult ischemic injury and hypertensive heart disease.

    PubMed

    Braitsch, Caitlin M; Kanisicak, Onur; van Berlo, Jop H; Molkentin, Jeffery D; Yutzey, Katherine E

    2013-12-01

    During embryonic heart development, the transcription factors Tcf21, Wt1, and Tbx18 regulate activation and differentiation of epicardium-derived cells, including fibroblast lineages. Expression of these epicardial progenitor factors and localization of cardiac fibrosis were examined in mouse models of cardiovascular disease and in human diseased hearts. Following ischemic injury in mice, epicardial fibrosis is apparent in the thickened layer of subepicardial cells that express Wt1, Tbx18, and Tcf21. Perivascular fibrosis with predominant expression of Tcf21, but not Wt1 or Tbx18, occurs in mouse models of pressure overload or hypertensive heart disease, but not following ischemic injury. Areas of interstitial fibrosis in ischemic and hypertensive hearts actively express Tcf21, Wt1, and Tbx18. In all areas of fibrosis, cells that express epicardial progenitor factors are distinct from CD45-positive immune cells. In human diseased hearts, differential expression of Tcf21, Wt1, and Tbx18 also is detected with epicardial, perivascular, and interstitial fibrosis, indicating conservation of reactivated developmental mechanisms in cardiac fibrosis in mice and humans. Together, these data provide evidence for distinct fibrogenic mechanisms that include Tcf21, separate from Wt1 and Tbx18, in different fibroblast populations in response to specific types of cardiac injury.

  1. Characterization of the development of renal injury in Type-1 diabetic Dahl salt-sensitive rats.

    PubMed

    Slaughter, Tiffani N; Paige, Adrienne; Spires, Denisha; Kojima, Naoki; Kyle, Patrick B; Garrett, Michael R; Roman, Richard J; Williams, Jan M

    2013-10-01

    The present study compared the progression of renal injury in Sprague-Dawley (SD) and Dahl salt-sensitive (SS) treated with streptozotocin (STZ). The rats received an injection of STZ (50 mg/kg ip) and an insulin pellet (2 U/day sc) to maintain the blood glucose levels between 400 and 600 mg/dl. Twelve weeks later, arterial pressure (143 ± 6 vs. 107 ± 8 mmHg) and proteinuria (557 ± 85 vs. 81 ± 6 mg/day) were significantly elevated in STZ-SS rats compared with the values observed in STZ-SD rats, respectively. The kidneys from STZ-SS rats exhibited thickening of glomerular basement membrane, mesangial expansion, severe glomerulosclerosis, renal interstitial fibrosis, and occasional glomerular nodule formation. In additional studies, treatment with a therapeutic dose of insulin (4 U/day sc) attenuated the development of proteinuria (212 ± 32 mg/day) and renal injury independent of changes in arterial pressure in STZ-SS rats. Since STZ-SS rats developed severe renal injury, we characterized the time course of changes in renal hemodynamics during the progression of renal injury. Nine weeks after diabetes onset, there was a 42% increase in glomerular filtration rate in STZ-SS rats vs. time-control SS rats with reduced renal blood flow. These results indicate that SS rats treated with STZ develop hyperfiltration and progressive proteinuria and display renal histological lesions characteristic of those seen in patients with diabetic nephropathy. Overall, this model may be useful to study signaling pathways and mechanisms that play a role in the progression of diabetes-induced renal disease and the development of new therapies to slow the progression of diabetic nephropathy. PMID:23926133

  2. Microvesicles derived from human Wharton’s Jelly mesenchymal stromal cells ameliorate renal ischemia-reperfusion injury in rats by suppressing CX3CL1

    PubMed Central

    2014-01-01

    Introduction Studies have demonstrated that mesenchymal stromal cells (MSCs) could reverse acute and chronic kidney injury by a paracrine or endocrine mechanism, and microvesicles (MVs) have been regarded as a crucial means of intercellular communication. In the current study, we focused on the therapeutic effects of human Wharton-Jelly MSCs derived microvesicles (hWJMSC-MVs) in renal ischemia/reperfusion injury and its potential mechanisms. Methods MVs isolated from conditioned medium were injected intravenously in rats immediately after ischemia of the left kidney for 60 minutes. The animals were sacrificed at 24 hours, 48 hours and 2 weeks after reperfusion. The infiltration of inflammatory cells was identified by the immunostaining of CD68+ cells. ELISA was employed to determine the inflammatory factors in the kidney and serum von Willebrand Factor (VWF). Tubular cell proliferation and apoptosis were identified by immunostaining. Renal fibrosis was assessed by Masson’s tri-chrome straining and alpha-smooth muscle actin (α-SMA) staining. The CX3CL1 expression in the kidney was measured by immunostaining and Western blot, respectively. In vitro, human umbilical vein endothelial cells were treated with or without MVs for 24 or 48 hours under hypoxia injury to test the CX3CL1 by immunostaining and Western blot. Results After administration of hWJMSC-MVs in acute kidney injury (AKI) rats, renal cell apoptosis was mitigated and proliferation was enhanced, inflammation was also alleviated in the first 48 hours. MVs also could suppress the expression of CX3CL1 and decrease the number of CD68+ macrophages in the kidney. In the late period, improvement of renal function and abrogation of renal fibrosis were observed. In vitro, MVs could down-regulate the expression of CX3CL1 in human umbilical vein endothelial cells under hypoxia injury at 24 or 48 hours. Conclusions A single administration of MVs immediately after ischemic AKI could ameliorate renal injury in

  3. Effects of alprostadil and iloprost on renal, lung, and skeletal muscle injury following hindlimb ischemia–reperfusion injury in rats

    PubMed Central

    Erer, Dilek; Özer, Abdullah; Demirtaş, Hüseyin; Gönül, İpek Işık; Kara, Halil; Arpacı, Hande; Çomu, Faruk Metin; Oktar, Gürsel Levent; Arslan, Mustafa; Küçük, Ayşegül

    2016-01-01

    Objectives To evaluate the effects of alprostadil (prostaglandin [PGE1] analog) and iloprost (prostacyclin [PGI2] analog) on renal, lung, and skeletal muscle tissues after ischemia reperfusion (I/R) injury in an experimental rat model. Materials and methods Wistar albino rats underwent 2 hours of ischemia via infrarenal aorta clamping with subsequent 2 hours of reperfusion. Alprostadil and iloprost were given starting simultaneously with the reperfusion period. Effects of agents on renal, lung, and skeletal muscle (gastrocnemius) tissue specimens were examined. Results Renal medullary congestion, cytoplasmic swelling, and mean tubular dilatation scores were significantly lower in the alprostadil-treated group than those found in the I/R-only group (P<0.0001, P=0.015, and P<0.01, respectively). Polymorphonuclear leukocyte infiltration, pulmonary partial destruction, consolidation, alveolar edema, and hemorrhage scores were significantly lower in alprostadil- and iloprost-treated groups (P=0.017 and P=0.001; P<0.01 and P<0.0001). Polymorphonuclear leukocyte infiltration scores in skeletal muscle tissue were significantly lower in the iloprost-treated group than the scores found in the nontreated I/R group (P<0.0001). Conclusion Alprostadil and iloprost significantly reduce lung tissue I/R injury. Alprostadil has more prominent protective effects against renal I/R injury, while iloprost is superior in terms of protecting the skeletal muscle tissue against I/R injury.

  4. Effects of alprostadil and iloprost on renal, lung, and skeletal muscle injury following hindlimb ischemia–reperfusion injury in rats

    PubMed Central

    Erer, Dilek; Özer, Abdullah; Demirtaş, Hüseyin; Gönül, İpek Işık; Kara, Halil; Arpacı, Hande; Çomu, Faruk Metin; Oktar, Gürsel Levent; Arslan, Mustafa; Küçük, Ayşegül

    2016-01-01

    Objectives To evaluate the effects of alprostadil (prostaglandin [PGE1] analog) and iloprost (prostacyclin [PGI2] analog) on renal, lung, and skeletal muscle tissues after ischemia reperfusion (I/R) injury in an experimental rat model. Materials and methods Wistar albino rats underwent 2 hours of ischemia via infrarenal aorta clamping with subsequent 2 hours of reperfusion. Alprostadil and iloprost were given starting simultaneously with the reperfusion period. Effects of agents on renal, lung, and skeletal muscle (gastrocnemius) tissue specimens were examined. Results Renal medullary congestion, cytoplasmic swelling, and mean tubular dilatation scores were significantly lower in the alprostadil-treated group than those found in the I/R-only group (P<0.0001, P=0.015, and P<0.01, respectively). Polymorphonuclear leukocyte infiltration, pulmonary partial destruction, consolidation, alveolar edema, and hemorrhage scores were significantly lower in alprostadil- and iloprost-treated groups (P=0.017 and P=0.001; P<0.01 and P<0.0001). Polymorphonuclear leukocyte infiltration scores in skeletal muscle tissue were significantly lower in the iloprost-treated group than the scores found in the nontreated I/R group (P<0.0001). Conclusion Alprostadil and iloprost significantly reduce lung tissue I/R injury. Alprostadil has more prominent protective effects against renal I/R injury, while iloprost is superior in terms of protecting the skeletal muscle tissue against I/R injury. PMID:27601882

  5. Attenuation of Ischemic Liver Injury by Monoclonal Anti-Endothelin Antibody, AwETN40

    PubMed Central

    Urakami, Atsushi; Todo, Satoru; Zhu, Yue; Zhang, Shimin; Jin, Maeng Bong; Ishizaki, Naoki; Shimamura, Tsuyoshi; Totsuka, Eishi; Subbotin, Vladimir; Lee, Randall; Starzl, Thomas E.

    2009-01-01

    Background Enhanced production of endothelin-1 (ET-1), vasoconstrictive 21 amino acids produced by endothelial cells during ischemia and after reperfusion of the liver, is known to cause sinusoidal constriction and microcirculatory disturbances, which lead to severe tissue damage. Using a 2-hour hepatic vascular exclusion model in dogs, we tested our hypothesis that neutralization of ET-1 by monoclonal anti-ET-1 and anti-ET-2 antibody (AwETN40) abates vascular dysfunction and ameliorates ischemia/reperfusion injury of the liver. Study Design After skeletonization, the liver was made totally ischemic by cross-clamping the portal vein, the hepatic artery, and the vena cava (above and below the liver). Veno-venous bypass was used to decompress splanchnic and inferior systemic congestion. AwETN40, 5 mg/kg, was administered intravenously 10 minutes before ischemia (treatment group, n = 5). Nontreated animals were used as controls (control group, n = 10). Animal survival, hepatic tissue blood flow, liver function tests, total bile acid, high-energy phosphate, ET-1 levels, and liver histopathology were studied. Results Treatment with AwETN40 improved 2-week animal survival from 30% to 100%. Hepatic tissue blood flow after reperfusion was significantly higher in the treatment group. The treatment significantly attenuated liver enzyme release, total bile acid, and changes in adenine nucleotides. Immunoreactive ET-1 levels in the hepatic venous blood of the control group showed a significant increase and remained high for up to 24 hours after reperfusion. Histopathologic alterations were significantly lessened in the treatment group. Conclusions These results indicate that ET-1 is involved in ischemia/reperfusion injury of the liver, which can be ameliorated by the monoclonal anti-ET-1 and anti-ET-2 antibody AwETN40. PMID:9328384

  6. Striatal astrocytes transdifferentiate into functional mature neurons following ischemic brain injury

    PubMed Central

    Duan, Chun‐Ling; Liu, Chong‐Wei; Shen, Shu‐Wen; Yu, Zhang; Mo, Jia‐Lin; Chen, Xian‐Hua

    2015-01-01

    To determine whether reactive astrocytes stimulated by brain injury can transdifferentiate into functional new neurons, we labeled these cells by injecting a glial fibrillary acidic protein (GFAP) targeted enhanced green fluorescence protein plasmid (pGfa2‐eGFP plasmid) into the striatum of adult rats immediately following a transient middle cerebral artery occlusion (MCAO) and performed immunolabeling with specific neuronal markers to trace the neural fates of eGFP‐expressing (GFP+) reactive astrocytes. The results showed that a portion of striatal GFP+ astrocytes could transdifferentiate into immature neurons at 1 week after MCAO and mature neurons at 2 weeks as determined by double staining GFP‐expressing cells with βIII‐tubulin (GFP+‐Tuj‐1+) and microtubule associated protein‐2 (GFP+‐MAP‐2+), respectively. GFP+ neurons further expressed choline acetyltransferase, glutamic acid decarboxylase, dopamine receptor D2‐like family proteins, and the N‐methyl‐d‐aspartate receptor subunit R2, indicating that astrocyte‐derived neurons could develop into cholinergic or GABAergic neurons and express dopamine and glutamate receptors on their membranes. Electron microscopy analysis indicated that GFP+ neurons could form synapses with other neurons at 13 weeks after MCAO. Electrophysiological recordings revealed that action potentials and active postsynaptic currents could be recorded in the neuron‐like GFP+ cells but not in the astrocyte‐like GFP+ cells, demonstrating that new GFP+ neurons possessed the capacity to fire action potentials and receive synaptic inputs. These results demonstrated that striatal astrocyte‐derived new neurons participate in the rebuilding of functional neural networks, a fundamental basis for brain repair after injury. These results may lead to new therapeutic strategies for enhancing brain repair after ischemic stroke. GLIA 2015;63:1660–1670 PMID:26031629

  7. Role of spleen-derived monocytes/macrophages in acute ischemic brain injury.

    PubMed

    Kim, Eunhee; Yang, Jiwon; Beltran, Cesar D; Cho, Sunghee

    2014-08-01

    Monocytes/macrophages (MMs), mononuclear phagocytes, have been implicated in stroke-induced inflammation and injury. However, the presence of pro-inflammatory Ly-6C(high) and antiinflammatory Ly-6C(low) monocyte subsets raises uncertainty regarding their role in stroke pathologic assessment. With recent identification of the spleen as an immediate reservoir of MMs, this current study addresses whether the spleen-derived MMs are required for stroke pathologic assessment. We observed that the spleen was contracted in poststroke animals and the contraction was accompanied by decreased number of Ly-6C(high) and Ly-6C(low) subsets in the spleen. The deployment of these subsets from the spleen temporally coincided with respective increases in the ischemic brain. Compared to mice with the spleen, mice receiving a splenectomy just before the stroke displayed less accumulation of Ly-6C(high) and Ly-6C(low) MMs in the brain. Despite the reduced accumulation of both subsets, infarct size and swelling were not reduced in the asplenic mice. The dissociative findings of infarct size and extent of MM infiltration in the postischemic brain indicate minimal involvement of spleen-derived total MMs in acute infarct development. Selective Ly-6C(high) or Ly-6C(low) MM targeting is suggested to address the contribution of the individual subset to acute stroke pathologic assessment.

  8. Early effects of high-fat diet on neurovascular function and focal ischemic brain injury.

    PubMed

    Li, Weiguo; Prakash, Roshini; Chawla, Dhruv; Du, Wenting; Didion, Sean P; Filosa, Jessica A; Zhang, Quanguang; Brann, Darrell W; Lima, Victor V; Tostes, Rita C; Ergul, Adviye

    2013-06-01

    Obesity is a risk factor for stroke, but the early effects of high-fat diet (HFD) on neurovascular function and ischemic stroke outcomes remain unclear. The goal of this study was to test the hypotheses that HFD beginning early in life 1) impairs neurovascular coupling, 2) causes cerebrovascular dysfunction, and 3) worsens short-term outcomes after cerebral ischemia. Functional hyperemia and parenchymal arteriole (PA) reactivity were measured in rats after 8 wk of HFD. The effect of HFD on basilar artery function after middle cerebral artery occlusion (MCAO) and associated O-GlcNAcylation were assessed. Neuronal cell death, infarct size, hemorrhagic transformation (HT) frequency/severity, and neurological deficit were evaluated after global ischemia and transient MCAO. HFD caused a 10% increase in body weight and doubled adiposity without a change in lipid profile, blood glucose, and blood pressure. Functional hyperemia and PA relaxation were decreased with HFD. Basilar arteries from stroked HFD rats were more sensitive to contractile factors, and acetylcholine-mediated relaxation was impaired. Vascular O-GlcNAcylated protein content was increased with HFD. This group also showed greater mortality rate, infarct volume, HT occurrence rate, and HT severity and poor functional outcome compared with the control diet group. These results indicate that HFD negatively affects neurovascular coupling and cerebrovascular function even in the absence of dyslipidemia. These early cerebrovascular changes may be the cause of greater cerebral injury and poor outcomes of stroke in these animals. PMID:23576615

  9. Suppressing cardiac vagal modulation and changing sleep patterns in rats after chronic ischemic stroke injury.

    PubMed

    Huang, Shiang-Suo; Su, Hsing-Hui; Kuo, Terry B J; Chen, Chun-Yu; Lan, Yi-Yun; Liu, Bi-Yu; Yang, Ding-I; Tsai, Shih-Chih; Yang, Cheryl C H

    2012-08-16

    Chronic autonomic function and sleep architecture changes in patients post-stroke are not well understood. Using wireless polysomnographic recordings, this study aimed to investigate the long-term effects on sleep patterns and autonomic function in free moving rats after middle cerebral artery occlusion (MCAO). The sleep pattern and heart rate variability (HRV) of Wistar-Kyoto rats (WKY) were analyzed. After 7-10days, the rats were divided into two groups: an MCAO group (n=8) and a sham surgery group (n=8). Compared with shams, MCAO rats showed decreased accumulated quiet sleep (QS) time over 24h during the 3rd week. The time percentage, duration and delta power of QS were also significantly decreased in the MCAO group during the dark period. Compared with baseline, there were significant increases in the parasympathetic-associated HRV measures in the sham group, including the total power (TP), high frequency power (HF) and lower frequency power (LF), throughout the post-operative weeks (primarily the 2nd and 3rd weeks), reflecting a developmental increase of parasympathetic modulation; the normalized LF and the LF-HF ratio were unaffected. In great contrast, however, most of the HRV measures in the MCAO group were not significantly changed. Therefore, this study showed that the long-term effects of ischemic stroke injury involve retardation of the establishment of parasympathetic enhancement and disturbance of the normal sleep-wake cycle. PMID:22727146

  10. Repair of Ischemic Injury by Pluripotent Stem Cell Based Cell Therapy without Teratoma through Selective Photosensitivity.

    PubMed

    Cho, Seung-Ju; Kim, So-Yeon; Jeong, Ho-Chang; Cheong, Hyeonsik; Kim, Doseok; Park, Soon-Jung; Choi, Jong-Jin; Kim, Hyongbum; Chung, Hyung-Min; Moon, Sung-Hwan; Cha, Hyuk-Jin

    2015-12-01

    Stem-toxic small molecules have been developed to induce selective cell death of pluripotent stem cells (PSCs) to lower the risk of teratoma formation. However, despite their high efficacies, chemical-based approaches may carry unexpected toxicities on specific differentiated cell types. Herein, we took advantage of KillerRed (KR) as a suicide gene, to selectively induce phototoxicity using visible light via the production of reactive oxygen species. PSCs in an undifferentiated state that exclusively expressed KR (KR-PSCs) were eliminated by a single exposure to visible light. This highly selective cell death in KR-PSCs was exploited to successfully inhibit teratoma formation. In particular, endothelial cells from KR-mPSCs remained fully functional in vitro and sufficient to repair ischemic injury in vivo regardless of light exposure, suggesting that a genetic approach in which KR is expressed in a tightly controlled manner would be a viable strategy to inhibit teratoma formation for future safe PSC-based therapies.

  11. A new approach to define acute kidney injury in term newborns with hypoxic ischemic encephalopathy

    PubMed Central

    Gupta, Charu; Massaro, An N.

    2016-01-01

    Background Current definitions of acute kidney injury (AKI) are not sufficiently sensitive to identify all newborns with AKI during the first week of life. Methods To determine whether the rate of decline of serum creatinine (SCr) during the first week of life can be used to identify newborns with AKI, we reviewed the medical records of 106 term neonates at risk of AKI who were treated with hypothermia for hypoxic ischemic encephalopathy (HIE). Results Of the newborns enrolled in the study, 69 % showed a normal rate of decline of SCr to ≥50 % and/or reached SCr levels of ≤0.6 mg/dl before the 7th day of life, and therefore had an excellent clinical outcome (control group). Thirteen newborns with HIE (12 %) developed AKI according to an established neonatal definition (AKI–KIDGO group), and an additional 20 newborns (19 %) showed a rate of decline of SCr of <33, <40, and <46 % from birth to days 3, 5, or 7 of life, respectively (delayed rise in estimated SCr clearance group). Compared to the control group, newborns in the other two groups required more days of mechanical ventilation and vasopressor drugs and had higher gentamicin levels, more fluid overload, lower urinary epidermal growth factor levels, and a prolonged length of stay. Conclusions The rate of decline of SCr provides a sensitive approach to identify term newborns with AKI during the first week of life. PMID:26857710

  12. Activation of SHH signaling pathway promotes vasculogenesis in post-myocardial ischemic-reperfusion injury.

    PubMed

    Guo, Wei; Yi, Xin; Ren, Faxin; Liu, Liwen; Wu, Suning; Yang, Jun

    2015-01-01

    This study aimed to investigate the potential roles of sonic Hedgehog (SHH) expression in vasculogenesis in post-myocardial ischemic-reperfusion injury (MIRI) and its underlying mechanism. Cardiac microvascular endothelial cells (CMECs) isolated from the SD rat hearts tissues were used to construct the MIRI model. mRNA level of SHH in control cells and MIRI cells was detected using RT-PCR analysis. Furthermore, effects of SHH expression on CMECs viability and apoptosis were analyzed using MTT assay and Annexin-V-FITC kit respectively. Moreover, effects of SHH expression on the pathway signal proteins expression was analyzed using ELISA and western blotting. mRNA level of SHH was significantly decreased compared to the controls (P<0.05). Besides, CMECs viability was significantly increased while cell apoptosis was decreased by SHH application compared with the controls (P<0.05). Vasculogenesis-related factors including VEGF, FGF and Ang were significantly increased by SHH application, as well as the SHH signal proteins including Patch-1, Gli1, Gli2 and SMO (P<0.05). However, these effects of SHH application on biological factors levels were reversed by the SHH inhibitor application. This study suggested that SHH over expression may play a pivotal contribute role in vasculogenesis through activating the SHH signals in post-MIRI. PMID:26722433

  13. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury.

    PubMed

    Biernaskie, Jeff; Chernenko, Garry; Corbett, Dale

    2004-02-01

    To maximize the effectiveness of rehabilitative therapies after stroke, it is critical to determine when the brain is most responsive (i.e., plastic) to sensorimotor experience after injury and to focus such efforts within this period. Here, we compared the efficacy of 5 weeks of enriched rehabilitation (ER) initiated at 5 d (ER5), ER14, or ER30 after focal ischemia, as judged by functional outcome and neuromorphological change. ER5 provided marked improvement in skilled forelimb reaching ability and ladder-rung- and narrow-beam-walking tasks and attenuated the stroke-induced reliance on the unaffected forepaw for postural support. ER14 provided improvement to a somewhat lesser extent, whereas recovery was diminished after ER30 such that motor function did not differ from ischemic animals exposed to social housing. To examine potential neural substrates of the improved function, we examined dendritic morphology in the undamaged motor cortex because our previous work (Biernaskie and Corbett, 2001) suggested that recovery was associated with enhanced dendritic growth in this region. ER5 increased the number of branches and complexity of layer V neurons compared with both social housing and control animals. Dendritic arbor after ER14 (although increased) and ER30 did not differ from those exposed to social housing. These data suggest that the poststroke brain displays heightened sensitivity to rehabilitative experience early after the stroke but declines with time. These findings have important implications for rehabilitation of stroke patients, many of whom experience considerable delays before therapy is initiated. PMID:14762143

  14. Vascular and circulating microRNAs in renal ischaemia–reperfusion injury

    PubMed Central

    Lorenzen, Johan M

    2015-01-01

    Ischaemia–reperfusion (I/R) injury of the kidney is a major cause of acute kidney injury. It may result in worsening or even loss of organ function. Transient occlusion of the renal vessel is followed by a reperfusion period, which induces further tissue damage by release of reactive oxygen and nitrogen species. Ischaemia–reperfusion injury of the kidney may be associated with surgical interventions in native kidneys and is also a common and unavoidable phenomenon in kidney transplantation. MicroRNAs are fascinating modulators of gene expression. They are capable of post-transcriptional silencing of genetic information by targeting the 3′-untranslated region of mRNAs, culminating in a suppression of protein synthesis or an increase in mRNA degradation. They might therefore be useful diagnostic and therapeutic entities during renal I/R injury; for instance, miR-21 has been shown to be enriched in kidney tissue in mice and humans with acute kidney injury. Interestingly, most recent literature suggests that modulation of vascular microRNAs might result in the amelioration of kidney function during renal I/R injury. To that end, miR-126 and miR-24, which have been demonstrated to be highly enriched in endothelial cells, were therapeutically modulated and shown to ameliorate renal I/R injury in mice. MicroRNAs in plasma, urine or enriched in microvesicles have been shown to serve as non-invasive tools for disease monitoring and to have potential impact on downstream mechanisms in recipient cells. This review highlights the latest developments regarding the role of microRNAs in renal I/R injury. PMID:25691473

  15. Short-term menhaden oil rich diet changes renal lipid profile in acute kidney injury.

    PubMed

    Ossani, Georgina P; Denninghoff, Valeria C; Uceda, Ana M; Díaz, Maria L; Uicich, Raúl; Monserrat, Alberto J

    2015-01-01

    Weanling male Wistar rats fed a choline-deficient diet develop acute kidney injury. Menhaden oil, which is a very important source of omega-3 fatty acids, has a notorious protective effect. The mechanism of this protection is unknown; one possibility could be that menhaden oil changes renal lipid profile, with an impact on the functions of biological membranes. The aim of this work was to study the renal lipid profile in rats fed a choline-deficient diet with menhaden oil or vegetable oil as lipids. Rats were divided into 4 groups and fed four different diets for 7 days: choline-deficient or choline-supplemented diets with corn and hydrogenated oils or menhaden oil. Serum homocysteine, vitamin B12, and folic acid were analyzed. Renal lipid profile, as well as the fatty acid composition of the three oils, was measured. Choline-deficient rats fed vegetable oils showed renal cortical necrosis. Renal omega-6 fatty acids were higher in rats fed a cholinedeficient diet and a choline-supplemented diet with vegetable oils, while renal omega-3 fatty acids were higher in rats fed a choline-deficient diet and a choline-supplemented diet with menhaden oil. Rats fed menhaden oil diets had higher levels of renal eicosapentaenoic and docosahexaenoic acids. Renal myristic acid was increased in rats fed menhaden oil. The lipid renal profile varied quickly according to the type of oil present in the diet.

  16. Role of NADPH Oxidase in Metabolic Disease-Related Renal Injury: An Update

    PubMed Central

    Su, Hua

    2016-01-01

    Metabolic syndrome has been linked to an increased risk of chronic kidney disease. The underlying pathogenesis of metabolic disease-related renal injury remains obscure. Accumulating evidence has shown that NADPH oxidase is a major source of intrarenal oxidative stress and is upregulated by metabolic factors leading to overproduction of ROS in podocytes, endothelial cells, and mesangial cells in glomeruli, which is closely associated with the initiation and progression of glomerular diseases. This review focuses on the role of NADPH oxidase-induced oxidative stress in the pathogenesis of metabolic disease-related renal injury. Understanding of the mechanism may help find potential therapeutic strategies.

  17. Role of NADPH Oxidase in Metabolic Disease-Related Renal Injury: An Update.

    PubMed

    Wan, Cheng; Su, Hua; Zhang, Chun

    2016-01-01

    Metabolic syndrome has been linked to an increased risk of chronic kidney disease. The underlying pathogenesis of metabolic disease-related renal injury remains obscure. Accumulating evidence has shown that NADPH oxidase is a major source of intrarenal oxidative stress and is upregulated by metabolic factors leading to overproduction of ROS in podocytes, endothelial cells, and mesangial cells in glomeruli, which is closely associated with the initiation and progression of glomerular diseases. This review focuses on the role of NADPH oxidase-induced oxidative stress in the pathogenesis of metabolic disease-related renal injury. Understanding of the mechanism may help find potential therapeutic strategies. PMID:27597884

  18. Role of NADPH Oxidase in Metabolic Disease-Related Renal Injury: An Update

    PubMed Central

    Su, Hua

    2016-01-01

    Metabolic syndrome has been linked to an increased risk of chronic kidney disease. The underlying pathogenesis of metabolic disease-related renal injury remains obscure. Accumulating evidence has shown that NADPH oxidase is a major source of intrarenal oxidative stress and is upregulated by metabolic factors leading to overproduction of ROS in podocytes, endothelial cells, and mesangial cells in glomeruli, which is closely associated with the initiation and progression of glomerular diseases. This review focuses on the role of NADPH oxidase-induced oxidative stress in the pathogenesis of metabolic disease-related renal injury. Understanding of the mechanism may help find potential therapeutic strategies. PMID:27597884

  19. Potential Reparative Role of Resident Adult Renal Stem/Progenitor Cells in Acute Kidney Injury

    PubMed Central

    Sallustio, Fabio; Serino, Grazia; Schena, Francesco Paolo

    2015-01-01

    Abstract Human kidney is particularly susceptible to ischemia and toxins with consequential tubular necrosis and activation of inflammatory processes. This process can lead to the acute renal injury, and even if the kidney has a great capacity for regeneration after tubular damage, in several circumstances, the normal renal repair program may not be sufficient to achieve a successful regeneration. Resident adult renal stem/progenitor cells could participate in this repair process and have the potentiality to enhance the renal regenerative mechanism. This could be achieved both directly, by means of their capacity to differentiate and integrate into the renal tissues, and by means of paracrine factors able to induce or improve the renal repair or regeneration. Recent genetic fate-tracing studies indicated that tubular damage is instead repaired by proliferative duplication of epithelial cells, acquiring a transient progenitor phenotype and by fate-restricted clonal cell progeny emerging from different nephron segments. In this review, we discuss about the properties and the reparative characteristics of high regenerative CD133+/CD24+ cells, with a view to a future application of these cells for the treatment of acute renal injury. PMID:26309808

  20. Protective effects of icariin on cisplatin-induced acute renal injury in mice

    PubMed Central

    Ma, Pei; Zhang, Sen; Su, Xinlin; Qiu, Guixing; Wu, Zhihong

    2015-01-01

    Cisplatin chemotherapy often causes acute kidney injury in cancer patients. Icariin is a bioactive flavonoid, which has renal protection and anti-inflammation effects. This study investigated the mechanism underlying the attenuation of cisplatin-induced renal injury by icariin. BALB/c mice were treated with cisplatin (15 mg/kg) with or without treatment with icariin (30 or 60 mg/kg for 5 days). Renal function, histological changes, degree of oxidative stress and tubular apoptosis were examined. The effects of icariin on cisplatin-induced expression of renal TNF-α, NF-κB, cleaved caspase-3 and Bcl-2 family proteins were evaluated. Treatment of mice with cisplatin resulted in renal damage, showing an increase in blood urea nitrogen and creatinine levels, tubular damage, oxidative stress and apoptosis. These renal changes could be significantly improved by icariin treatment, especially in high dose of icariin group. Examination of molecules involving inflammation and apoptosis of the kidney revealed that treatment of icariin reduced expression of TNF-α, NF-κB, cleaved caspase-3, and Bax, increased the expression of BCL-2. These results indicate that icariin ameliorates the cisplatin-mediated nephrotoxicity via improving renal oxidant status, consequent NF-κB activation and inflammation cascade and apoptosis, and the following disturbed expression of apoptosis related proteins. PMID:26692955

  1. Intravenous Administration of Cilostazol Nanoparticles Ameliorates Acute Ischemic Stroke in a Cerebral Ischemia/Reperfusion-Induced Injury Model.

    PubMed

    Nagai, Noriaki; Yoshioka, Chiaki; Ito, Yoshimasa; Funakami, Yoshinori; Nishikawa, Hiroyuki; Kawabata, Atsufumi

    2015-01-01

    It was reported that cilostazol (CLZ) suppressed disruption of the microvasculature in ischemic areas. In this study, we have designed novel injection formulations containing CLZ nanoparticles using 0.5% methylcellulose, 0.2% docusate sodium salt, and mill methods (CLZnano dispersion; particle size 81 ± 59 nm, mean ± S.D.), and investigated their toxicity and usefulness in a cerebral ischemia/reperfusion-induced injury model (MCAO/reperfusion mice). The pharmacokinetics of injections of CLZnano dispersions is similar to that of CLZ solutions prepared with 2-hydroxypropyl-β-cyclodextrin, and no changes in the rate of hemolysis of rabbit red blood cells, a model of cell injury, were observed with CLZnano dispersions. In addition, the intravenous injection of 0.6 mg/kg CLZnano dispersions does not affect the blood pressure and blood flow, and the 0.6 mg/kg CLZnano dispersions ameliorate neurological deficits and ischemic stroke in MCAO/reperfusion mice. It is possible that the CLZnano dispersions will provide effective therapy for ischemic stroke patients, and that injection preparations of lipophilic drugs containing drug nanoparticles expand their therapeutic usage. PMID:26690139

  2. The effects of cilostazol on tissue oxygenation upon an ischemic-reperfusion injury in the mouse cerebrum.

    PubMed

    Morikawa, Takayuki; Hattori, Katsuji; Kajimura, Mayumi; Suematsu, Makoto

    2010-01-01

    Although cilostazol, an inhibitor of cyclic nucleotide phosphodiesterase 3 (PDE3), is known to exert a potent antiplatelet function by raising intracellular cAMP concentration, its effect on cerebral microcirculation upon an ischemic insult is not clearly understood. To examine effects of cilostazol on the global ischemic injury in the brain, we first measured the plasma leakage using modified Miles assay after mice had been subjected to 60 min of a bilateral common carotid artery (BCCA) occlusion followed by reperfusion for 4 h. Oral treatment with cilostazol (30 mg/kg) significantly increased plasma leakage. This result led us to examine if the treatment with cilostazol recruits more capillaries leading to an increase in surface area for exchange and oxygen transport to tissues. To do so, we simultaneously measured degrees of tissue hypoxia and vessel perfusion. Pimonidazol was injected intraperitoneally 1 h before sacrifice and capillary patency was assessed by fluorescein isothiocyanate-labeled Lycopersicon esculentum lectin bound to the endothelial surface. Treatment with cilostazol markedly increased the capillary patency which was accompanied by a reduction in the hypoxic area. Although the treatment with cilostazol caused an increase in the flux of plasma proteins across endothelial barrier that may imply an adverse role after a BCCA occlusion, this increase in protein leakage was attributable to the increased surface area for exchange which in turn brought about a reduction in tissue hypoxia. Taken together cilostazol appears to produce a protective effect against the ischemic-reperfusion injury.

  3. C1q/TNF-related protein-1 functions to protect against acute ischemic injury in the heart.

    PubMed

    Yuasa, Daisuke; Ohashi, Koji; Shibata, Rei; Mizutani, Naoki; Kataoka, Yoshiyuki; Kambara, Takahiro; Uemura, Yusuke; Matsuo, Kazuhiro; Kanemura, Noriyoshi; Hayakawa, Satoko; Hiramatsu-Ito, Mizuho; Ito, Masanori; Ogawa, Hayato; Murate, Takashi; Murohara, Toyoaki; Ouchi, Noriyuki

    2016-03-01

    Obesity is associated with an increased risk of cardiovascular disease. C1q/TNF-related protein (CTRP)-1 is a poorly characterized adipokine that is up-regulated in association with ischemic heart disease. We investigated the role of CTRP1 in myocardial ischemia injury. CTRP1-knockout mice showed increased myocardial infarct size, cardiomyocyte apoptosis, and proinflammatory gene expression after I/R compared with wild-type (WT) mice. In contrast, systemic delivery of CTRP1 attenuated myocardial damage after I/R in WT mice. Treatment of cardiomyocytes with CTRP1 led to reduction of hypoxia-reoxygenation-induced apoptosis and lipopolysaccharide-stimulated expression of proinflammatory cytokines, which was reversed by inhibition of sphingosine-1-phosphate (S1P) signaling. Treatment of cardiomyocytes with CTRP1 also resulted in the increased production of cAMP, which was blocked by suppression of S1P signaling. The antiapoptotic and anti-inflammatory actions of CTRP1 were cancelled by inhibition of adenylyl cyclase or knockdown of adiponectin receptor 1. Furthermore, blockade of S1P signaling reversed CTRP1-mediated inhibition of myocardial infarct size, apoptosis, and inflammation after I/R in vivo. These data indicate that CTRP1 protects against myocardial ischemic injury by reducing apoptosis and inflammatory response through activation of the S1P/cAMP signaling pathways in cardiomyocytes, suggesting that CTRP1 plays a crucial role in the pathogenesis of ischemic heart disease.

  4. Intravenous Administration of Cilostazol Nanoparticles Ameliorates Acute Ischemic Stroke in a Cerebral Ischemia/Reperfusion-Induced Injury Model

    PubMed Central

    Nagai, Noriaki; Yoshioka, Chiaki; Ito, Yoshimasa; Funakami, Yoshinori; Nishikawa, Hiroyuki; Kawabata, Atsufumi

    2015-01-01

    It was reported that cilostazol (CLZ) suppressed disruption of the microvasculature in ischemic areas. In this study, we have designed novel injection formulations containing CLZ nanoparticles using 0.5% methylcellulose, 0.2% docusate sodium salt, and mill methods (CLZnano dispersion; particle size 81 ± 59 nm, mean ± S.D.), and investigated their toxicity and usefulness in a cerebral ischemia/reperfusion-induced injury model (MCAO/reperfusion mice). The pharmacokinetics of injections of CLZnano dispersions is similar to that of CLZ solutions prepared with 2-hydroxypropyl-β-cyclodextrin, and no changes in the rate of hemolysis of rabbit red blood cells, a model of cell injury, were observed with CLZnano dispersions. In addition, the intravenous injection of 0.6 mg/kg CLZnano dispersions does not affect the blood pressure and blood flow, and the 0.6 mg/kg CLZnano dispersions ameliorate neurological deficits and ischemic stroke in MCAO/reperfusion mice. It is possible that the CLZnano dispersions will provide effective therapy for ischemic stroke patients, and that injection preparations of lipophilic drugs containing drug nanoparticles expand their therapeutic usage. PMID:26690139

  5. CHBPR N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Attenuates Renal Injury and Dysfunction in Hypertensive Rats with Reduced Renal Mass

    PubMed Central

    Liao, Tang-Dong; Yang, Xiao-Ping; D’Ambrosio, Martin; Zhang, Yanlu; Rhaleb, Nour-Eddine; Carretero, Oscar A.

    2010-01-01

    N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring peptide whose plasma concentration is increased 4- to 5-fold by angiotensin-converting enzyme inhibitors. We previously reported that in models of both hypertension and postmyocardial infarction, Ac-SDKP reduces cardiac inflammation and fibrosis. However, it is unknown whether Ac-SDKP can prevent or reverse renal injury and dysfunction in hypertension. In the present study, we tested the hypothesis that in rats with 5/6 Nephrectomy (5/6Nx) -induced hypertension, Ac-SDKP reduces renal damage, albuminuria and dysfunction by decreasing inflammatory cell infiltration and renal fibrosis and increasing nephrin protein. Ac-SDKP (800 μg/kg/day, i.p. via osmotic mini-pump) or vehicle was either a) started 7 days before 5/6Nx (prevention) and continued for 3 weeks or b) started 3 weeks after 5/6Nx (reversal) and continued for up to 6 weeks. Rats with 5/6Nx developed high blood pressure (BP), left ventricular hypertrophy (LVH), albuminuria, decreased glomerular filtration rate (GFR) and increased macrophage infiltration (inflammation) and renal collagen content (fibrosis). Ac-SDKP did not affect BP or LVH in either group; however, it significantly reduced albuminuria, renal inflammation and fibrosis and improved GFR in both prevention and reversal groups. Moreover, slit diaphragm nephrin protein expression in the glomerular filtration barrier was significantly decreased in hypertensive rats. This effect was partially prevented or reversed by Ac-SDKP. We concluded that Ac-SDKP greatly attenuates albuminuria and renal fibrosis and improves renal function in rats with 5/6Nx. These effects may be related to decreased inflammation (macrophages) and increased nephrin protein. PMID:20026760

  6. Protective effect of tea polyphenols on renal ischemia/reperfusion injury via suppressing the activation of TLR4/NF-κB p65 signal pathway.

    PubMed

    Li, Yan-Wei; Zhang, Yan; Zhang, Ling; Li, Xu; Yu, Jian-Bo; Zhang, Hong-Tao; Tan, Bin-Bin; Jiang, Lian-Hao; Wang, Ya-Xin; Liang, Yu; Zhang, Xiu-Shan; Wang, Wen-Sheng; Liu, Hai-Gen

    2014-05-25

    ischemic/reperfusion injury through the suppression extrinsic apoptotic signal pathway induced by TLR4/NF-κB p65 signal pathway. Moreover, supplement of AMAE can increased renal protection effect of TP.

  7. Vitamin D3 pretreatment regulates renal inflammatory responses during lipopolysaccharide-induced acute kidney injury.

    PubMed

    Xu, Shen; Chen, Yuan-Hua; Tan, Zhu-Xia; Xie, Dong-Dong; Zhang, Cheng; Zhang, Zhi-Hui; Wang, Hua; Zhao, Hui; Yu, De-Xin; Xu, De-Xiang

    2015-01-01

    Vitamin D receptor (VDR) is highly expressed in human and mouse kidneys. Nevertheless, its functions remain obscure. This study investigated the effects of vitamin D3 (VitD3) pretreatment on renal inflammation during lipopolysaccharide (LPS)-induced acute kidney injury. Mice were intraperitoneally injected with LPS. In VitD3 + LPS group, mice were pretreated with VitD3 (25 μg/kg) at 48, 24 and 1 h before LPS injection. As expected, an obvious reduction of renal function and pathological damage was observed in LPS-treated mice. VitD3 pretreatment significantly alleviated LPS-induced reduction of renal function and pathological damage. Moreover, VitD3 pretreatment attenuated LPS-induced renal inflammatory cytokines, chemokines and adhesion molecules. In addition, pretreatment with 1,25(OH)2D3, the active form of VitD3, alleviated LPS-induced up-regulation of inflammatory cytokines and chemokines in human HK-2 cells, a renal tubular epithelial cell line, in a VDR-dependent manner. Further analysis showed that VitD3, which activated renal VDR, specifically repressed LPS-induced nuclear translocation of nuclear factor kappa B (NF-κB) p65 subunit in the renal tubules. LPS, which activated renal NF-κB, reciprocally suppressed renal VDR and its target gene. Moreover, VitD3 reinforced the physical interaction between renal VDR and NF-κB p65 subunit. These results provide a mechanistic explanation for VitD3-mediated anti-inflammatory activity during LPS-induced acute kidney injury. PMID:26691774

  8. Sodium nitrite potentiates renal oxidative stress and injury in hemoglobin exposed guinea pigs.

    PubMed

    Baek, Jin Hyen; Zhang, Xiaoyuan; Williams, Matthew C; Hicks, Wayne; Buehler, Paul W; D'Agnillo, Felice

    2015-07-01

    Methemoglobin-forming drugs, such as sodium nitrite (NaNO2), may exacerbate oxidative toxicity under certain chronic or acute hemolytic settings. In this study, we evaluated markers of renal oxidative stress and injury in guinea pigs exposed to extracellular hemoglobin (Hb) followed by NaNO2 at doses sufficient to simulate clinically relevant acute methemoglobinemia. NaNO2 induced rapid and extensive oxidation of plasma Hb in this model. This was accompanied by increased renal expression of the oxidative response effectors nuclear factor erythroid 2-derived-factor 2 (Nrf-2) and heme oxygenase-1 (HO-1), elevated non-heme iron deposition, lipid peroxidation, interstitial inflammatory cell activation, increased expression of tubular injury markers kidney injury-1 marker (KIM-1) and liver-fatty acid binding protein (L-FABP), podocyte injury, and cell death. Importantly, these indicators of renal oxidative stress and injury were minimal or absent following infusion of Hb or NaNO2 alone. Together, these results suggest that the exposure to NaNO2 in settings associated with increased extracellular Hb may potentiate acute renal toxicity via processes that are independent of NaNO2 induced erythrocyte methemoglobinemia. PMID:25891524

  9. Mitogen-Activated Protein Kinases and Hypoxic/Ischemic Nephropathy.

    PubMed

    Luo, Fengbao; Shi, Jian; Shi, Qianqian; Xu, Xianlin; Xia, Ying; He, Xiaozhou

    2016-01-01

    Tissue hypoxia/ischemia is a pathological feature of many human disorders including stroke, myocardial infarction, hypoxic/ischemic nephropathy, as well as cancer. In the kidney, the combination of limited oxygen supply to the tissues and high oxygen demand is considered the main reason for the susceptibility of the kidney to hypoxic/ischemic injury. In recent years, increasing evidence has indicated that a reduction in renal oxygen tension/blood supply plays an important role in acute kidney injury, chronic kidney disease, and renal tumorigenesis. However, the underlying signaling mechanisms, whereby hypoxia alters cellular behaviors, remain poorly understood. Mitogen-activated protein kinases (MAPKs) are key signal-transducing enzymes activated by a wide range of extracellular stimuli, including hypoxia/ischemia. There are four major family members of MAPKs: the extracellular signal-regulated kinases-1 and -2 (ERK1/2), the c-Jun N-terminal kinases (JNK), p38 MAPKs, and extracellular signal-regulated kinase-5 (ERK5/BMK1). Recent studies, including ours, suggest that these MAPKs are differentially involved in renal responses to hypoxic/ischemic stress. This review will discuss their changes in hypoxic/ischemic pathophysiology with acute kidney injury, chronic kidney diseases and renal carcinoma. PMID:27544204

  10. THE PATHOGENESIS OF THE RENAL INJURY PRODUCED IN THE DOG BY HEMOGLOBIN OR METHEMOGLOBIN

    PubMed Central

    Harrison, H. E.; Bunting, H.; Ordway, N. K.; Albrink, W. S.

    1947-01-01

    Severe and persistent impairment of kidney function has been produced in dogs by intravascular hemolysis due to arsine, or by the intravenous injection of solutions of dog hemoglobin and methemoglobin. The kidneys of these animals have been examined by the usual histological methods and also by means of the ferrocyanide histochemical method to determine the pathogenesis of the renal injury. These observations indicate that obstruction to flow of urine through the renal tubules is an important factor in the early reduction of kidney function. The material filling the lumina of the renal tubules was found to be chiefly methemoglobin in concentrated solution of gel-like consistency. No evidence of formation of a pigment insoluble at the pH of the urine such as hemochromogen or hematin was found. The cessation of urine flow is most readily explained by the increased viscosity of the tubule contents. The intravenous administration of methemoglobin was found to produce more severe renal injury than the injection of equal amounts of oxyhemoglobin. Necrosis of the proximal convoluted tubule cells was present as a late lesion in animals injected with methemoglobin, large amounts of hemoglobin, or following extensive intravascular hemolysis. Such injury is probably a contributing factor in the persistent severe depression of renal function seen in these animals. Following disappearance of most of the intratubular pigment, a large number of collapsed tubules lined by hemosiderin-filled cells were found. The ferrocyanide histochemical studies indicated that these represented non-functioning nephrons although no obstructing intratubular material was present. Direct measurements in two animals failed to reveal any reduction of renal blood flow following the injection of methemoglobin in amounts sufficient to produce renal injury. PMID:19871682

  11. εPKC confers acute tolerance to cerebral ischemic reperfusion injury

    PubMed Central

    Bright, Rachel; Sun, Guo-Hua; Yenari, Midori A.; Steinberg, Gary K.; Mochly-Rosen, Daria

    2008-01-01

    In response to mild ischemic stress, the brain elicits endogenous survival mechanisms to protect cells against a subsequent lethal ischemic stress, referred to as ischemic tolerance. The molecular signals that mediate this protection are thought to involve the expression and activation of multiple kinases, including protein kinase C (PKC). Here we demonstrate that εPKC mediates cerebral ischemic tolerance in vivo. Systemic delivery of ψεRACK, an εPKC-selective peptide activator, confers neuroprotection against a subsequent cerebral ischemic event when delivered immediately prior to stroke. In addition, activation of εPKC by ψεRACK treatment decreases vascular tone in vivo, as demonstrated by a reduction in microvascular cerebral blood flow. Here we demonstrate the role of acute and transient εPKC in early cerebral tolerance in vivo and suggest that extra-parenchymal mechanisms, such as vasoconstriction, may contribute to the conferred protection. PMID:18586397

  12. Epigallocatechin-3-gallate attenuates cadmium-induced chronic renal injury and fibrosis.

    PubMed

    Chen, Jinglou; Du, Lifen; Li, Jingjing; Song, Hongping

    2016-10-01

    Cadmium (Cd) pollution is a serious environmental problem. Kidney is a main target organ of Cd toxicity. This study was undertaken to investigate the potential protective effects of epigallocatechin-3-gallate (EGCG) against chronic renal injury and fibrosis induced by CdCl2. Rat model was induced by exposing to 250 mg/L CdCl2 through drinking water. The renal function was evaluated by detecting the levels of blood urea nitrogen (BUN) and serum creatinine (SCR). The oxidative stress was measured by detecting the levels of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione/oxidized glutathione (GSH/GSSG) and renal enzymatic antioxidant status. Additionally, the renal levels of transforming growth factor-β1 (TGF-β1), Smad3, phosphorylation-Smad3 (pp-Smad3), α-smooth muscle actin (α-SMA), vimentin and E-cadherin were measured by western blot assay. Renal levels of microRNA-21 (miR-21), miR-29a/b/c and miR-192 were measured by quantitative RT-PCR. It was found that EGCG ameliorated the CdCl2-induced renal injury, inhibited the level of oxidative stress, normalized renal enzymatic antioxidant status and E-cadherin level, as well as attenuated the over generation of TGF-β1, pp-Smad3, vimentin and α-SMA. EGCG also decreased the production of miR-21 and miR-192, and enhanced the levels of miR-29a/b/c. These results showed that EGCG could attenuate Cd induced chronic renal injury. PMID:27474435

  13. Epigallocatechin-3-gallate attenuates cadmium-induced chronic renal injury and fibrosis.

    PubMed

    Chen, Jinglou; Du, Lifen; Li, Jingjing; Song, Hongping

    2016-10-01

    Cadmium (Cd) pollution is a serious environmental problem. Kidney is a main target organ of Cd toxicity. This study was undertaken to investigate the potential protective effects of epigallocatechin-3-gallate (EGCG) against chronic renal injury and fibrosis induced by CdCl2. Rat model was induced by exposing to 250 mg/L CdCl2 through drinking water. The renal function was evaluated by detecting the levels of blood urea nitrogen (BUN) and serum creatinine (SCR). The oxidative stress was measured by detecting the levels of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione/oxidized glutathione (GSH/GSSG) and renal enzymatic antioxidant status. Additionally, the renal levels of transforming growth factor-β1 (TGF-β1), Smad3, phosphorylation-Smad3 (pp-Smad3), α-smooth muscle actin (α-SMA), vimentin and E-cadherin were measured by western blot assay. Renal levels of microRNA-21 (miR-21), miR-29a/b/c and miR-192 were measured by quantitative RT-PCR. It was found that EGCG ameliorated the CdCl2-induced renal injury, inhibited the level of oxidative stress, normalized renal enzymatic antioxidant status and E-cadherin level, as well as attenuated the over generation of TGF-β1, pp-Smad3, vimentin and α-SMA. EGCG also decreased the production of miR-21 and miR-192, and enhanced the levels of miR-29a/b/c. These results showed that EGCG could attenuate Cd induced chronic renal injury.

  14. Spatiotemporal Characteristics of Freezing of Gait in Patients After Hypoxic-Ischemic Brain Injury

    PubMed Central

    Yoon, Seo Yeon; Lee, Sang Chul; Kim, Yong Wook

    2016-01-01

    Abstract The objective of this study was to investigate spatiotemporal characteristics with gait variability in patients with freezing of gait (FOG) after hypoxic-ischemic brain injury (HIBI). Eleven patients showing FOG after HIBI and 15 normal controls were consecutively enrolled. We performed gait analysis using a computerized gait system (VICON MX-T10 Motion Analysis System) and compared spatiotemporal characteristics and gait variability in both groups. Additionally, we performed correlation analysis to identify the gait parameters associated with severity of freezing, which we measured based on unified Parkinson disease Rating Scale subscore. Spatiotemporal characteristic of FOG patients showed increased stance time and double support phase and decreased swing time, single support phase, stride length, step length, and gait velocity compared with normal controls (P < 0.05). Besides baseline spatiotemporal characteristics, step time asymmetry and step length asymmetry were significantly increased in HIBI patients with FOG (P < 0.05). The coefficient of variation, which reflects the variability of each parameter, demonstrated increased cadence, stride time, swing time, single support phase, stride length, step length, and gait velocity variability in HIBI patients with FOG compared with normal controls (P < 0.05). Correlation analysis between FOG severity and spatiotemporal parameters revealed gait velocity, step length, and single support phase to be spatiotemporal parameters related to FOG severity (P < 0.05). Our findings suggest that bilateral gait coordination deterioration plays a considerable role for pathophysiology of FOG in HIBI patients. Additional studies with a larger number of subjects are needed to further investigate the neural mechanism of FOG after HIBI. PMID:27175696

  15. Matrine attenuates focal cerebral ischemic injury by improving antioxidant activity and inhibiting apoptosis in mice

    PubMed Central

    ZHAO, PENG; ZHOU, RU; ZHU, XIAO-YUN; HAO, YIN-JU; LI, NAN; WANG, JIE; NIU, YANG; SUN, TAO; LI, YU-XIANG; YU, JIAN-QIANG

    2015-01-01

    cerebral ischemic injury and that these effects are associated with its antioxidant and anti-apoptotic properties. PMID:26135032

  16. Is oxidative stress primarily involved in reperfusion injury of the ischemic heart

    SciTech Connect

    Nohl, H.; Stolze, K.; Napetschnig, S.; Ishikawa, T. )

    1991-01-01

    Reperfusion injury of ischemic organs is suggested to result from metabolic derangements initiating an imbalanced formation of free oxygen radicals. Most investigators in this field have used the spin-trap 5,5'-dimethyl-N-pyrroline-N-oxide (DMPO) to stabilize these short-lived radicals and make them visible by means of the electron spin resonance (ESR) technique. ESR signals obtained from intravascular DMPO were reported to indicate the formation of free OH. radicals and, in some cases, also carbon-centered radicals. We were unable to confirm these findings. Carbon-centered radicals were not obtained irrespectively of conditions studied, while oxygen-centered DMPO-adducts could only be detected in minor amounts. Instead, we observed an ascorbyl-related ESR signal. The addition of ethylenediaminetetraacetic acid (EDTA), which was used by many investigators in this field, was found to greatly influence ESR-spectra of the reperfusion fluid. The ascorbyl radical concentration was clearly reduced and the DMPO-OH. adduct became more prominent. The addition of iron further stimulated this change eliciting a Fenton-type reaction responsible for DMPO-OH.-related ESR spectra in the perfusate after ischemia. Accordingly, we observed the release of iron and ascorbic acid into the perfusate as a consequence of ischemia. We could demonstrate that iron in the presence of ascorbate and EDTA causes both types of radicals detected in the perfusate. DMPO-OH. generation in the presence of EDTA was found to result from free OH. radicals that were not generated in the absence of EDTA.

  17. Matrine attenuates focal cerebral ischemic injury by improving antioxidant activity and inhibiting apoptosis in mice.

    PubMed

    Zhao, Peng; Zhou, Ru; Zhu, Xiao-Yun; Hao, Yin-Ju; Li, Nan; Wang, Jie; Niu, Yang; Sun, Tao; Li, Yu-Xiang; Yu, Jian-Qiang

    2015-09-01

    cerebral ischemic injury and that these effects are associated with its antioxidant and anti-apoptotic properties.

  18. Role of platelet-activating factor in the reperfusion injury of rabbit ischemic heart.

    PubMed Central

    Montrucchio, G.; Alloatti, G.; Mariano, F.; de Paulis, R.; Comino, A.; Emanuelli, G.; Camussi, G.

    1990-01-01

    This study shows that the administration of the PAF receptor antagonist SDZ 63.675 (5 mg/kg body weight) before reperfusion significantly reduced the hematologic and hemodynamic alterations, as well as the size of necrotic area in rabbits subjected to 40 minutes of coronary occlusion and reperfusion. Pretreatment with SDZ 63.675 prevented the reduction of platelet counts in the blood obtained from the right ventricle (86.6 +/- 2.8% of the control preischemia value) and the transient bradycardia (85.0 +/- 2.8%), the systemic hypotension (58.0 +/- 2.8%), and the increase in right ventricular pressure (125.0 +/- 3.6%) that were evident in the first minutes of reperfusion in untreated control rabbits. Two as well as 24 hours after reperfusion, the infarct size, judged by staining with tetrazolium, was significantly reduced in rabbits treated with SDZ 63.675 (infarct size in control animals, 66.0 +/- 2.9% and 63.46 +/- 2.09% of the risk region at 2 or 24 hours, respectively, compared with 38.9 +/- 5.2% and 37.11 +/- 2.44% of the risk region at 2 and 24 hours in rabbits treated with SDZ 63.675). This result was confirmed by histologic examination of cardiac tissue 24 hours after reperfusion. In addition, SDZ 63.675 markedly reduced the accumulation of 111In-oxine-labeled platelets that occurs 15 minutes after reperfusion in the central ischemic area of the heart and in the lungs. These results suggest that PAF plays a role in the evolution of myocardial injury observed during reperfusion. Images Figure 8 PMID:2372044

  19. Matrine attenuates focal cerebral ischemic injury by improving antioxidant activity and inhibiting apoptosis in mice.

    PubMed

    Zhao, Peng; Zhou, Ru; Zhu, Xiao-Yun; Hao, Yin-Ju; Li, Nan; Wang, Jie; Niu, Yang; Sun, Tao; Li, Yu-Xiang; Yu, Jian-Qiang

    2015-09-01

    cerebral ischemic injury and that these effects are associated with its antioxidant and anti-apoptotic properties. PMID:26135032

  20. Adenosine A1 receptors contribute to immune regulation after neonatal hypoxic ischemic brain injury.

    PubMed

    Winerdal, Max; Winerdal, Malin E; Wang, Ying-Qing; Fredholm, Bertil B; Winqvist, Ola; Ådén, Ulrika

    2016-03-01

    Neonatal brain hypoxic ischemia (HI) often results in long-term motor and cognitive impairments. Post-ischemic inflammation greatly effects outcome and adenosine receptor signaling modulates both HI and immune cell function. Here, we investigated the influence of adenosine A1 receptor deficiency (A1R(-/-)) on key immune cell populations in a neonatal brain HI model. Ten-day-old mice were subjected to HI. Functional outcome was assessed by open locomotion and beam walking test and infarction size evaluated. Flow cytometry was performed on brain-infiltrating cells, and semi-automated analysis of flow cytometric data was applied. A1R(-/-) mice displayed larger infarctions (+33%, p < 0.05) and performed worse in beam walking tests (44% more mistakes, p < 0.05) than wild-type (WT) mice. Myeloid cell activation after injury was enhanced in A1R(-/-) versus WT brains. Activated B lymphocytes expressing IL-10 infiltrated the brain after HI in WT, but were less activated and did not increase in relative frequency in A1R(-/-). Also, A1R(-/-) B lymphocytes expressed less IL-10 than their WT counterparts, the A1R antagonist DPCPX decreased IL-10 expression whereas the A1R agonist CPA increased it. CD4(+) T lymphocytes including FoxP3(+) T regulatory cells, were unaffected by genotype, whereas CD8(+) T lymphocyte responses were smaller in A1R(-/-) mice. Using PCA to characterize the immune profile, we could discriminate the A1R(-/-) and WT genotypes as well as sham operated from HI-subjected animals. We conclude that A1R signaling modulates IL-10 expression by immune cells, influences the activation of these cells in vivo, and affects outcome after HI. PMID:26608888

  1. Conventional protein kinase Cβ-mediated phosphorylation inhibits collapsin response-mediated protein 2 proteolysis and alleviates ischemic injury in cultured cortical neurons and ischemic stroke-induced mice.

    PubMed

    Yang, Xuan; Zhang, Xinxin; Li, Yun; Han, Song; Howells, David W; Li, Shujuan; Li, Junfa

    2016-05-01

    We previously reported that conventional protein kinase C (cPKC)β participated in hypoxic preconditioning-induced neuroprotection against cerebral ischemic injury, and collapsin response-mediated protein 2 (CRMP2) was identified as a cPKCβ interacting protein. In this study, we explored the regulation of CRMP2 phosphorylation and proteolysis by cPKCβ, and their role in ischemic injury of oxygen-glucose deprivation (OGD)-treated cortical neurons and brains of mice with middle cerebral artery occlusion-induced ischemic stroke. The results demonstrated that cPKCβ-mediated CRMP2 phosphorylation via the cPKCβ-selective activator 12-deoxyphorbol 13-phenylacetate 20-acetate (DOPPA) and inhibition of calpain-mediated CRMP2 proteolysis by calpeptin and a fusing peptide containing TAT peptide and the calpain cleavage site of CRMP2 (TAT-CRMP2) protected neurons against OGD-induced cell death through inhibiting CRMP2 proteolysis in cultured cortical neurons. The OGD-induced nuclear translocation of the CRMP2 breakdown product was inhibited by DOPPA, calpeptin, and TAT-CRMP2 in cortical neurons. In addition, both cPKCβ activation and CRMP2 proteolysis inhibition by hypoxic preconditioning and intracerebroventricular injections of DOPPA, calpeptin, and TAT-CRMP2 improved the neurological deficit in addition to reducing the infarct volume and proportions of cells with pyknotic nuclei in the peri-infact region of mice with ischemic stroke. These results suggested that cPKCβ modulates CRMP2 phosphorylation and proteolysis, and cPKCβ activation alleviates ischemic injury in the cultured cortical neurons and brains of mice with ischemic stroke through inhibiting CRMP2 proteolysis by phosphorylation. Focal cerebral ischemia induces a large flux of Ca(2+) to activate calpain which cleaves collapsin response mediator (CRMP) 2 into breakdown product (BDP). Inhibition of CRMP2 cleavage by calpeptin and TAT-CRMP2 alleviates ischemic injury. Conventional protein kinase C (c

  2. Betaine supplementation protects against high-fructose-induced renal injury in rats.

    PubMed

    Fan, Chen-Yu; Wang, Ming-Xing; Ge, Chen-Xu; Wang, Xing; Li, Jian-Mei; Kong, Ling-Dong

    2014-03-01

    High fructose intake causes metabolic syndrome, being an increased risk of chronic kidney disease development in humans and animals. In this study, we examined the influence of betaine on high-fructose-induced renal damage involving renal inflammation, insulin resistance and lipid accumulation in rats and explored its possible mechanisms. Betaine was found to improve high-fructose-induced metabolic syndrome including hyperuricemia, dyslipidemia and insulin resistance in rats with systemic inflammation. Betaine also showed a protection against renal dysfunction and tubular injury with its restoration of the increased glucose transporter 9 and renal-specific transporter in renal brush bolder membrane and the decreased organic anion transporter 1 and adenosine-triphosphate-binding cassette transporter 2 in the renal cortex in this model. These protective effects were relevant to the anti-inflammatory action by inhibiting the production of inflammatory cytokines including interleukin (IL)-1β, IL-18, IL-6 and tumor necrosis factor-α in renal tissue of high-fructose-fed rat, being more likely to suppress renal NOD-like receptor superfamily, pyrin domain containing 3 inflammasome activation than nuclear factor κB activation. Subsequently, betaine with anti-inflammation ameliorated insulin signaling impairment by reducing the up-regulation of suppressor of cytokine signaling 3 and lipid accumulation partly by regulating peroxisome proliferator-activated receptor α/palmityltransferase 1/carnitine/organic cation transporter 2 pathway in kidney of high-fructose-fed rats. These results indicate that the inflammatory inhibition plays a pivotal role in betaine's improvement of high-fructose-induced renal injury with insulin resistance and lipid accumulation in rats.

  3. Histological, molecular and biochemical detection of renal injury after Echis pyramidum snake envenomation in rats

    PubMed Central

    Al-Johany, Awadh M.; Al-Sadoon, Mohamed K.; Abdel Moneim, Ahmed E.; Bauomy, Amira A.; Diab, Marwa S.M.

    2014-01-01

    Nephrotoxicity is a common sign of snake envenomation. The present work aimed to clarify the effect of intraperitoneal injection of 1/8 LD50 and 1/4 LD50 doses of Echis pyramidum snake venom on the renal tissue of rats after 2, 4 and 6 h from envenomation. Histopathological examination showed intense dose and time dependent abnormalities, including swelling glomerulus and tubular necrosis and damage as well as signs of intertubular medullary hemorrhage at early stages of envenomation. However, at late stages of envenomation by any of the doses under investigation, no intact renal corpuscles were recorded and complete lysis in renal corpuscles with ruptured Bowman’s capsules was observed. Immunohistochemistry by immunohistochemical staining was used to test the protein expression of Bax in renal tissue of rats. The result showed that the expression of Bax in renal tissue sections of envenomated rats was increased according to dose and time-dependant manner. The isolation of DNA from the renal cells of envenomed rats pointed out to the occurrence of DNA fragmentation, which is another indicator for renal tissue injury especially after 6 h of 1/4 LD50 of E. pyramidum envenomation. Oxidative stress biomarkers malondialdehyde and nitrite/nitrate levels, antioxidant parameters; glutathione, total antioxidant capacity and catalase were assayed in renal tissue homogenates. The venom induced significant increase in the levels of malondialdehyde and nitrite/nitrate while the levels of glutathione, total antioxidant capacity and catalase were significantly decreased, especially after 6 h of envenomation. The results revealed that the E. pyramidum induced dose and time-dependant significant disturbances in the physiological parameters in the kidney. We conclude that the use of the immunohistochemical techniques, the detection of DNA integrity and oxidative stress marker estimations are more specific tools that can clarify cellular injury and could point out to the defense

  4. Epidermal growth factor enhances renal tubule cell regeneration and repair and accelerates the recovery of renal function in postischemic acute renal failure.

    PubMed Central

    Humes, H D; Cieslinski, D A; Coimbra, T M; Messana, J M; Galvao, C

    1989-01-01

    To determine the timing and location of renal cell regeneration after ischemic injury to the kidney and to assess whether exogenous epidermal growth factor (EGF) enhances this regenerative repair process to accelerate recovery of renal function, experiments were undertaken in rats undergoing 30 min of bilateral renal artery clamp ischemia followed by reperfusion for varying time intervals. Renal cell regeneration, as reflected by incorporation of radiolabeled thymidine within the kidney, began between 24 to 48 h and reached a peak at 72 h after renal ischemia. As demonstrated by histoautoradiography, renal thymidine incorporation was essentially confined to tubule cells. Morphometric analysis of histoautoradiograph sections of renal tissue demonstrated that the majority of labeled cells were found in renal cortex, but some labeled cells were also located in the inner stripe of the outer medulla, suggesting that injury to medullary thick ascending limbs also occurs in this ischemic model. Exogenous EGF administration produced increases in renal thymidine incorporation compared with non-treated animals at 24, 48, and 72 h after ischemic injury. This accelerated DNA replicative process was associated with significantly lower peak blood urea nitrogen (BUN) and serum creatinine levels, averaging 63 +/- 20 and 3.1 +/- 0.4 mg/dl in EGF-treated ischemic rats compared with 149 +/- 20 and 5.1 +/- 0.1 mg/dl, respectively, in nontreated ischemic rats, and was also associated with a return to near normal BUN and serum creatinine levels in EGF-treated animals approximately 4 d earlier than that observed in nontreated animals. This report is the first demonstration that EGF accelerates the repair process of a visceral organ after an injurious insult. Images PMID:2592559

  5. Pretreatment with Darbepoetin Attenuates Renal Injury in a Rat Model of Cisplatin-Induced Nephrotoxicity

    PubMed Central

    Choi, Dae Eun; Jeong, Jin Young; Lim, Beom Jin; Lee, Kang Wook; Shin, Young-Tai

    2009-01-01

    Background/Aims Darbepoetin alfa (DPO) exhibits comparable renoprotective effects to erythropoietin (EPO) in several animal models of acute renal injury. We examined whether DPO also attenuated renal injury in a rat model of cisplatin nephrotoxicity. Methods Male Spague-Dawley rats were divided into four groups: untreated, DPO-treated, cisplatin-injected, and DPO-treated cisplatin-injected. DPO pretreatment was conducted 24 hours after and just before cisplatin administration. Ninety-six hours after cisplatin administration, animals in all experimental groups were sacrificed. We examined serology; real-time reverse transcription polymerase chain reaction (RT-PCR) for TNF-α, Bcl-2, and MCP-1 gene expression; and Western blots for caspase-3. We also conducted terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and light microscopy. Results Pretreatment with DPO significantly reduced the levels of blood urea nitrogen and serum creatinine, the magnitude of renal tubular epithelial damage, and renal gene expression of TNF-α, Fas, and MCP-1 in kidneys injured by cisplatin. Pretreatment with DPO significantly increased Bcl-2 mRNA levels in kidneys injured by cisplatin, and significantly reduced activated caspase-3 and TUNEL-positive cells. Conclusions DPO exhibits a renoprotective effect in experimental cisplatin-induced renal injury, the mechanism of which may involve DPO antiinflammatory and antiapoptotic effects. PMID:19721861

  6. Low molecular weight fucoidan protects renal tubular cells from injury induced by albumin overload

    PubMed Central

    Jia, Yingli; Sun, Yi; Weng, Lin; Li, Yingjie; Zhang, Quanbin; Zhou, Hong; Yang, Baoxue

    2016-01-01

    Albuminuria is a causative and aggravating factor for progressive renal damage in chronic kidney disease (CKD). The aim of this study was to determine if low molecular weight fucoidan (LMWF) could protect renal function and tubular cells from albumin overload caused injury. Treatment with 10 mg/g bovine serum albumin caused renal dysfunction, morphological changes, and overexpression of inflammation and fibrosis associated proteins in 129S2/Sv mice. LMWF (100 mg/kg) protected against kidney injury and renal dysfunction with decreased blood creatinine by 34% and urea nitrogen by 25%, increased creatinine clearance by 48%, and decreased significantly urinary albumin concentration. In vitro proximal tubule epithelial cell (NRK-52E) model showed that LMWF dose-dependently inhibited overexpression of proinflammatory and profibrotic factors, oxidative stress and apoptosis caused by albumin overload. These experimental results indicate that LMWF protects against albumin overload caused renal injury by inhibiting inflammation, fibrosis, oxidative stress and apoptosis, which suggests that LMWF could be a promising candidate drug for preventing CKD. PMID:27545472

  7. Molecular dialogs between the ischemic brain and the peripheral immune system: dualistic roles in injury and repair.

    PubMed

    An, Chengrui; Shi, Yejie; Li, Peiying; Hu, Xiaoming; Gan, Yu; Stetler, Ruth A; Leak, Rehana K; Gao, Yanqin; Sun, Bao-Liang; Zheng, Ping; Chen, Jun

    2014-04-01

    Immune and inflammatory responses actively modulate the pathophysiological processes of acute brain injuries such as stroke. Soon after the onset of stroke, signals such as brain-derived antigens, danger-associated molecular patterns (DAMPs), cytokines, and chemokines are released from the injured brain into the systemic circulation. The injured brain also communicates with peripheral organs through the parasympathetic and sympathetic branches of the autonomic nervous system. Many of these diverse signals not only activate resident immune cells in the brain, but also trigger robust immune responses in the periphery. Peripheral immune cells then migrate toward the site of injury and release additional cytokines, chemokines, and other molecules, causing further disruptive or protective effects in the ischemic brain. Bidirectional communication between the injured brain and the peripheral immune system is now known to regulate the progression of stroke pathology as well as tissue repair. In the end, this exquisitely coordinated crosstalk helps determine the fate of animals after stroke. This article reviews the literature on ischemic brain-derived signals through which peripheral immune responses are triggered, and the potential impact of these peripheral responses on brain injury and repair. Pharmacological strategies and cell-based therapies that target the dialog between the brain and peripheral immune system show promise as potential novel treatments for stroke.

  8. CPG15, a new factor upregulated after ischemic brain injury, contributes to neuronal network re-establishment after glutamate-induced injury.

    PubMed

    Han, Yu; Chen, Xianhua; Shi, Fumin; Li, Shujing; Huang, Jia; Xie, Minhao; Hu, Lingchuan; Hoidal, John R; Xu, Ping

    2007-04-01

    Candidate plasticity-related gene 15 (cpg15) encodes a protein that regulates dendritic and axonal arbor growth and synaptic maturation. In the present study, we investigated the potential role of CPG15 in regulating the neuronal network re-establishment after ischemic brain injury. In the mouse model with transient global ischemia (TGI), CPG15 transcripts and proteins were determined using RT-PCR and Western blot analyses. Cell proliferation was observed using 5'-bromo-2'-deoxyuridine-5'-monophosphate (BrdU) labeling. Double immunostaining and depletion of soluble CPG15 proteins were performed to examine the cellular distribution of CPG15 and the role of soluble CPG15 in the neurite outgrowth during the neuronal network re-establishment in primarily cultured hippocampal cells after glutamate-induced injury. We demonstrated that CPG15 expression in the hippocampus was upregulated at 1-2 weeks after TGI. In the dentate gyrus, the number of CPG15 and BrdU positive cells increased concurrently after the injury. During the neuronal network re-establishment after the glutamate-induced injury of primarily cultured hippocampal cells, CPG15 was mainly located at the ends and turn-off regions of the growth cones and in the vesicles. Depletion of soluble CPG15 proteins secreted from the hippocampal cells in the culture media significantly reduced the neurite outgrowth and neuron-neuron connection. The results indicate that CPG15 may function as a new factor required in re-establishment of neuronal network after the injury. Our findings will be important in developing a new strategy to enhance endogenous neurogenesis after an ischemic brain injury. PMID:17439354

  9. Thoracic combined spinal epidural anesthesia for laparoscopic cholecystectomy in a geriatric patient with ischemic heart disease and renal insufficiency.

    PubMed

    Mehta, Nandita; Gupta, Sunana; Sharma, Atul; Dar, Mohd Reidwan

    2015-01-01

    Older people undergoing any surgery have a higher incidence of morbidity and mortality, resulting from a decline in physiological reserves, associated comorbidities, polypharmacy, cognitive dysfunction, and frailty. Most of the clinical trials comparing regional versus general anesthesia in elderly have failed to establish superiority of any single technique. However, the ideal approach in elderly is to be least invasive, thus minimizing alterations in homeostasis. The goal of anesthetic management in laparoscopic procedures includes management of pneumoperitoneum, achieving an adequate level of sensory blockade without any respiratory compromise, management of shoulder tip pain, provision of adequate postoperative pain relief, and early ambulation. Regional anesthesia fulfills all the aforementioned criteria and aids in quick recovery and thus has been suggested to be a suitable alternative to general anesthesia for laparoscopic surgeries, particularly in patients who are at high risk while under general anesthesia or for patients unwilling to undergo general anesthesia. In conclusion, we report results of successful management with thoracic combined spinal epidural for laparoscopic cholecystectomy of a geriatric patient with ischemic heart disease with chronic obstructive pulmonary disease and renal insufficiency.

  10. Thoracic combined spinal epidural anesthesia for laparoscopic cholecystectomy in a geriatric patient with ischemic heart disease and renal insufficiency

    PubMed Central

    Mehta, Nandita; Gupta, Sunana; Sharma, Atul; Dar, Mohd Reidwan

    2015-01-01

    Older people undergoing any surgery have a higher incidence of morbidity and mortality, resulting from a decline in physiological reserves, associated comorbidities, polypharmacy, cognitive dysfunction, and frailty. Most of the clinical trials comparing regional versus general anesthesia in elderly have failed to establish superiority of any single technique. However, the ideal approach in elderly is to be least invasive, thus minimizing alterations in homeostasis. The goal of anesthetic management in laparoscopic procedures includes management of pneumoperitoneum, achieving an adequate level of sensory blockade without any respiratory compromise, management of shoulder tip pain, provision of adequate postoperative pain relief, and early ambulation. Regional anesthesia fulfills all the aforementioned criteria and aids in quick recovery and thus has been suggested to be a suitable alternative to general anesthesia for laparoscopic surgeries, particularly in patients who are at high risk while under general anesthesia or for patients unwilling to undergo general anesthesia. In conclusion, we report results of successful management with thoracic combined spinal epidural for laparoscopic cholecystectomy of a geriatric patient with ischemic heart disease with chronic obstructive pulmonary disease and renal insufficiency. PMID:26664202

  11. New Biomarkers of Acute Kidney Injury and the Cardio-renal Syndrome

    PubMed Central

    2011-01-01

    Changes in renal function are one of the most common manifestations of severe illness. There is a clinical need to intervene early with proven treatments in patients with potentially deleterious changes in renal function. Unfortunately progress has been hindered by poor definitions of renal dysfunction and a lack of early biomarkers of renal injury. In recent years, the definitional problem has been addressed with the establishment of a new well-defined diagnostic entity, acute kidney injury (AKI), which encompasses the wide spectrum of kidney dysfunction, together with clearer definition and sub-classification of the cardio-renal syndromes. From the laboratory have emerged new biomarkers which allow early detection of AKI, including neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C. This review describes the new concepts of AKI and the cardio-renal syndromes as well as novel biomarkers which allow early detection of AKI. Panels of AKI biomarker tests are likely to revolutionise the diagnosis and management of critically ill patients in the coming years. Earlier diagnosis and intervention should significantly reduce the morbidity and mortality associated with acute kidney damage. PMID:21474979

  12. The protein kinase 2 inhibitor tetrabromobenzotriazole protects against renal ischemia reperfusion injury

    PubMed Central

    Ka, Sun-O; Hwang, Hong Pil; Jang, Jong-Hwa; Hyuk Bang, In; Bae, Ui-Jin; Yu, Hee Chul; Cho, Baik Hwan; Park, Byung-Hyun

    2015-01-01

    Protein kinase 2 (CK2) activation was reported to enhance reactive oxygen species production and activate the nuclear factor κB (NF-κB) pathway. Because oxidative stress and inflammation are critical events for tissue destruction during ischemia reperfusion (I/R), we sought to determine whether CK2 was important in the renal response to I/R. Mice underwent 25 min of renal ischemia and were then reperfused. We confirmed an increased expression of CK2α during the reperfusion period, while expression of CK2β remained consistent. We administered tetrabromobenzotriazole (TBBt), a selective CK2α inhibitor before inducing I/R injury. Mice subjected to I/R injury showed typical patterns of acute kidney injury; blood urea nitrogen and serum creatinine levels, tubular necrosis and apoptosis, inflammatory cell infiltration and proinflammatory cytokine production, and oxidative stress were markedly increased when compared to sham mice. However, pretreatment with TBBt abolished these changes and improved renal function and architecture. Similar renoprotective effects of CK2α inhibition were observed for emodin. Renoprotective effects of CK2α inhibition were associated with suppression of NF-κB and mitogen activated protein kinase (MAPK) pathways. Taken together, these results suggest that CK2α mediates proapoptotic and proinflammatory signaling, thus the CK2α inhibitor may be used to prevent renal I/R injuries observed in clinical settings. PMID:26423352

  13. Aging causes exacerbated ischemic brain injury and failure of sevoflurane post-conditioning: role of B-cell lymphoma-2.

    PubMed

    Dong, P; Zhao, J; Zhang, Y; Dong, J; Zhang, L; Li, D; Li, L; Zhang, X; Yang, B; Lei, W

    2014-09-01

    Aging is associated with exacerbated brain injury after ischemic stroke. Herein, we explored the possible mechanisms underlying the age-associated exacerbated brain injury after ischemic stroke and determined whether therapeutic intervention with anesthetic post-conditioning would provide neuroprotection in aged rats. Male Fisher 344 rats (young, 4 months; aged, 24 months) underwent 2h of middle cerebral artery occlusion (MCAO) followed by 24-h reperfusion, with or without sevoflurane post-conditioning for 15 min immediately at the onset of reperfusion. Compared with young rats, aged rats showed larger infarct size, worse neurological scores and more TUNEL-positive cells in the penumbral cerebral cortex at 24h after MCAO. However, edema formation and motor coordination were similar in both groups. Sevoflurane reduced the infarct size, edema formation, and TUNEL-positive cells, and improved the neurological outcome in young rats but not in aged rats. Molecular studies revealed that basal expression of the anti-apoptotic molecule B-cell lymphoma-2 (Bcl-2) in the brain was lower in aged rats compared with young rats before MCAO, while basal expression of the pro-apoptotic molecule Bcl-2-associated X protein (Bax) showed similar levels in both groups. MCAO reduced Bcl-2 expression and increased Bax expression in both groups; however, Bax increase was more pronounced in aged rats. In young rats, sevoflurane reversed the above MCAO-induced changes. In contrast, sevoflurane failed to enhance Bcl-2 expression but decreased Bax expression in aged rats. These findings suggest that aging-associated reduction in basal Bcl-2 expression in the brain contributes to increased neuronal injury by enhancing cell apoptosis after ischemic stroke. Sevoflurane post-conditioning failed to provide neuroprotection in aged rats, probably due to its inability to increase Bcl-2 levels and prevent apoptosis in the brain.

  14. Experimental model considerations for the study of protein-energy malnutrition co-existing with ischemic brain injury.

    PubMed

    Prosser-Loose, Erin J; Smith, Shari E; Paterson, Phyllis G

    2011-05-01

    Protein-energy malnutrition (PEM) affects ~16% of patients at admission for stroke. We previously modeled this in a gerbil global cerebral ischemia model and found that PEM impairs functional outcome and influences mechanisms of ischemic brain injury and recovery. Since this model is no longer reliable, we investigated the utility of the rat 2-vessel occlusion (2-VO) with hypotension model of global ischemia for further study of this clinical problem. Male, Sprague-Dawley rats were exposed to either control diet (18% protein) or PEM induced by feeding a low protein diet (2% protein) for 7d prior to either global ischemia or sham surgery. PEM did not significantly alter the hippocampal CA1 neuron death (p = 0.195 by 2-factor ANOVA) or the increase in dendritic injury caused by exposure to global ischemia. Unexpectedly, however, a strong trend was evident for PEM to decrease the consistency of hippocampal damage, as shown by an increased incidence of unilateral or no hippocampal damage (p=0.069 by chi-square analysis). Although PEM caused significant changes to baseline arterial blood pH, pO(2), pCO(2), and fasting glucose (p<0.05), none of these variables (nor hematocrit) correlated significantly with CA1 cell counts in the malnourished group exposed to 2-VO (p>0.269). Intra-ischemic tympanic temperature and blood pressure were strictly and equally controlled between ischemic groups. We conclude that co-existing PEM confounded the consistency of hippocampal injury in the 2-VO model. Although the mechanisms responsible were not identified, this model of brain ischemia should not be used for studying this co-morbidity factor.

  15. Podocyte NF-κB is dispensable for the pathogenesis of renal ischemia-reperfusion injury.

    PubMed

    Yamashita, Maho; Yoshida, Tadashi; Hayashi, Matsuhiko

    2016-08-01

    Podocytes play a central role in the formation of the glomerular filtration barrier in the kidney, and their dysfunction has been shown to result in multiple proteinuric kidney diseases. In this study, we sought to determine whether NF-κB, a proinflammatory signaling, within podocytes was involved in renal ischemia-reperfusion (I/R) injury. Podocyte-specific IκBΔN transgenic (Pod-IκBΔN) mice, in which NF-κB was inhibited specifically in podocytes, were generated by the Cre-loxP technology, and their phenotype was compared with control mice after bilateral renal ischemia. The effect of systemic administration of a NF-κB inhibitor, pyrrolidinedithiocarbamate (PDTC), on renal I/R injury was also examined. Pod-IκBΔN mice were phenotypically normal before surgery. Following renal I/R injury, serum concentrations of urea nitrogen and creatinine were elevated in both Pod-IκBΔN and control mice to a similar extent, whereas PDTC treatment attenuated the elevation of these parameters. Renal histological damage in I/R-injured Pod-IκBΔN mice was also similar to I/R-injured control mice, although it was improved by PDTC treatment. Moreover, I/R induced accumulation of inflammatory cells, such as neutrophils and macrophages, was reduced by PDTC treatment, but not by podocyte-specific NF-κB inhibition. These results provide evidence that the NF-κB activity in podocytes does not contribute to the pathogenesis of renal I/R injury. PMID:27565904

  16. Baicalin attenuates focal cerebral ischemic reperfusion injury through inhibition of nuclear factor {kappa}B p65 activation

    SciTech Connect

    Xue, Xia; Qu, Xian-Jun; Yang, Ying; Sheng, Xie-Huang; Cheng, Fang; Jiang, E-Nang; Wang, Jian-hua; Bu, Wen; Liu, Zhao-Ping

    2010-12-17

    Research highlights: {yields} Permanent NF-{kappa}B p65 activation contributes to the infarction after ischemia-reperfusion injury in rats. {yields} Baicalin can markedly inhibit the nuclear NF-{kappa}B p65 expression and m RNA levels after ischemia-reperfusion injury in rats. {yields} Baicalin decreased the cerebral infarction area via inhibiting the activation of nuclear NF-{kappa}B p65. -- Abstract: Baicalin is a flavonoid compound purified from plant Scutellaria baicalensis Georgi. We aimed to evaluate the neuroprotective effects of baicalin against cerebral ischemic reperfusion injury. Male Wistar rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion for 24 h. Baicalin at doses of 50, 100 and 200 mg/kg was intravenously injected after ischemia onset. Twenty-four hours after reperfusion, the neurological deficit was scored and infarct volume was measured. Hematoxylin and eosin (HE) staining was performed to analyze the histopathological changes of cortex and hippocampus neurons. We examined the levels of NF-{kappa}B p65 in ischemic cortexes by Western blot analysis and RT-PCR assay. The results showed that the neurological deficit scores were significantly decreased from 2.0 {+-} 0.7 to 1.2 {+-} 0.4 and the volume of infarction was reduced by 25% after baicalin injection. Histopathological examination showed that the increase of neurons with pycnotic shape and condensed nuclear in cortex and hippocampus were not observed in baicalin treated animals. Further examination showed that NF-{kappa}B p65 in cortex was increased after ischemia reperfusion injury, indicating the molecular mechanism of ischemia reperfusion injury. The level of NF-{kappa}B p65 was decreased by 73% after baicalin treatment. These results suggest that baicalin might be useful as a potential neuroprotective agent in stroke therapy. The neuroprotective effects of baicalin may relate to inhibition of NF-{kappa}B p65.

  17. The protective activity of noscapine on renal ischemia–reperfusion injury in male Wistar rat

    PubMed Central

    Khanmoradi, Mehrangiz; Ali Mard, Seyyed; Aboutaleb, Nahid; Nobakht, Malihe; Mahmoudian, Masoud

    2014-01-01

    Objective(s): Bradykinin is a part of the kinin-kallikrein system which is involved in ischemia-reperfusion injury via B1 and B2 receptors. Noscapine is a non-competitive antagonist of bradykinin receptors. Noscapine has been reported to to be able to protect some organs against ischemia-reperfusion injury but its effect on renal ischemia-reperfusion injury (RIR) in rats is unknown. Therefore, the present study was designed to evaluate the effect of noscapine on renal ischemia-reperfusion injury in rats. Materials and Methods: Twenty four rats were randomly assigned to four groups; sham, RIR control, pre-and post-treatment with noscapine. To induce RIR injury, 20 days after right nephrectomy, animals underwent a midline laparotomy and the renal artery was clamped for 40 min to induce ischemia, and the clamp was then removed to allow reperfusion for 48 hr. Animals received noscapine or vehicle 1 hr before RIR or just prior to reperfusion. At the end of the experiment, animals were killed by cardiac exsanguination. Blood samples were collected to assess blood urea nitrogen (BUN) and creatinine. The kidneys were also removed for histopathlogical and western-blot analysis. Results: Noscapine treatment 1 hr before RIR or just prior to reperfusion protects the renal tissue structure as compared with the control. The expression levels of the studied inflammatory mediators, TNF-α and MCP-1in pretreated-, and treated-noscapine groups decreased as compared with the control group. The levels of BUN and creatinine in pre-, and post-treated noscapine groups were significantly lower than in control animals. Conclusion: Noscapine protects renal tissue structure and function against RIR through down-regulation of the inflammatory mediators. PMID:24904716

  18. Oral Supplementation of Glucosamine Fails to Alleviate Acute Kidney Injury in Renal Ischemia-Reperfusion Damage.

    PubMed

    Johnsen, Marc; Späth, Martin Richard; Denzel, Martin S; Göbel, Heike; Kubacki, Torsten; Hoyer, Karla Johanna Ruth; Hinze, Yvonne; Benzing, Thomas; Schermer, Bernhard; Antebi, Adam; Burst, Volker; Müller, Roman-Ulrich

    2016-01-01

    Acute kidney injury is a leading contributor to morbidity and mortality in the ageing population. Proteotoxic stress response pathways have been suggested to contribute to the development of acute renal injury. Recent evidence suggests that increased synthesis of N-glycan precursors in the hexosamine pathway as well as feeding of animals with aminosugars produced in the hexosamine pathway may increase stress resistance through reducing proteotoxic stress and alleviate pathology in model organisms. As feeding of the hexosamine pathway metabolite glucosamine to aged mice increased their life expectancy we tested whether supplementation of this aminosugar may also protect mice from acute kidney injury after renal ischemia and reperfusion. Animals were fed for 4 weeks ad libitum with standard chow or standard chow supplemented with 0.5% N-acetylglucosamine. Preconditioning with caloric restriction for four weeks prior to surgery served as a positive control for protective dietary effects. Whereas caloric restriction demonstrated the known protective effect both on renal function as well as survival in the treated animals, glucosamine supplementation failed to promote any protection from ischemia-reperfusion injury. These data show that although hexosamine pathway metabolites have a proven role in enhancing protein quality control and survival in model organisms oral glucosamine supplementation at moderate doses that would be amenable to humans does not promote protection from ischemia-reperfusion injury of the kidney. PMID:27557097

  19. Oral Supplementation of Glucosamine Fails to Alleviate Acute Kidney Injury in Renal Ischemia-Reperfusion Damage

    PubMed Central

    Johnsen, Marc; Späth, Martin Richard; Denzel, Martin S.; Göbel, Heike; Kubacki, Torsten; Hoyer, Karla Johanna Ruth; Hinze, Yvonne; Benzing, Thomas; Schermer, Bernhard; Antebi, Adam; Burst, Volker; Müller, Roman-Ulrich

    2016-01-01

    Acute kidney injury is a leading contributor to morbidity and mortality in the ageing population. Proteotoxic stress response pathways have been suggested to contribute to the development of acute renal injury. Recent evidence suggests that increased synthesis of N-glycan precursors in the hexosamine pathway as well as feeding of animals with aminosugars produced in the hexosamine pathway may increase stress resistance through reducing proteotoxic stress and alleviate pathology in model organisms. As feeding of the hexosamine pathway metabolite glucosamine to aged mice increased their life expectancy we tested whether supplementation of this aminosugar may also protect mice from acute kidney injury after renal ischemia and reperfusion. Animals were fed for 4 weeks ad libitum with standard chow or standard chow supplemented with 0.5% N-acetylglucosamine. Preconditioning with caloric restriction for four weeks prior to surgery served as a positive control for protective dietary effects. Whereas caloric restriction demonstrated the known protective effect both on renal function as well as survival in the treated animals, glucosamine supplementation failed to promote any protection from ischemia-reperfusion injury. These data show that although hexosamine pathway metabolites have a proven role in enhancing protein quality control and survival in model organisms oral glucosamine supplementation at moderate doses that would be amenable to humans does not promote protection from ischemia-reperfusion injury of the kidney. PMID:27557097

  20. Platelets are relevant mediators of renal injury induced by primary endothelial lesions.

    PubMed

    Schwarzenberger, Claudia; Sradnick, Jan; Lerea, Kenneth M; Goligorsky, Michael S; Nieswandt, Bernhard; Hugo, Christian P M; Hohenstein, Bernd

    2015-06-01

    Several studies have suggested a prominent (pro)inflammatory and harmful role of platelets in renal disease, and newer work has also demonstrated platelet release of proangiogenic factors. In the present study, we investigated the role of platelets in a mouse model of selective endothelial cell injury using either platelet depletion or the pharmacological P2Y12 receptor blocker clopidogrel as an interventional strategy. The concanavalin A/anti-concanavalin A model was induced in left kidneys of C57bl/6J wild-type mice after initial platelet depletion or platelet-inhibiting therapy using clopidogrel. FACS analysis of glycoprotein IIb/IIIa/P-selectin double-positive platelets and platelet-derived microparticles demonstrated relevant platelet activation after the induction of selective endothelial injury in mice. Enhanced platelet activation persisted for 5 days after disease induction and was accompanied by increased amounts of circulating platelet-derived microparticles as potential mediators of a prolonged procoagulant state. By immunohistochemistry, we detected significantly reduced glomerular injury in platelet-depleted mice compared with control mice. In parallel, we also saw reduced endothelial loss and a consequently reduced repair response as indicated by diminished proliferative activity. The P2Y12 receptor blocker clopidogrel demonstrated efficacy in limiting platelet activation and subsequent endothelial injury in this mouse model of renal microvascular injury. In conclusion, platelets are relevant mediators of renal injury induced by primary endothelial lesions early on, as demonstrated by platelet depletion as well as platelet inhibition via the P2Y12 receptor. While strategies to prevent platelet-endothelial interactions have shown protective effects, the contribution of platelets during renal regeneration remains unknown.

  1. Platelets are relevant mediators of renal injury induced by primary endothelial lesions

    PubMed Central

    Schwarzenberger, Claudia; Sradnick, Jan; Lerea, Kenneth M.; Goligorsky, Michael S.; Nieswandt, Bernhard; Hugo, Christian P. M.

    2015-01-01

    Several studies have suggested a prominent (pro)inflammatory and harmful role of platelets in renal disease, and newer work has also demonstrated platelet release of proangiogenic factors. In the present study, we investigated the role of platelets in a mouse model of selective endothelial cell injury using either platelet depletion or the pharmacological P2Y12 receptor blocker clopidogrel as an interventional strategy. The concanavalin A/anti-concanavalin A model was induced in left kidneys of C57bl/6J wild-type mice after initial platelet depletion or platelet-inhibiting therapy using clopidogrel. FACS analysis of glycoprotein IIb/IIIa/P-selectin double-positive platelets and platelet-derived microparticles demonstrated relevant platelet activation after the induction of selective endothelial injury in mice. Enhanced platelet activation persisted for 5 days after disease induction and was accompanied by increased amounts of circulating platelet-derived microparticles as potential mediators of a prolonged procoagulant state. By immunohistochemistry, we detected significantly reduced glomerular injury in platelet-depleted mice compared with control mice. In parallel, we also saw reduced endothelial loss and a consequently reduced repair response as indicated by diminished proliferative activity. The P2Y12 receptor blocker clopidogrel demonstrated efficacy in limiting platelet activation and subsequent endothelial injury in this mouse model of renal microvascular injury. In conclusion, platelets are relevant mediators of renal injury induced by primary endothelial lesions early on, as demonstrated by platelet depletion as well as platelet inhibition via the P2Y12 receptor. While strategies to prevent platelet-endothelial interactions have shown protective effects, the contribution of platelets during renal regeneration remains unknown. PMID:25834071

  2. Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury.

    PubMed

    Farrar, Conrad A; Tran, David; Li, Ke; Wu, Weiju; Peng, Qi; Schwaeble, Wilhelm; Zhou, Wuding; Sacks, Steven H

    2016-05-01

    Physiochemical stress induces tissue injury as a result of the detection of abnormal molecular patterns by sensory molecules of the innate immune system. Here, we have described how the recently discovered C-type lectin collectin-11 (CL-11, also known as CL-K1 and encoded by COLEC11) recognizes an abnormal pattern of L-fucose on postischemic renal tubule cells and activates a destructive inflammatory response. We found that intrarenal expression of CL-11 rapidly increases in the postischemic period and colocalizes with complement deposited along the basolateral surface of the proximal renal tubule in association with L-fucose, the potential binding ligand for CL-11. Mice with either generalized or kidney-specific deficiency of CL-11 were strongly protected against loss of renal function and tubule injury due to reduced complement deposition. Ex vivo renal tubule cells showed a marked capacity for CL-11 binding that was induced by cell stress under hypoxic or hypothermic conditions and prevented by specific removal of L-fucose. Further analysis revealed that cell-bound CL-11 required the lectin complement pathway-associated protease MASP-2 to trigger complement deposition. Given these results, we conclude that lectin complement pathway activation triggered by ligand-CL-11 interaction in postischemic tissue is a potent source of acute kidney injury and is amenable to sugar-specific blockade.

  3. Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury

    PubMed Central

    Farrar, Conrad A.; Tran, David; Li, Ke; Wu, Weiju; Peng, Qi; Schwaeble, Wilhelm; Zhou, Wuding

    2016-01-01

    Physiochemical stress induces tissue injury as a result of the detection of abnormal molecular patterns by sensory molecules of the innate immune system. Here, we have described how the recently discovered C-type lectin collectin-11 (CL-11, also known as CL-K1 and encoded by COLEC11) recognizes an abnormal pattern of L-fucose on postischemic renal tubule cells and activates a destructive inflammatory response. We found that intrarenal expression of CL-11 rapidly increases in the postischemic period and colocalizes with complement deposited along the basolateral surface of the proximal renal tubule in association with L-fucose, the potential binding ligand for CL-11. Mice with either generalized or kidney-specific deficiency of CL-11 were strongly protected against loss of renal function and tubule injury due to reduced complement deposition. Ex vivo renal tubule cells showed a marked capacity for CL-11 binding that was induced by cell stress under hypoxic or hypothermic conditions and prevented by specific removal of L-fucose. Further analysis revealed that cell-bound CL-11 required the lectin complement pathway–associated protease MASP-2 to trigger complement deposition. Given these results, we conclude that lectin complement pathway activation triggered by ligand–CL-11 interaction in postischemic tissue is a potent source of acute kidney injury and is amenable to sugar-specific blockade. PMID:27088797

  4. Renal Podocyte Injury in a Rat Model of Type 2 Diabetes Is Prevented by Metformin

    PubMed Central

    Kim, Junghyun; Shon, Eunjin; Kim, Chan-Sik; Kim, Jin Sook

    2012-01-01

    Hyperglycemia promotes oxidative stress and hence generation of reactive oxygen species (ROS), which is known to play a crucial role in the pathogenesis of diabetic nephropathy. Metformin, an oral hypoglycemic drug, possesses antioxidant effects. The aim of this paper is to investigate the protective effects of metformin on the injury of renal podocytes in spontaneously diabetic Torii (SDT) rats, a new model for nonobese type 2 diabetes. Metformin (350 mg/kg/day) was given to SDT rats for 17 weeks. Blood glucose, glycated haemoglobin (HbA1c), and albuminuria were examined. Kidney histopathology, renal 8-hydroxydeoxyguanosine (8-OHdG) levels and apoptosis were examined. In 43-week-old SDT rats, severe hyperglycemia was developed, and albuminuria was markedly increased. Diabetes induced significant alterations in renal glomerular structure. In addition, urinary and renal 8-OHdG levels were highly increased, and podocyte loss was shown through application of the TUNEL and synaptopodin staining. However, treatment of SDT rats with metformin restored all these renal changes. Our data suggested that diabetes-induced podocyte loss in diabetic nephropathy could be suppressed by the antidiabetes drug, metformin, through the repression of oxidative injury. PMID:23056035

  5. Hydrogen Sulfide Inhibits High-Salt Diet-Induced Renal Oxidative Stress and Kidney Injury in Dahl Rats

    PubMed Central

    Huang, Pan; Shen, Zhizhou; Liu, Jia; Huang, Yaqian; Chen, Siyao; Yu, Wen; Wang, Suxia; Ren, Yali; Li, Xiaohui; Tang, Chaoshu; Du, Junbao; Jin, Hongfang

    2016-01-01

    Background. The study was designed to investigate if H2S could inhibit high-salt diet-induced renal excessive oxidative stress and kidney injury in Dahl rats. Methods. Male salt-sensitive Dahl and SD rats were used. Blood pressure (BP), serum creatinine, urea, creatinine clearance rate, and 24-hour urine protein were measured. Renal ultra- and microstructures were observed. Collagen-I and -III contents the oxidants and antioxidants levels in renal tissue were detected. Keap1/Nrf2 association and Keap1 s-sulfhydration were detected. Results. After 8 weeks of high-salt diet, BP was significantly increased, renal function and structure were impaired, and collagen deposition was abundant in renal tissues with increased renal MPO activity, H2O2, MDA, GSSG, and •OH contents, reduced renal T-AOC and GSH contents, CAT, GSH-PX and SOD activity, and SOD expressions in Dahl rats. Furthermore, endogenous H2S in renal tissues was decreased in Dahl rats. H2S donor, however, decreased BP, improved renal function and structure, and inhibited collagen excessive deposition in kidney, in association with increased antioxidative activity and reduced oxidative stress in renal tissues. H2S activated Nrf2 by inducing Keap1 s-sulfhydration and subsequent Keap1/Nrf2 disassociation. Conclusions. H2S protected against high-salt diet-induced renal injury associated with enhanced antioxidant capacity and inhibited renal oxidative stress. PMID:26823949

  6. Hydrogen Sulfide Inhibits High-Salt Diet-Induced Renal Oxidative Stress and Kidney Injury in Dahl Rats.

    PubMed

    Huang, Pan; Shen, Zhizhou; Liu, Jia; Huang, Yaqian; Chen, Siyao; Yu, Wen; Wang, Suxia; Ren, Yali; Li, Xiaohui; Tang, Chaoshu; Du, Junbao; Jin, Hongfang

    2016-01-01

    BACKGROUND. The study was designed to investigate if H2S could inhibit high-salt diet-induced renal excessive oxidative stress and kidney injury in Dahl rats. METHODS. Male salt-sensitive Dahl and SD rats were used. Blood pressure (BP), serum creatinine, urea, creatinine clearance rate, and 24-hour urine protein were measured. Renal ultra- and microstructures were observed. Collagen-I and -III contents the oxidants and antioxidants levels in renal tissue were detected. Keap1/Nrf2 association and Keap1 s-sulfhydration were detected. RESULTS. After 8 weeks of high-salt diet, BP was significantly increased, renal function and structure were impaired, and collagen deposition was abundant in renal tissues with increased renal MPO activity, H2O2, MDA, GSSG, and (•)OH contents, reduced renal T-AOC and GSH contents, CAT, GSH-PX and SOD activity, and SOD expressions in Dahl rats. Furthermore, endogenous H2S in renal tissues was decreased in Dahl rats. H2S donor, however, decreased BP, improved renal function and structure, and inhibited collagen excessive deposition in kidney, in association with increased antioxidative activity and reduced oxidative stress in renal tissues. H2S activated Nrf2 by inducing Keap1 s-sulfhydration and subsequent Keap1/Nrf2 disassociation. CONCLUSIONS. H2S protected against high-salt diet-induced renal injury associated with enhanced antioxidant capacity and inhibited renal oxidative stress. PMID:26823949

  7. Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury: Involvement of PARK2-dependent mitophagy.

    PubMed

    Zhang, Xiangnan; Yuan, Yang; Jiang, Lei; Zhang, Jingying; Gao, Jieqiong; Shen, Zhe; Zheng, Yanrong; Deng, Tian; Yan, Haijing; Li, Wenlu; Hou, Wei-Wei; Lu, Jianxin; Shen, Yao; Dai, Haibing; Hu, Wei-Wei; Zhang, Zhuohua; Chen, Zhong

    2014-10-01

    Transient cerebral ischemia leads to endoplasmic reticulum (ER) stress. However, the contributions of ER stress to cerebral ischemia are not clear. To address this issue, the ER stress activators tunicamycin (TM) and thapsigargin (TG) were administered to transient middle cerebral artery occluded (tMCAO) mice and oxygen-glucose deprivation-reperfusion (OGD-Rep.)-treated neurons. Both TM and TG showed significant protection against ischemia-induced brain injury, as revealed by reduced brain infarct volume and increased glucose uptake rate in ischemic tissue. In OGD-Rep.-treated neurons, 4-PBA, the ER stress releasing mechanism, counteracted the neuronal protection of TM and TG, which also supports a protective role of ER stress in transient brain ischemia. Knocking down the ER stress sensor Eif2s1, which is further activated by TM and TG, reduced the OGD-Rep.-induced neuronal cell death. In addition, both TM and TG prevented PARK2 loss, promoted its recruitment to mitochondria, and activated mitophagy during reperfusion after ischemia. The neuroprotection of TM and TG was reversed by autophagy inhibition (3-methyladenine and Atg7 knockdown) as well as Park2 silencing. The neuroprotection was also diminished in Park2(+/-) mice. Moreover, Eif2s1 and downstream Atf4 silencing reduced PARK2 expression, impaired mitophagy induction, and counteracted the neuroprotection. Taken together, the present investigation demonstrates that the ER stress induced by TM and TG protects against the transient ischemic brain injury. The PARK2-mediated mitophagy may be underlying the protection of ER stress. These findings may provide a new strategy to rescue ischemic brains by inducing mitophagy through ER stress activation.

  8. Protective Role of Ramipril and Candesartan against Myocardial Ischemic Reperfusion Injury: A Biochemical and Transmission Electron Microscopical Study

    PubMed Central

    Reddy, Rajitha Bodd; Punuru, Priyanka; Chakka, Gopinath; Karunakaran, Gauthaman

    2016-01-01

    The present study was designed to investigate the role of combined administration of Ramipril and Candesartan against in vitro myocardial ischemic reperfusion injury in rat. Male Wistar albino rats were divided into five groups (n = 6) and treated with saline (10 mL/kg), Ramipril (2 mg/kg), Candesartan (1 mg/kg), and the combination of both drugs, respectively 24 h before induction of global ischemia (5 min of stabilization, 9 min of global ischemia, and 12 min of reflow). Combination of Ramipril and Candesartan when compared to the monotherapy significantly increased the levels of superoxide dismutase, reduced glutathione, catalase, and nitric oxide and decreased the levels of thiobarbituric acid reactive substances. In addition, the superior protective role of combination of Ramipril and Candesartan on ischemia induced myocardial damage was further confirmed by well preserved myocardial tissue architecture in light microscopy and transmission electron microscopy analysis studies. The combination was proved to be effective in salvaging the myocardial tissue against ischemic reperfusion injury when compared to the monotherapy of individual drugs and further investigations on protective mechanism of drugs by increasing the nitric oxide level at molecular levels are needed. PMID:27042175

  9. Intranasal Delivery of Granulocyte Colony-Stimulating Factor Enhances Its Neuroprotective Effects Against Ischemic Brain Injury in Rats.

    PubMed

    Sun, Bao-liang; He, Mei-qing; Han, Xiang-yu; Sun, Jing-yi; Yang, Ming-feng; Yuan, Hui; Fan, Cun-dong; Zhang, Shuai; Mao, Lei-lei; Li, Da-wei; Zhang, Zong-yong; Zheng, Cheng-bi; Yang, Xiao-yi; Li, Yang V; Stetler, R Anne; Chen, Jun; Zhang, Feng

    2016-01-01

    Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with strong neuroprotective properties. However, it has limited capacity to cross the blood-brain barrier and thus potentially limiting its protective capacity. Recent studies demonstrated that intranasal drug administration is a promising way in delivering neuroprotective agents to the central nervous system. The current study therefore aimed at determining whether intranasal administration of G-CSF increases its delivery to the brain and its neuroprotective effect against ischemic brain injury. Transient focal cerebral ischemia in rat was induced with middle cerebral artery occlusion. Our resulted showed that intranasal administration is 8-12 times more effective than subcutaneous injection in delivering G-CSF to cerebrospinal fluid and brain parenchyma. Intranasal delivery enhanced the protective effects of G-CSF against ischemic injury in rats, indicated by decreased infarct volume and increased recovery of neurological function. The neuroprotective mechanisms of G-CSF involved enhanced upregulation of HO-1 and reduced calcium overload following ischemia. Intranasal G-CSF application also promoted angiogenesis and neurogenesis following brain ischemia. Taken together, G-CSF is a legitimate neuroprotective agent and intranasal administration of G-CSF is more effective in delivery and neuroprotection and could be a practical approach in clinic.

  10. Primary and secondary genetic responses after folic acid-induced acute renal injury in the mouse.

    PubMed

    Calvet, J P; Chadwick, L J

    1994-12-01

    Folic acid-induced acute renal injury results in dramatic changes in gene expression. Among the genes affected by folic acid treatment are the primary response genes, c-fos and c-myc, which are thought to function to initiate cell cycle events. In this report, changes in the expression of three other genes in response to folic acid injury have been investigated: ornithine decarboxylase, epidermal growth factor (EGF), and sulfated glycoprotein-2 (SGP-2). Renal injury was found to cause a rapid decrease in EGF mRNA, which remained absent for several days after the initial injury, gradually returning to normal levels over an approximately 3-wk regeneration and recovery period. Ornithine decarboxylase mRNA showed a similar decrease. In contrast, folic acid caused a rapid increase in SGP-2 mRNA, which peaked several days after treatment, decreasing to normal levels over the 3-wk period. The mRNAs for the primary response genes were superinduced in the injured kidneys in the presence of the protein synthesis inhibitor cycloheximide. In contrast, the changes in EGF and SGP-2 mRNA levels were blocked by cycloheximide, indicating that these responses required new protein synthesis during the first few hours after folic acid injury. The opposite but parallel responses in the expression of the EGF and SGP-2 genes suggest that their regulation is coupled to the initial injury-induced dedifferentiation and subsequent return to the fully differentiated state.

  11. Fungal granulomatous interstitial nephritis presenting as acute kidney injury diagnosed by renal histology including PCR assay

    PubMed Central

    Ogura, Makoto; Kagami, Shino; Nakao, Masatsugu; Kono, Midori; Kanetsuna, Yukiko; Hosoya, Tatsuo

    2012-01-01

    We describe two cases of fungal granulomatous interstitial nephritis (GIN) presenting as acute kidney injury (AKI). Increased serum creatinine was detected in Patient 1 after chemotherapy for pharyngeal cancer and in Patient 2 after steroid pulse therapy for bronchial asthma. Renal histology of both patients revealed GIN. Polymerase chain reaction (PCR)-based detection of fungal DNA sequences from kidney tissue demonstrated Trichosporon laibachii and Candida albicans, respectively. When AKI occurs in an immunocompromised host, differential diagnosis of fungal interstitial nephritis should be considered. Furthermore, PCR-based detection of fungal DNA sequences from renal specimens can be useful for rapid diagnosis. PMID:23936627

  12. Fungal granulomatous interstitial nephritis presenting as acute kidney injury diagnosed by renal histology including PCR assay.

    PubMed

    Ogura, Makoto; Kagami, Shino; Nakao, Masatsugu; Kono, Midori; Kanetsuna, Yukiko; Hosoya, Tatsuo

    2012-10-01

    We describe two cases of fungal granulomatous interstitial nephritis (GIN) presenting as acute kidney injury (AKI). Increased serum creatinine was detected in Patient 1 after chemotherapy for pharyngeal cancer and in Patient 2 after steroid pulse therapy for bronchial asthma. Renal histology of both patients revealed GIN. Polymerase chain reaction (PCR)-based detection of fungal DNA sequences from kidney tissue demonstrated Trichosporon laibachii and Candida albicans, respectively. When AKI occurs in an immunocompromised host, differential diagnosis of fungal interstitial nephritis should be considered. Furthermore, PCR-based detection of fungal DNA sequences from renal specimens can be useful for rapid diagnosis.

  13. Rehydration with soft drink-like beverages exacerbates dehydration and worsens dehydration-associated renal injury.

    PubMed

    García-Arroyo, Fernando E; Cristóbal, Magdalena; Arellano-Buendía, Abraham S; Osorio, Horacio; Tapia, Edilia; Soto, Virgilia; Madero, Magdalena; Lanaspa, Miguel A; Roncal-Jiménez, Carlos; Bankir, Lise; Johnson, Richard J; Sánchez-Lozada, Laura-Gabriela

    2016-07-01

    Recurrent dehydration, such as commonly occurs with manual labor in tropical environments, has been recently shown to result in chronic kidney injury, likely through the effects of hyperosmolarity to activate both vasopressin and aldose reductase-fructokinase pathways. The observation that the latter pathway can be directly engaged by simple sugars (glucose and fructose) leads to the hypothesis that soft drinks (which contain these sugars) might worsen rather than benefit dehydration associated kidney disease. Recurrent dehydration was induced in rats by exposure to heat (36°C) for 1 h/24 h followed by access for 2 h to plain water (W), a 11% fructose-glucose solution (FG, same composition as typical soft drinks), or water sweetened with noncaloric stevia (ST). After 4 wk plasma and urine samples were collected, and kidneys were examined for oxidative stress, inflammation, and injury. Recurrent heat-induced dehydration with ad libitum water repletion resulted in plasma and urinary hyperosmolarity with stimulation of the vasopressin (copeptin) levels and resulted in mild tubular injury and renal oxidative stress. Rehydration with 11% FG solution, despite larger total fluid intake, resulted in greater dehydration (higher osmolarity and copeptin levels) and worse renal injury, with activation of aldose reductase and fructokinase, whereas rehydration with stevia water had opposite effects. In animals that are dehydrated, rehydration acutely with soft drinks worsens dehydration and exacerbates dehydration associated renal damage. These studies emphasize the danger of drinking soft drink-like beverages as an attempt to rehydrate following dehydration. PMID:27053647

  14. Autophagy Limits Endotoxemic Acute Kidney Injury and Alters Renal Tubular Epithelial Cell Cytokine Expression.

    PubMed

    Leventhal, Jeremy S; Ni, Jie; Osmond, Morgan; Lee, Kyung; Gusella, G Luca; Salem, Fadi; Ross, Michael J

    2016-01-01

    Sepsis related acute kidney injury (AKI) is a common in-hospital complication with a dismal prognosis. Our incomplete understanding of disease pathogenesis has prevented the identification of hypothesis-driven preventive or therapeutic interventions. Increasing evidence in ischemia-reperfusion and nephrotoxic mouse models of AKI support the theory that autophagy protects renal tubular epithelial cells (RTEC) from injury. However, the role of RTEC autophagy in septic AKI remains unclear. We observed that lipopolysaccharide (LPS), a mediator of gram-negative bacterial sepsis, induces RTEC autophagy in vivo and in vitro through TLR4-initiated signaling. We modeled septic AKI through intraperitoneal LPS injection in mice in which autophagy-related protein 7 was specifically knocked out in the renal proximal tubules (ATG7KO). Compared to control littermates, ATG7KO mice developed more severe renal dysfunction (24hr BUN 100.1mg/dl +/- 14.8 vs 54.6mg/dl +/- 11.3) and parenchymal injury. After injection with LPS, analysis of kidney lysates identified higher IL-6 expression and increased STAT3 activation in kidney lysates from ATG7KO mice compared to controls. In vitro experiments confirmed an altered response to LPS in RTEC with genetic or pharmacological impairment of autophagy. In conclusion, RTEC autophagy protects against endotoxin induced injury and regulates downstream effects of RTEC TLR4 signaling.

  15. Autophagy Limits Endotoxemic Acute Kidney Injury and Alters Renal Tubular Epithelial Cell Cytokine Expression

    PubMed Central

    Leventhal, Jeremy S.; Ni, Jie; Osmond, Morgan; Lee, Kyung; Gusella, G. Luca; Salem, Fadi; Ross, Michael J.

    2016-01-01

    Sepsis related acute kidney injury (AKI) is a common in-hospital complication with a dismal prognosis. Our incomplete understanding of disease pathogenesis has prevented the identification of hypothesis-driven preventive or therapeutic interventions. Increasing evidence in ischemia-reperfusion and nephrotoxic mouse models of AKI support the theory that autophagy protects renal tubular epithelial cells (RTEC) from injury. However, the role of RTEC autophagy in septic AKI remains unclear. We observed that lipopolysaccharide (LPS), a mediator of gram-negative bacterial sepsis, induces RTEC autophagy in vivo and in vitro through TLR4-initiated signaling. We modeled septic AKI through intraperitoneal LPS injection in mice in which autophagy-related protein 7 was specifically knocked out in the renal proximal tubules (ATG7KO). Compared to control littermates, ATG7KO mice developed more severe renal dysfunction (24hr BUN 100.1mg/dl +/- 14.8 vs 54.6mg/dl +/- 11.3) and parenchymal injury. After injection with LPS, analysis of kidney lysates identified higher IL-6 expression and increased STAT3 activation in kidney lysates from ATG7KO mice compared to controls. In vitro experiments confirmed an altered response to LPS in RTEC with genetic or pharmacological impairment of autophagy. In conclusion, RTEC autophagy protects against endotoxin induced injury and regulates downstream effects of RTEC TLR4 signaling. PMID:26990086

  16. Renoprotective effect of the xanthine oxidoreductase inhibitor topiroxostat on adenine-induced renal injury.

    PubMed

    Kamijo-Ikemori, Atsuko; Sugaya, Takeshi; Hibi, Chihiro; Nakamura, Takashi; Murase, Takayo; Oikawa, Tsuyoshi; Hoshino, Seiko; Hisamichi, Mikako; Hirata, Kazuaki; Kimura, Kenjiro; Shibagaki, Yugo

    2016-06-01

    The aim of the present study was to reveal the effect of a xanthine oxidoreductase (XOR) inhibitor, topiroxostat (Top), compared with another inhibitor, febuxostat (Feb), in an adenine-induced renal injury model. We used human liver-type fatty acid-binding protein (L-FABP) chromosomal transgenic mice, and urinary L-FABP, a biomarker of tubulointerstitial damage, was used to evaluate tubulointerstitial damage. Male transgenic mice (n = 24) were fed a 0.2% (wt/wt) adenine-containing diet. Two weeks after the start of this diet, renal dysfunction was confirmed, and the mice were divided into the following four groups: the adenine group was given only the diet containing adenine, and the Feb, high-dose Top (Top-H), and low-dose Top (Top-L) groups were given diets containing Feb (3 mg/kg), Top-H (3 mg/kg), and Top-L (1 mg/kg) in addition to adenine for another 2 wk. After withdrawal of the adenine diet, each medication was continued for 2 wk. Serum creatinine levels, the degree of macrophage infiltration, tubulointerstitial damage, renal fibrosis, urinary 15-F2t-isoprostane levels, and renal XOR activity were significantly attenuated in the kidneys of the Feb, Top-L, and Top-H groups compared with the adenine group. Serum creatinine levels in the Top-L and Top-H groups as well as renal XOR in the Top-H group were significantly lower than those in the Feb group. Urinary excretion of L-FABP in both the Top-H and Top-L groups was significantly lower than in the adenine and Feb groups. In conclusion, Top attenuated renal damage in an adenine-induced renal injury model. PMID:27029427

  17. Renoprotective effect of the xanthine oxidoreductase inhibitor topiroxostat on adenine-induced renal injury.

    PubMed

    Kamijo-Ikemori, Atsuko; Sugaya, Takeshi; Hibi, Chihiro; Nakamura, Takashi; Murase, Takayo; Oikawa, Tsuyoshi; Hoshino, Seiko; Hisamichi, Mikako; Hirata, Kazuaki; Kimura, Kenjiro; Shibagaki, Yugo

    2016-06-01

    The aim of the present study was to reveal the effect of a xanthine oxidoreductase (XOR) inhibitor, topiroxostat (Top), compared with another inhibitor, febuxostat (Feb), in an adenine-induced renal injury model. We used human liver-type fatty acid-binding protein (L-FABP) chromosomal transgenic mice, and urinary L-FABP, a biomarker of tubulointerstitial damage, was used to evaluate tubulointerstitial damage. Male transgenic mice (n = 24) were fed a 0.2% (wt/wt) adenine-containing diet. Two weeks after the start of this diet, renal dysfunction was confirmed, and the mice were divided into the following four groups: the adenine group was given only the diet containing adenine, and the Feb, high-dose Top (Top-H), and low-dose Top (Top-L) groups were given diets containing Feb (3 mg/kg), Top-H (3 mg/kg), and Top-L (1 mg/kg) in addition to adenine for another 2 wk. After withdrawal of the adenine diet, each medication was continued for 2 wk. Serum creatinine levels, the degree of macrophage infiltration, tubulointerstitial damage, renal fibrosis, urinary 15-F2t-isoprostane levels, and renal XOR activity were significantly attenuated in the kidneys of the Feb, Top-L, and Top-H groups compared with the adenine group. Serum creatinine levels in the Top-L and Top-H groups as well as renal XOR in the Top-H group were significantly lower than those in the Feb group. Urinary excretion of L-FABP in both the Top-H and Top-L groups was significantly lower than in the adenine and Feb groups. In conclusion, Top attenuated renal damage in an adenine-induced renal injury model.

  18. Vulnerability of the developing brain to hypoxic-ischemic damage: contribution of the cerebral vasculature to injury and repair?

    PubMed Central

    Baburamani, Ana A.; Ek, C. Joakim; Walker, David W.; Castillo-Melendez, Margie

    2012-01-01

    As clinicians attempt to understand the underlying reasons for the vulnerability of different regions of the developing brain to injury, it is apparent that little is known as to how hypoxia-ischemia may affect the cerebrovasculature in the developing infant. Most of the research investigating the pathogenesis of perinatal brain injury following hypoxia-ischemia has focused on excitotoxicity, oxidative stress and an inflammatory response, with the response of the developing cerebrovasculature receiving less attention. This is surprising as the presentation of devastating and permanent injury such as germinal matrix-intraventricular haemorrhage (GM-IVH) and perinatal stroke are of vascular origin, and the origin of periventricular leukomalacia (PVL) may also arise from poor perfusion of the white matter. This highlights that cerebrovasculature injury following hypoxia could primarily be responsible for the injury seen in the brain of many infants diagnosed with hypoxic-ischemic encephalopathy (HIE). Interestingly the highly dynamic nature of the cerebral blood vessels in the fetus, and the fluctuations of cerebral blood flow and metabolic demand that occur following hypoxia suggest that the response of blood vessels could explain both regional protection and vulnerability in the developing brain. However, research into how blood vessels respond following hypoxia-ischemia have mostly been conducted in adult models of ischemia or stroke, further highlighting the need to investigate how the developing cerebrovasculature responds and the possible contribution to perinatal brain injury following hypoxia. This review discusses the current concepts on the pathogenesis of perinatal brain injury, the development of the fetal cerebrovasculature and the blood brain barrier (BBB), and key mediators involved with the response of cerebral blood vessels to hypoxia. PMID:23162470

  19. Proximal renal tubular injury in rats sub-chronically exposed to low fluoride concentrations.

    PubMed

    Cárdenas-González, Mariana C; Del Razo, Luz M; Barrera-Chimal, Jonatan; Jacobo-Estrada, Tania; López-Bayghen, Esther; Bobadilla, Norma A; Barbier, Olivier

    2013-11-01

    Fluoride is usually found in groundwater at a very wide range of concentration between 0.5 and 25 ppm. At present, few studies have assessed the renal effects of fluoride at environmentally relevant concentrations. Furthermore, most of these studies have used insensitive and nonspecific biomarkers of kidney injury. The aim of this study was to use early and sensitive biomarkers to evaluate kidney injury after fluoride exposure to environmentally relevant concentrations. Recently weaned male Wistar rats were exposed to low (15 ppm) and high (50 ppm) fluoride concentrations in drinking water for a period of 40 days. At the end of the exposure period, kidney injury biomarkers were measured in urine and renal mRNA expression levels were assessed by real time RT-PCR. Our results showed that the urinary kidney injury molecule (Kim-1), clusterin (Clu), osteopontin (OPN) and heat shock protein 72 excretion rate significantly increased in the group exposed to the high fluoride concentration. Accordingly, fluoride exposure increased renal Kim-1, Clu and OPN mRNA expression levels. Moreover, there was a significant dose-dependent increase in urinary β-2-microglobulin and cystatin-C excretion rate. Additionally, a tendency towards a dose dependent increase of tubular damage in the histopathological light microscopy findings confirmed the preferential impact of fluoride on the tubular structure. All of these changes occurred at early stages in which, the renal function was not altered. In conclusion using early and sensitive biomarkers of kidney injury, we were able to found proximal tubular alterations in rats sub-chronically exposed to fluoride.

  20. Curcumin and dexmedetomidine prevents oxidative stress and renal injury in hind limb ischemia/reperfusion injury in a rat model.

    PubMed

    Karahan, M A; Yalcin, S; Aydogan, H; Büyükfirat, E; Kücük, A; Kocarslan, S; Yüce, H H; Taskın, A; Aksoy, N

    2016-06-01

    Curcumin and dexmedetomidine have been shown to have protective effects in ischemia-reperfusion injury on various organs. However, their protective effects on kidney tissue against ischemia-reperfusion injury remain unclear. We aimed to determine whether curcumin or dexmedetomidine prevents renal tissue from injury that was induced by hind limb ischemia-reperfusion in rats. Fifty rats were divided into five groups: sham, control, curcumin (CUR) group (200 mg/kg curcumin, n = 10), dexmedetomidine (DEX) group (25 μg/kg dexmedetomidine, n = 10), and curcumin-dexmedetomidine (CUR-DEX) group (200 mg/kg curcumin and 25 μg/kg dexmedetomidine). Curcumin and dexmedetomidine were administered intraperitoneally immediately after the end of 4 h ischemia, just 5 min before reperfusion. The extremity re-perfused for 2 h and then blood samples were taken and total antioxidant capacity (TAC), total oxidative status (TOS) levels, and oxidative stress index (OSI) were measured, and renal tissue samples were histopathologically examined. The TAC activity levels in blood samples were significantly lower in the control than the other groups (p < 0.01 for all comparisons). The TOS activity levels in blood samples were significantly higher in Control group and than the other groups (p <  0.01 for all comparison). The OSI were found to be significantly increased in the control group compared to others groups (p < 0.001 for all comparisons). Histopathological examination revealed less severe lesions in the sham, CUR, DEX, and CUR-DEX groups, compared with the control group (p < 0.01). Rat hind limb ischemia-reperfusion causes histopathological changes in the kidneys. Curcumin and dexmedetomidine administered intraperitoneally was effective in reducing oxidative stress and renal histopathologic injury in an acute hind limb I/R rat model. PMID:26983591

  1. Remote preconditioning-endocrine factors in organ protection against ischemic injury.

    PubMed

    Bolte, Craig S; Liao, Siyun; Gross, Garrett J; Schultz, Jo El J

    2007-09-01

    Cardiovascular disease is the leading cause of death in the United States and developing world. Experimental and clinical studies have demonstrated that a number of interventions including brief periods of ischemia or hypoxia and certain endogenous factors such as opioids, bradykinin, growth factors or pharmacological agents are capable of protecting the heart against post-ischemic contractile dysfunction, arrhythmias and myocardial infarction. This conventional cardioprotection occurs via an autocrine or paracrine action in which these protective factors are released from the heart to act upon itself. Over the last ten years, a growing body of evidence indicates that a brief ischemic insult on one organ releases endogenous factors that protect other organs against a prolonged ischemic insult. This phenomenon, termed remote preconditioning or preconditioning at a distance, implicates an endocrine action, and may involve humoral or neural-endocrine signaling. This review will summarize the endocrine factors identified and implicated in this inter-organ cytoprotection. PMID:17897043

  2. Proximal renal tubular injury in rats sub-chronically exposed to low fluoride concentrations

    SciTech Connect

    Cárdenas-González, Mariana C.; Del Razo, Luz M.; Barrera-Chimal, Jonatan; Jacobo-Estrada, Tania; López-Bayghen, Esther; and others

    2013-11-01

    Fluoride is usually found in groundwater at a very wide range of concentration between 0.5 and 25 ppm. At present, few studies have assessed the renal effects of fluoride at environmentally relevant concentrations. Furthermore, most of these studies have used insensitive and nonspecific biomarkers of kidney injury. The aim of this study was to use early and sensitive biomarkers to evaluate kidney injury after fluoride exposure to environmentally relevant concentrations. Recently weaned male Wistar rats were exposed to low (15 ppm) and high (50 ppm) fluoride concentrations in drinking water for a period of 40 days. At the end of the exposure period, kidney injury biomarkers were measured in urine and renal mRNA expression levels were assessed by real time RT-PCR. Our results showed that the urinary kidney injury molecule (Kim-1), clusterin (Clu), osteopontin (OPN) and heat shock protein 72 excretion rate significantly increased in the group exposed to the high fluoride concentration. Accordingly, fluoride exposure increased renal Kim-1, Clu and OPN mRNA expression levels. Moreover, there was a significant dose-dependent increase in urinary β-2-microglobulin and cystatin-C excretion rate. Additionally, a tendency towards a dose dependent increase of tubular damage in the histopathological light microscopy findings confirmed the preferential impact of fluoride on the tubular structure. All of these changes occurred at early stages in which, the renal function was not altered. In conclusion using early and sensitive biomarkers of kidney injury, we were able to found proximal tubular alterations in rats sub-chronically exposed to fluoride. - Highlights: • Exposure to low concentrations of fluoride induced proximal tubular injury • Increase in urinary Kim-1, Clu, OPN and Hsp72 in 50 ppm fluoride-exposed group • Increase in urinary B2M and CysC in 15 and 50 ppm fluoride-exposed groups • Fluoride exposure increased renal Kim, Clu and OPN mRNA expression levels.

  3. Renal

    MedlinePlus

    ... term "renal" refers to the kidney. For example, renal failure means kidney failure. Related topics: Kidney disease Kidney disease - diet Kidney failure Kidney function tests Renal scan Kidney transplant

  4. Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

    PubMed Central

    Jung, Yeon Suk; Park, Jung Hwa; Kim, Hyunha; Kim, So Young; Hwang, Ji Young; Hong, Ki Whan; Bae, Sun Sik; Choi, Byung Tae; Lee, Sae-Won; Shin, Hwa Kyoung

    2016-01-01

    Aim: Increasing evidence suggests that probucol, a lipid-lowering agent with anti-oxidant activities, may be useful for the treatment of ischemic stroke with hyperlipidemia via reduction in cholesterol and neuroinflammation. In this study we examined whether probucol could protect against brain ischemic injury via anti-neuroinflammatory action in normal and hyperlipidemic mice. Methods: Primary mouse microglia and murine BV2 microglia were exposed to lipopolysaccharide (LPS) for 3 h, and the release NO, PGE2, IL-1β and IL-6, as well as the changes in NF-κB, MAPK and AP-1 signaling pathways were assessed. ApoE KO mice were fed a high-fat diet containing 0.004%, 0.02%, 0.1% (wt/wt) probucol for 10 weeks, whereas normal C57BL/6J mice received probucol (3, 10, 30 mg·kg-1·d-1, po) for 4 d. Then all the mice were subjected to focal cerebral ischemia through middle cerebral artery occlusion (MCAO). The neurological deficits were scored 24 h after the surgery, and then brains were removed for measuring the cerebral infarct size and the production of pro-inflammatory mediators. Results: In LPS-treated BV2 cells and primary microglial cells, pretreatment with probucol (1, 5, 10 μmol/L) dose-dependently inhibited the release of NO, PGE2, IL-1β and IL-6, which occurred at the transcription levels. Furthermore, the inhibitory actions of probucol were associated with the downregulation of the NF-κB, MAPK and AP-1 signaling pathways. In the normal mice with MCAO, pre-administration of probucol dose-dependently decreased the infarct volume and improved neurological function. These effects were accompanied by the decreased production of pro-inflammatory mediators (iNOS, COX-2, IL-1, IL-6). In ApoE KO mice fed a high-fat diet, pre-administration of 0.1% probucol significantly reduced the infarct volume, improved the neurological deficits following MCAO, and decreased the total- and LDL-cholesterol levels. Conclusion: Probucol inhibits LPS-induced microglia activation and

  5. Hydrosulfide attenuates acute myocardial ischemic injury through the glycogen synthase kinase-3β/β-catenin signaling pathway.

    PubMed

    Ge, Ning; Liu, Chao; Li, Guofeng; Xie, Lijun; Zhang, Qinzeng; Li, Liping; Hao, Na; Zhang, Jianxin

    2016-05-01

    The endogenous signaling gasotransmitter, hydrosulfide (H2S), has been shown to exert cardioprotective effects against acute myocardial infarction (AMI) due to ischemic injury. However, the mechanisms responsible for these effects are not yet fully understood. In this study, we investigated whether sodium hydrogen sulfide (NaHS), an H2S donor, attenuates acute myocardial ischemic injury through glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling. For this purpose, we utilized an in vivo rat model of AMI by occluding the left anterior descending coronary artery. NaHS (0.39, 0.78 or 1.56 mg/kg, intraperitoneally), the GSK-3β inhibitor, SB216763 (0.6 mg/kg, intravenously), or 1% dimethylsulfoxide (2 ml/kg, intravenously) were administered to the rats. The results demonstrated that the administration of medium- and high-dose NaHS and SB216763 significantly improved rat cardiac function, as evidenced by an increase in the mean arterial pressure, left ventricular developed pressure, contraction and relaxation rates, as well as a decrease in left ventricular end-diastolic pressure. In addition, the administration of NaHS and SB216763 attenuated myocardial injury as reflected by a decrease in apoptotic cell death and in the serum lactate dehydrogenase concentrations, and prevented myocardial structural changes. The administration of NaHS and SB216763 increased the concentrations of phosphorylated (p-)GSK-3β, the p-GSK-3β/t-GSK-3β ratio and downstream protein β-catenin. Moreover, western blot and immunohistochemical analyses of apoptotic signaling pathway proteins further established the cardioprotective potential of NaHS, as reflected by the upregulation of Bcl-2 expression, the downregulation of Bax expression, and a decrease in the number of TUNEL-positive stained cells. These findings suggest that hydrosulfide exerts cardioprotective effects against AMI-induced apoptosis through the GSK-3β/β-catenin signaling pathway.

  6. Hydrosulfide attenuates acute myocardial ischemic injury through the glycogen synthase kinase-3β/β-catenin signaling pathway

    PubMed Central

    GE, NING; LIU, CHAO; LI, GUOFENG; XIE, LIJUN; ZHANG, QINZENG; LI, LIPING; HAO, NA; ZHANG, JIANXIN

    2016-01-01

    The endogenous signaling gasotransmitter, hydrosulfide (H2S), has been shown to exert cardioprotective effects against acute myocardial infarction (AMI) due to ischemic injury. However, the mechanisms responsible for these effects are not yet fully understood. In this study, we investigated whether sodium hydrogen sulfide (NaHS), an H2S donor, attenuates acute myocardial ischemic injury through glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling. For this purpose, we utilized an in vivo rat model of AMI by occluding the left anterior descending coronary artery. NaHS (0.39, 0.78 or 1.56 mg/kg, intraperitoneally), the GSK-3β inhibitor, SB216763 (0.6 mg/kg, intravenously), or 1% dimethylsulfoxide (2 ml/kg, intravenously) were administered to the rats. The results demonstrated that the administration of medium- and high-dose NaHS and SB216763 significantly improved rat cardiac function, as evidenced by an increase in the mean arterial pressure, left ventricular developed pressure, contraction and relaxation rates, as well as a decrease in left ventricular end-diastolic pressure. In addition, the administration of NaHS and SB216763 attenuated myocardial injury as reflected by a decrease in apoptotic cell death and in the serum lactate dehydrogenase concentrations, and prevented myocardial structural changes. The administration of NaHS and SB216763 increased the concentrations of phosphorylated (p-)GSK-3β, the p-GSK-3β/t-GSK-3β ratio and downstream protein β-catenin. Moreover, western blot and immunohistochemical analyses of apoptotic signaling pathway proteins further established the cardioprotective potential of NaHS, as reflected by the upregulation of Bcl-2 expression, the downregulation of Bax expression, and a decrease in the number of TUNEL-positive stained cells. These findings suggest that hydrosulfide exerts cardioprotective effects against AMI-induced apoptosis through the GSK-3β/β-catenin signaling pathway. PMID:27035393

  7. Sulfasalazine-induced renal and hepatic injury in rats and the protective role of taurine

    PubMed Central

    Heidari, Reza; Rasti, Maryam; Shirazi Yeganeh, Babak; Niknahad, Hossein; Saeedi, Arastoo; Najibi, Asma

    2016-01-01

    Introduction: Sulfasalazine is a drug commonly administrated against inflammatory-based disorders. On the other hand, kidney and liver injury are serious adverse events accompanied by sulfasalazine administration. No specific therapeutic option is available against this complication. The current investigation was designed to evaluate the potential protective effects of taurine against sulfasalazine-induced kidney and liver injury in rats. Methods: Male Sprague-Dawley rats were administered with sulfasalazine (600 mg/kg, oral) for 14 consecutive days. Animals received different doses of taurine (250, 500 and 1000 mg/ kg, i.p.) every day. Markers of organ injury were evaluated on day 15th, 24 h after the last dose of sulfasalazine. Results: Sulfasalazine caused renal and hepatic injury as judged by an increase in serum level of creatinine (Cr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP). The levels of reactive oxygen species (ROS) and lipid peroxidation were raised in kidney and liver of sulfasalazine-treated animals. Moreover, tissue glutathione reservoirs were depleted after sulfasalazine administration. Histopathological changes of kidney and liver also endorsed organ injury. Taurine administration (250, 500 and 1000 mg/kg/day, i.p) alleviated sulfasalazine-induced renal and hepatic damage. Conclusion: Taurine administration could serve as a potential protective agent with therapeutic capabilities against sulfasalazine adverse effects. PMID:27340618

  8. Embolization of Iatrogenic Vascular Injuries of Renal Transplants: Immediate and Follow-Up Results

    SciTech Connect

    Dorffner, Roland; Thurnher, Siegfried; Prokesch, Rupert; Bankier, Alexander; Turetschek, Karl; Schmidt, Alice; Lammer, Johannes

    1998-03-15

    Purpose: To evaluate the outcome in seven patients in whom iatrogenic vascular complications were treated with catheter embolization. Methods: Angiography showed an arteriovenous fistula in six of the seven patients, a pseudoaneurysm in three patients, and an arteriocaliceal fistula in three patients. Embolization was performed with GAW coils or microcoils in all cases. In three patients enbucrilate, polyvinyl alcohol, or absorbable gelatin powder was administered as an adjunct to the coils. Results: Angiographic success with total occlusion of the vascular injury was achieved in five of the seven patients and clinical success was achieved in four of seven cases. In two cases, nephrectomy after embolization was necessary because of renal artery occlusion or acute hemorrhage at the renal artery anastomosis, respectively. Infarction of 30%-50% of the renal parenchyma was seen in two cases. Conclusion: Angiographically successful embolization is not necessarily associated with clinical success. The complication rate is high.

  9. Acute kidney injury as the first sign of spontaneous renal vein thrombosis: report of 2 cases.

    PubMed

    Shumei, Shi; Ling, Xu; Yanxia, Wang; Lei, Zhang; Yuanyuan, Sun

    2012-01-01

    Spontaneous renal vein thrombosis (RVT) is very rare in the absence of nephrotic syndrome. It is more common in newborns and infants. RVT should always be included in the differential diagnosis of flank pain and hematuria, and because RVT can induce acute renal injury. A 19-year-old man was admitted to our hospital because he complained of right flank pain and oliguria for 3 days. Another patient, a 24-year-old man, complained of a severe and sudden onset of bilateral flank pain and anuria for a day. They were both healthy before they developed the described symptoms and had different levels of decrease in renal function when they visited the hospital. Color Doppler ultrasonography revealed RVT in both the patients. The patients received therapy, including anticoagulation and thrombolysis, following their diagnoses, and they recovered in a few days.

  10. Forced diuresis with the RenalGuard system: impact on contrast induced acute kidney injury.

    PubMed

    Solomon, Richard

    2014-01-01

    Kidney injury following the administration of iodinated contrast media occurs particularly in patients with reduced kidney and cardiac function and when large doses of contrast are used. There is little compelling evidence that vasodilators and anti-oxidants prevent this injury. Most prevention trials have employed intravenous volume loading as a central strategy. However, the success of this approach depends upon maintaining euvolemia while producing a vigorous diuresis. A novel strategy for maintaining euvolemia and inducing a vigorous diuresis has been developed using the RenalGuard system. In this review; the mechanism of protective action is reviewed. The trials of the RenalGuard device are reviewed and future uses of the device are discussed.

  11. The Effect of Autophagy on Inflammation Cytokines in Renal Ischemia/Reperfusion Injury.

    PubMed

    Ling, Haibin; Chen, Hongguang; Wei, Miao; Meng, Xiaoyin; Yu, Yonghao; Xie, Keliang

    2016-02-01

    Acute kidney injury (AKI) is characterized by a rapid loss of kidney function and an antigen-independent inflammatory process that causes tissue damage, which was one of the main manifestations of kidney ischemia/reperfusion (I/R). Recent studies have demonstrated autophagy participated in the pathological process of acute kidney injury. In this study, we discuss how autophagy regulated inflammation response in the kidney I/R. AKI was performed by renal I/R. Autophagy activator rapamycin (Rap) and inhibitor 3-methyladenine (MA) were used to investigate the role of autophagy on kidney function and inflammation response. After the experiment, kidney tissues were obtained for the detection of autophagy-related protein microtubule-associated protein light chain 3(LC3)II, Beclin1, and Rab7 and lysosome-associated membrane protein type (LAMP)2 protein by reverse transcription-polymerase chain reaction (PT-PCR) and Western blotting, and histopathology and tissue injury scores also. The blood was harvested to measure kidney function (creatinine (Cr) and blood urea nitrogen (BUN) levels) after I/R. Cytokines TNF-α, IL-6, HMGB1, and IL-10 were measured after I/R. I/R induced the expression of LC3II, Beclin1, LAMP2, and Rab7. The activation and inhibition of autophagy by rapamycin and 3-MA were promoted and attenuated histological and renal function in renal I/R rats, respectively. Cytokines TNF-α, IL-6, and HMGB1 were decreased, and IL-10 was further increased after activation of autophagy treated in I/R rats, while 3-MA exacerbated the pro-inflammatory cytokines TNF-α, IL-6, HMGB1, and anti-inflammatory cytokine IL-10 in renal I/R. I/R can activated the autophagy, and autophagy increase mitigated the renal injury by decreasing kidney injury score, levels of Cr and BUN after renal I/R, and inflammation response via regulating the balance of pro-inflammation and anti-inflammation cytokines.

  12. Histone Acetylation and CREB Binding Protein Are Required for Neuronal Resistance against Ischemic Injury

    PubMed Central

    Yildirim, Ferah; Ji, Shengbo; Kronenberg, Golo; Barco, Angel; Olivares, Roman; Benito, Eva; Dirnagl, Ulrich; Gertz, Karen; Endres, Matthias

    2014-01-01

    Epigenetic transcriptional regulation by histone acetylation depends on the balance between histone acetyltransferase (HAT) and deacetylase activities (HDAC). Inhibition of HDAC activity provides neuroprotection, indicating that the outcome of cerebral ischemia depends crucially on the acetylation status of histones. In the present study, we characterized the changes in histone acetylation levels in ischemia models of focal cerebral ischemia and identified cAMP-response element binding protein (CREB)–binding protein (CBP) as a crucial factor in the susceptibility of neurons to ischemic stress. Both neuron-specific RNA interference and neurons derived from CBP heterozygous knockout mice showed increased damage after oxygen-glucose deprivation (OGD) in vitro. Furthermore, we demonstrated that ischemic preconditioning by a short (5 min) subthreshold occlusion of the middle cerebral artery (MCA), followed 24 h afterwards by a 30 min occlusion of the MCA, increased histone acetylation levels in vivo. Ischemic preconditioning enhanced CBP recruitment and histone acetylation at the promoter of the neuroprotective gene gelsolin leading to increased gelsolin expression in neurons. Inhibition of CBP's HAT activity attenuated neuronal ischemic preconditioning. Taken together, our findings suggest that the levels of CBP and histone acetylation determine stroke outcome and are crucially associated with the induction of an ischemia-resistant state in neurons. PMID:24748101

  13. Cinnamon Polyphenols Attenuate Neuronal Death and Glial Swelling in Ischemic Injury

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Brain edema is a major complication associated with ischemic stroke and is characterized by a volumetric enlargement of the brain. Astrocyte swelling is a major component of brain edema. We investigated the protective effects of polyphenols isolated from green tea and cinnamon in C6 glial cultures s...

  14. Rational clinical trial design for antibody mediated renal allograft injury

    PubMed Central

    Sandal, Shaifali; Zand, Martin S.

    2015-01-01

    Antibody mediated renal allograft rejection is a significant cause of acute and chronic graft loss. Recent work has revealed that AMR is a complex processes, involving B and plasma cells, donor-specific antibodies, complement, vascular endothelial cells, NK cells, Fc receptors, cytokines and chemokines. These insights have led to the development of numerous new therapies, and adaptation of others originally developed for treatment of hemetologic malignancies, autoimmune and complement mediated conditions. Here we review emerging insights into the pathophysiology of AMR as well as current and emerging therapies for both acute and chronic AMR. Finally, we discuss rational clinical trial design in light of antibody and B cell immunobiology, as well as appropriate efficacy metrics to identify robust protocols and therapeutic agents. PMID:25553476

  15. Relationship between red cell distribution width and early renal injury in patients with gestational diabetes mellitus.

    PubMed

    Cheng, Dong; Zhao, Jiangtao; Jian, Liguo; Ding, Tongbin; Liu, Shichao

    2016-09-01

    Previous studies found that red cell distribution width was related to adverse cardiovascular events. However, few studies reported the relationship between red cell distribution width and early-stage renal injury in pregnant women with gestational diabetes mellitus. Using a cross-sectional design, 334 pregnant women with gestational diabetes mellitus were enrolled according to the criterion of inclusion and exclusion. Demographic and clinical examination data were collected. Depended on the urine albumin, study population were divided into case group (n = 118) and control group (n = 216). Compared with control group, the case group tend to be higher red cell distribution width level (13.6 ± 0.9 vs.12.5 ± 0.6, p < 0.001). The red cell distribution width was positively associated with albuminuria creatinine ratio (r = 0.567, p < 0.001). Multiple logistic regressions showed that red cell distribution width was still associated with early-stage renal injury after adjusting for many other potential cofounders. Compared with the first quartile, the risk ratio of the second, the third and the fourth quartile were 1.38 (95%CI: 1.06-1.80), 1.57 (95%CI: 1.21-2.97), 2.71 (95%CI: 2.08-3.54), respectively. Besides, systolic blood pressure, estimated glomerular filtration rate, uric acid and blood urea nitrogen were also significantly associated with renal injury in gestational diabetes mellitus patients. The elevated red cell distribution width level might be a predictor of early-stage renal injury in pregnant women with gestational diabetes mellitus. As an easy and routine examination index, red cell distribution width may provide better clinical guidance when combined with other important indices.

  16. Plasma Kallikrein-Kinin system mediates immune-mediated renal injury in trichloroethylene-sensitized mice.

    PubMed

    Wang, Hui; Zhang, Jia-Xiang; Ye, Liang-Ping; Li, Shu-Long; Wang, Feng; Zha, Wan-Sheng; Shen, Tong; Wu, Changhao; Zhu, Qi-Xing

    2016-07-01

    Trichloroethylene (TCE) is a major environmental pollutant. An immunological response is a newly-recognized mechanism for TCE-induced kidney damage. However, the role of the plasma kallikrein-kinin system (KKS) in immune-mediated kidney injury has never been examined. This study aimed to explore the role of the key components of the KKS, i.e. plasma kallikrein (PK), bradykinin (BK) and its receptors B1R and B2R, in TCE-induced kidney injury. A mouse model of skin sensitization was used to explore the mechanism of injury with or without a PK inhibitor PKSI. Kidney function was evaluated by measuring blood urea nitrogen (BUN) and creatinine (Cr) in conjunction with histopathologic characterization. Plasma BK was determined by ELISA; Renal C5b-9 membrane attack complex was evaluated by immunohistochemistry. Expression of BK and PK in the kidney was detected by immunofluorescence. mRNA and protein levels of B1R and B2R were assessed by real-time qPCR and Western blot. As expected, numerous inflammatory cell infiltration and tubular epithelial cell vacuolar degeneration were observed in TCE-sensitized mice. Moreover, serum BUN and Cr and plasma BK were increased. In addition, deposition of BK, PK and C5b-9 were observed and B1R and B2R mRNA and proteins levels were up-regulated. Pre-treatment with PKSI, a highly selective inhibitor of PK, alleviated TCE-induced renal damage. In addition, PKSI attenuated TCE-induced up-regulation of BK, PK and its receptors and C5b-9. These results provided the first evidence that activation of the KKS contributed to immune-mediated renal injury induced by TCE and also helped to identify the KKS as a potential therapeutic target for mitigating chemical sensitization-induced renal damage. PMID:27027470

  17. Evaluation of aqueous extract of Murraya koenigii in unilateral renal ischemia reperfusion injury in rats

    PubMed Central

    Punuru, Priyanka; Sujatha, D.; Kumari, B. Pushpa; Charisma, V. V. L.

    2014-01-01

    Aim: The aqueous extract of leaves of Murraya koenigii was studied for its renoprotective potential against unilateral renal ischemia reperfusion (RIR) injury in male Wistar rats. Materials and Methods: Healthy adult male Wistar rats were divided into five groups (n = 8) and were treated with 200 mg/kg., p.o. of aqueous extract of M. koenigii (AEMK) for 30 days to assess both preventive and curative effects of AEMK. Except Group I, RIR was induced to all the groups by clamping the left renal artery using artery clamp for 1 h followed by reperfusion by removing the clamp. Groups II and III underwent RIR at 30th day whereas RIR was induced in Groups IV and V at 1st day of treatment schedule. Biochemical parameters (serum creatinine, blood urea nitrogen, serum total protein and serum Na+), urinary parameters (urine output, urinary creatinine, urinary urea, urinary total protein, urinary Na+), in vivo anti-oxidants, renal myeloperoxidase (MPO) activity and histopathology of kidneys were monitored. Statistical significance was set at P < 0.05. Results: Rats were treated with AEMK significantly (P < 0.05) restored the serum and urinary parameters with significant (P < 0.05) improvement in endogenous anti-oxidants such as superoxide dismutase, catalase and reduced glutathione and decreased levels of malondialdehyde and renal MPO when compared with the control groups. Histopathological examination also supported the biochemical and urinary tests. Conclusions: Aqueous extract of M. koenigii possesses both preventive and curative effects against RIR injury. PMID:24741188

  18. Cinnabar-Induced Subchronic Renal Injury Is Associated with Increased Apoptosis in Rats

    PubMed Central

    Wang, Ying; Wang, Dapeng; Wu, Jie; Wang, Bohan; Gao, Xianhui; Wang, Liangjun; Ma, Honglin

    2015-01-01

    The aim of this study was to explore the role of apoptosis in cinnabar-induced renal injury in rats. To test this role, rats were dosed orally with cinnabar (1 g/kg/day) for 8 weeks or 12 weeks, and the control rats were treated with 5% carboxymethylcellulose solution. Levels of urinary mercury (UHg), renal mercury (RHg), serum creatinine (SCr), and urine kidney injury molecule 1 (KIM-1) were assessed, and renal pathology was analyzed. Apoptotic cells were identified and the apoptotic index was calculated. A rat antibody array was used to analyze expression of cytokines associated with apoptosis. Results from these analyses showed that UHg, RHg, and urine KIM-1, but not SCr, levels were significantly increased in cinnabar-treated rats. Renal pathological changes in cinnabar-treated rats included vacuolization of tubular cells, formation of protein casts, infiltration of inflammatory cells, and increase in the number of apoptotic tubular cells. In comparison to the control group, expression of FasL, Fas, TNF-α, TRAIL, activin A, and adiponectin was upregulated in the cinnabar-treated group. Collectively, our results suggest that prolonged use of cinnabar results in kidney damage due to accumulation of mercury and that the underlying mechanism involves apoptosis of tubular cells via a death receptor-mediated pathway. PMID:25629042

  19. Tauroursodeoxycholic Acid Attenuates Renal Tubular Injury in a Mouse Model of Type 2 Diabetes.

    PubMed

    Zhang, Jing; Fan, Ying; Zeng, Chuchu; He, Li; Wang, Niansong

    2016-01-01

    Renal tubular injury is a critical factor in the pathogenesis of diabetic nephropathy (DN). Endoplasmic reticulum (ER) stress is involved in diabetic nephropathy. Tauroursodeoxycholic acid (TUDCA) is an effective inhibitor of ER stress. Here, we investigated the role of TUDCA in the progression of tubular injury in DN. For eight weeks, being treated with TUDCA at 250 mg/kg intraperitoneal injection (i.p.) twice a day, diabetic db/db mice had significantly reduced blood glucose, albuminuria and attenuated renal histopathology. These changes were associated with a significant decreased expression of ER stress markers. At the same time, diabetic db/db mice had more TUNEL-positive nuclei in the renal tubule, which were attenuated by TUDCA treatment, along with decreases in ER stress-associated apoptotic markers in the kidneys. In summary, the effect of TUDCA on tubular injury, in part, is associated with inhibition of ER stress in the kidneys of diabetic db/db mice. TUDCA shows potential as a therapeutic target for the prevention and treatment of DN. PMID:27669287

  20. Responses of proximal tubular cells to injury in congenital renal disease: fight or flight.

    PubMed

    Chevalier, Robert L; Forbes, Michael S; Galarreta, Carolina I; Thornhill, Barbara A

    2014-04-01

    Most chronic kidney disease in children results from congenital or inherited disorders, which can be studied in mouse models. Following 2 weeks of unilateral ureteral obstruction (UUO) in the adult mouse, nephron loss is due to proximal tubular mitochondrial injury and cell death. In neonatal mice, proximal tubular cell death is delayed beyond 2 weeks of complete UUO, and release of partial UUO allows remodeling of remaining nephrons. Progressive cyst expansion develops in polycystic kidney disease (PKD), a common inherited renal disorder. The polycystic kidney and fibrosis (pcy)-mutant mouse (which develops late-onset PKD) develops thinning of the glomerulotubular junction in parallel with growth of cysts in adulthood. Renal insufficiency in nephropathic cystinosis, a rare inherited renal disorder, results from progressive tubular cystine accumulation. In the Ctns knockout mouse (a model of cystinosis), proximal tubular cells become flattened, with loss of mitochondria and thickening of tubular basement membrane. In each model, persistent obstructive or metabolic stress leads ultimately to the formation of atubular glomeruli. The initial "fight" response (proximal tubular survival) switches to a "flight" response (proximal tubular cell death) with ongoing oxidative injury and mitochondrial damage. Therapies should be directed at reducing proximal tubular mitochondrial oxidative injury to enhance repair and regeneration.

  1. Tauroursodeoxycholic Acid Attenuates Renal Tubular Injury in a Mouse Model of Type 2 Diabetes.

    PubMed

    Zhang, Jing; Fan, Ying; Zeng, Chuchu; He, Li; Wang, Niansong

    2016-01-01

    Renal tubular injury is a critical factor in the pathogenesis of diabetic nephropathy (DN). Endoplasmic reticulum (ER) stress is involved in diabetic nephropathy. Tauroursodeoxycholic acid (TUDCA) is an effective inhibitor of ER stress. Here, we investigated the role of TUDCA in the progression of tubular injury in DN. For eight weeks, being treated with TUDCA at 250 mg/kg intraperitoneal injection (i.p.) twice a day, diabetic db/db mice had significantly reduced blood glucose, albuminuria and attenuated renal histopathology. These changes were associated with a significant decreased expression of ER stress markers. At the same time, diabetic db/db mice had more TUNEL-positive nuclei in the renal tubule, which were attenuated by TUDCA treatment, along with decreases in ER stress-associated apoptotic markers in the kidneys. In summary, the effect of TUDCA on tubular injury, in part, is associated with inhibition of ER stress in the kidneys of diabetic db/db mice. TUDCA shows potential as a therapeutic target for the prevention and treatment of DN.

  2. Tauroursodeoxycholic Acid Attenuates Renal Tubular Injury in a Mouse Model of Type 2 Diabetes

    PubMed Central

    Zhang, Jing; Fan, Ying; Zeng, Chuchu; He, Li; Wang, Niansong

    2016-01-01

    Renal tubular injury is a critical factor in the pathogenesis of diabetic nephropathy (DN). Endoplasmic reticulum (ER) stress is involved in diabetic nephropathy. Tauroursodeoxycholic acid (TUDCA) is an effective inhibitor of ER stress. Here, we investigated the role of TUDCA in the progression of tubular injury in DN. For eight weeks, being treated with TUDCA at 250 mg/kg intraperitoneal injection (i.p.) twice a day, diabetic db/db mice had significantly reduced blood glucose, albuminuria and attenuated renal histopathology. These changes were associated with a significant decreased expression of ER stress markers. At the same time, diabetic db/db mice had more TUNEL-positive nuclei in the renal tubule, which were attenuated by TUDCA treatment, along with decreases in ER stress–associated apoptotic markers in the kidneys. In summary, the effect of TUDCA on tubular injury, in part, is associated with inhibition of ER stress in the kidneys of diabetic db/db mice. TUDCA shows potential as a therapeutic target for the prevention and treatment of DN. PMID:27669287

  3. Resveratrol attenuates renal injury and fibrosis by inhibiting transforming growth factor-β pathway on matrix metalloproteinase 7

    PubMed Central

    Xiao, Zhou; Chen, Chen; Meng, Ting; Zhang, Wenzheng

    2015-01-01

    Renal injury has a strong relationship to the subsequent development of renal fibrosis. In developing renal fibrosis, tubular epithelial cells in the kidney underwent epithelial–mesenchymal transition (EMT). Matrix metalloproteinase 7 (MMP7) was reported to reduce E-cadherin and induce EMT by up-regulation of β-catenin/lymphoid enhancer-binding factor 1 (LEF1) signaling. In this research, we tried to evaluate the role of resveratrol (RSV) on EMT process in renal injury and fibrosis. Human tubular epithelial cell HK-2 cells were treated with aristolochic acid (AAs) and transforming growth factor-β(TGF-β) to induce EMT with or without the administration of RSV. The inhibitory role of RSV on EMT in renal injury and fibrosis was determined by Western blotting, real-time PCR, and immunofluorescence staining. The EMT repressing role of RSV was also evaluated in vivo by renal ischemia-reperfusion (I/R) injury and unilateral ureteral obstruction (UUO) models. The underlying mechanism was investigated by shRNA interfering MMP7 and sirtuin 1 (SIRT1) expression. The results indicated that RSV reversed human kidney 2 (HK-2) cell EMT, renal I/R injury, and renal fibrosis. MMP7 inhibition was responsible for RSV-induced EMT repression. SIRT1 was up-regulated by RSV inhibited TGF-β pathway on MMP7 via deacetylating Smad4. In conclusion, RSV attenuated renal injury and fibrosis by inhibiting EMT process which was attributed to the fact that the up-regulated SIRT1 by RSV deacetylated Smad4 and inhibited MMP7 expression. PMID:26316584

  4. Resveratrol attenuates renal injury and fibrosis by inhibiting transforming growth factor-β pathway on matrix metalloproteinase 7.

    PubMed

    Xiao, Zhou; Chen, Chen; Meng, Ting; Zhang, Wenzheng; Zhou, Qiaoling

    2016-01-01

    Renal injury has a strong relationship to the subsequent development of renal fibrosis. In developing renal fibrosis, tubular epithelial cells in the kidney underwent epithelial-mesenchymal transition (EMT). Matrix metalloproteinase 7 (MMP7) was reported to reduce E-cadherin and induce EMT by up-regulation of β-catenin/lymphoid enhancer-binding factor 1 (LEF1) signaling. In this research, we tried to evaluate the role of resveratrol (RSV) on EMT process in renal injury and fibrosis. Human tubular epithelial cell HK-2 cells were treated with aristolochic acid (AAs) and transforming growth factor-β(TGF-β) to induce EMT with or without the administration of RSV. The inhibitory role of RSV on EMT in renal injury and fibrosis was determined by Western blotting, real-time PCR, and immunofluorescence staining. The EMT repressing role of RSV was also evaluated in vivo by renal ischemia-reperfusion (I/R) injury and unilateral ureteral obstruction (UUO) models. The underlying mechanism was investigated by shRNA interfering MMP7 and sirtuin 1 (SIRT1) expression. The results indicated that RSV reversed human kidney 2 (HK-2) cell EMT, renal I/R injury, and renal fibrosis. MMP7 inhibition was responsible for RSV-induced EMT repression. SIRT1 was up-regulated by RSV inhibited TGF-β pathway on MMP7 via deacetylating Smad4. In conclusion, RSV attenuated renal injury and fibrosis by inhibiting EMT process which was attributed to the fact that the up-regulated SIRT1 by RSV deacetylated Smad4 and inhibited MMP7 expression.

  5. Probucol plus cilostazol attenuate hypercholesterolemia‑induced exacerbation in ischemic brain injury via anti-inflammatory effects.

    PubMed

    Kim, Ji Hyun; Hong, Ki Whan; Bae, Sun Sik; Shin, Yong-Il; Choi, Byung Tae; Shin, Hwa Kyoung

    2014-09-01

    Probucol, a lipid-lowering agent with anti-oxidant properties, is involved in protection against atherosclerosis, while cilostazol, an antiplatelet agent, has diverse neuroprotective properties. In this study, we investigated the anti-inflammatory effects of probucol and cilostazol on focal cerebral ischemia with hypercholesterolemia. Apolipoprotein E (ApoE) knockout (KO) mice were fed a high-fat diet (HFD) with or without 0.3% probucol and/or 0.2% cilostazol for 10 weeks. To assess the protective effects of the combined therapy of probucol and cilostazol on ischemic injury, the mice received 40 min of middle cerebral artery occlusion (MCAO). Infarct volumes, neurobehavioral deficits and neuroinflammatory mediators were subsequently evaluated 48 h after reperfusion. Probucol alone and probucol plus cilostazol significantly decreased total- and low-density lipoprotein (LDL)-cholesterol in ApoE KO with HFD. MCAO resulted in significantly larger infarct volumes in ApoE KO mice provided with HFD compared to those fed a regular diet, although these volumes were significantly reduced in the probucol plus cilostazol group. Consistent with a smaller infarct size, probucol alone and the combined treatment of probucol and cilostazol improved neurological and motor function. In addition, probucol alone and probucol plus cilostazol decreased MCP-1 expression and CD11b and GFAP immuno-reactivity in the ischemic cortex. These findings suggested that the inhibitory effects of probucol plus cilostazol in MCP-1 expression in the ischemic brain with hypercholesterolemia allowed the identification of one of the mechanisms responsible for anti-inflammatory action. Probucol plus cilostazol may therefore serve as a therapeutic strategy for reducing the impact of stroke in hypercholesterolemic subjects.

  6. Progesterone is neuroprotective against ischemic brain injury through its effects on the PI3K/Akt signaling pathway

    PubMed Central

    Ishrat, Tauheed; Sayeed, Iqbal; Atif, Fahim; Hua, Fang; Stein, Donald G.

    2012-01-01

    We tested the hypothesis that the phosphatidylinositol-3 kinase (PI3K/Akt) pathway mediates some of the neuroprotective effects of progesterone (PROG) after ischemic stroke. We examined whether PROG acting through the PI3K/Akt pathway could affect the expression of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). Rats underwent permanent focal cerebral ischemia (pMCAO) by electro-coagulation and received intraperitoneal injections of PROG (8mg/kg) or vehicle at 1h post-occlusion and subcutaneous injections at 6, 24, and 48h. PAkt/Akt levels, apoptosis and apoptosis-related proteins (pBAD, BAD, caspase-3, and cleaved caspase-3) were analyzed by TUNEL assays, Western blotting and immunohistochemistry at 24h post-pMCAO. VEGF and BDNF were analyzed at 24, 72h and 14 days post-pMCAO with Western blots. Following pMCAO, PROG treatment significantly (p<0.05) reduced ischemic lesion size and edema. Treatment with PROG significantly (p<0.05) decreased VEGF at 24 and 72h but increased VEGF expression 14d after injury. The treatment also increased BDNF, and attenuated apoptosis by increasing Akt phosphorylation compared to vehicle-alone. The selective PI3K inhibitor Wortmannin compromised PROG-induced neuroprotective effects and reduced the elevation of pAkt levels in the ischemic penumbra. Our findings lead us to suggest that the PI3K/Akt pathway can play a role in mediating the neuroprotective effects of PROG after stroke by altering the expression of trophic factors in the brain. PMID:22450229

  7. Cell Therapy Using Human Induced Pluripotent Stem Cell-Derived Renal Progenitors Ameliorates Acute Kidney Injury in Mice

    PubMed Central

    Toyohara, Takafumi; Mae, Shin-Ichi; Sueta, Shin-Ichi; Inoue, Tatsuyuki; Yamagishi, Yukiko; Kawamoto, Tatsuya; Kasahara, Tomoko; Hoshina, Azusa; Toyoda, Taro; Tanaka, Hiromi; Araoka, Toshikazu; Sato-Otsubo, Aiko; Takahashi, Kazutoshi; Sato, Yasunori; Yamaji, Noboru; Ogawa, Seishi; Yamanaka, Shinya

    2015-01-01

    Acute kidney injury (AKI) is defined as a rapid loss of renal function resulting from various etiologies, with a mortality rate exceeding 60% among intensive care patients. Because conventional treatments have failed to alleviate this condition, the development of regenerative therapies using human induced pluripotent stem cells (hiPSCs) presents a promising new therapeutic option for AKI. We describe our methodology for generating renal progenitors from hiPSCs that show potential in ameliorating AKI. We established a multistep differentiation protocol for inducing hiPSCs into OSR1+SIX2+ renal progenitors capable of reconstituting three-dimensional proximal renal tubule-like structures in vitro and in vivo. Moreover, we found that renal subcapsular transplantation of hiPSC-derived renal progenitors ameliorated the AKI in mice induced by ischemia/reperfusion injury, significantly suppressing the elevation of blood urea nitrogen and serum creatinine levels and attenuating histopathological changes, such as tubular necrosis, tubule dilatation with casts, and interstitial fibrosis. To our knowledge, few reports demonstrating the therapeutic efficacy of cell therapy with renal lineage cells generated from hiPSCs have been published. Our results suggest that regenerative medicine strategies for kidney diseases could be developed using hiPSC-derived renal cells. Significance This report is the first to demonstrate that the transplantation of renal progenitor cells differentiated from human induced pluripotent stem (iPS) cells has therapeutic effectiveness in mouse models of acute kidney injury induced by ischemia/reperfusion injury. In addition, this report clearly demonstrates that the therapeutic benefits come from trophic effects by the renal progenitor cells, and it identifies the renoprotective factors secreted by the progenitors. The results of this study indicate the feasibility of developing regenerative medicine strategy using iPS cells against renal diseases

  8. Slit2 prevents neutrophil recruitment and renal ischemia-reperfusion injury.

    PubMed

    Chaturvedi, Swasti; Yuen, Darren A; Bajwa, Amandeep; Huang, Yi-Wei; Sokollik, Christiane; Huang, Liping; Lam, Grace Y; Tole, Soumitra; Liu, Guang-Ying; Pan, Jerry; Chan, Lauren; Sokolskyy, Yaro; Puthia, Manoj; Godaly, Gabriela; John, Rohan; Wang, Changsen; Lee, Warren L; Brumell, John H; Okusa, Mark D; Robinson, Lisa A

    2013-07-01

    Neutrophils recruited to the postischemic kidney contribute to the pathogenesis of ischemia-reperfusion injury (IRI), which is the most common cause of renal failure among hospitalized patients. The Slit family of secreted proteins inhibits chemotaxis of leukocytes by preventing activation of Rho-family GTPases, suggesting that members of this family might modulate the recruitment of neutrophils and the resulting IRI. Here, in static and microfluidic shear assays, Slit2 inhibited multiple steps required for the infiltration of neutrophils into tissue. Specifically, Slit2 blocked the capture and firm adhesion of human neutrophils to inflamed vascular endothelial barriers as well as their subsequent transmigration. To examine whether these observations were relevant to renal IRI, we administered Slit2 to mice before bilateral clamping of the renal pedicles. Assessed at 18 hours after reperfusion, Slit2 significantly inhibited renal tubular necrosis, neutrophil and macrophage infiltration, and rise in plasma creatinine. In vitro, Slit2 did not impair the protective functions of neutrophils, including phagocytosis and superoxide production, and did not inhibit neutrophils from killing the extracellular pathogen Staphylococcus aureus. In vivo, administration of Slit2 did not attenuate neutrophil recruitment or bacterial clearance in mice with ascending Escherichia coli urinary tract infections and did not increase the bacterial load in the livers of mice infected with the intracellular pathogen Listeria monocytogenes. Collectively, these results suggest that Slit2 may hold promise as a strategy to combat renal IRI without compromising the protective innate immune response.

  9. Acute kidney injury in the perioperative period and in intensive care units (excluding renal replacement therapies).

    PubMed

    Ichai, Carole; Vinsonneau, Christophe; Souweine, Bertrand; Armando, Fabien; Canet, Emmanuel; Clec'h, Christophe; Constantin, Jean-Michel; Darmon, Michaël; Duranteau, Jacques; Gaillot, Théophille; Garnier, Arnaud; Jacob, Laurent; Joannes-Boyau, Olivier; Juillard, Laurent; Journois, Didier; Lautrette, Alexandre; Muller, Laurent; Legrand, Matthieu; Lerolle, Nicolas; Rimmelé, Thomas; Rondeau, Eric; Tamion, Fabienne; Walrave, Yannick; Velly, Lionel

    2016-12-01

    Acute kidney injury (AKI) is a syndrome that has progressed a great deal over the last 20 years. The decrease in urine output and the increase in classical renal biomarkers, such as blood urea nitrogen and serum creatinine, have largely been used as surrogate markers for decreased glomerular filtration rate (GFR), which defines AKI. However, using such markers of GFR as criteria for diagnosing AKI has several limits including the difficult diagnosis of non-organic AKI, also called "functional renal insufficiency" or "pre-renal insufficiency". This situation is characterized by an oliguria and an increase in creatininemia as a consequence of a reduction in renal blood flow related to systemic haemodynamic abnormalities. In this situation, "renal insufficiency" seems rather inappropriate as kidney function is not impaired. On the contrary, the kidney delivers an appropriate response aiming to recover optimal systemic physiological haemodynamic conditions. Considering the kidney as insufficient is erroneous because this suggests that it does not work correctly, whereas the opposite is occurring, because the kidney is healthy even in a threatening situation. With current definitions of AKI, normalization of volaemia is needed before defining AKI in order to avoid this pitfall. PMID:27230984

  10. Acute kidney injury in the perioperative period and in intensive care units (excluding renal replacement therapies).

    PubMed

    Ichai, Carole; Vinsonneau, Christophe; Souweine, Bertrand; Armando, Fabien; Canet, Emmanuel; Clec'h, Christophe; Constantin, Jean-Michel; Darmon, Michaël; Duranteau, Jacques; Gaillot, Théophille; Garnier, Arnaud; Jacob, Laurent; Joannes-Boyau, Olivier; Juillard, Laurent; Journois, Didier; Lautrette, Alexandre; Muller, Laurent; Legrand, Matthieu; Lerolle, Nicolas; Rimmelé, Thomas; Rondeau, Eric; Tamion, Fabienne; Walrave, Yannick; Velly, Lionel

    2016-12-01

    Acute kidney injury (AKI) is a syndrome that has progressed a great deal over the last 20 years. The decrease in urine output and the increase in classical renal biomarkers, such as blood urea nitrogen and serum creatinine, have largely been used as surrogate markers for decreased glomerular filtration rate (GFR), which defines AKI. However, using such markers of GFR as criteria for diagnosing AKI has several limits including the difficult diagnosis of non-organic AKI, also called "functional renal insufficiency" or "pre-renal insufficiency". This situation is characterized by an oliguria and an increase in creatininemia as a consequence of a reduction in renal blood flow related to systemic haemodynamic abnormalities. In this situation, "renal insufficiency" seems rather inappropriate as kidney function is not impaired. On the contrary, the kidney delivers an appropriate response aiming to recover optimal systemic physiological haemodynamic conditions. Considering the kidney as insufficient is erroneous because this suggests that it does not work correctly, whereas the opposite is occurring, because the kidney is healthy even in a threatening situation. With current definitions of AKI, normalization of volaemia is needed before defining AKI in order to avoid this pitfall.

  11. Ischemic optic neuropathy.

    PubMed

    Athappilly, Geetha; Pelak, Victoria S; Mandava, Naresh; Bennett, Jeffrey L

    2008-10-01

    Ischemic optic neuropathy is the most frequent cause of vision loss in middle age. Clinical and laboratory research studies have begun to clarify the natural history, clinical presentation, diagnostic criteria and pathogenesis of various ischemic nerve injuries. As a result, physicians are acquiring new tools to aid in the diagnosis and potential treatment of ischemic nerve injury. The aim of this review is to examine recent data on anterior and posterior ischemic optic neuropathy and to provide a framework for physicians to manage and counsel affected individuals. PMID:18826805

  12. Effects of Neonatal Hypoxic-Ischemic Injury and Hypothermic Neuroprotection on Neural Progenitor Cells in the Mouse Hippocampus.

    PubMed

    Kwak, Minhye; Lim, Sanghee; Kang, Eunchai; Furmanski, Orion; Song, Hongjun; Ryu, Yun Kyoung; Mintz, C David

    2015-01-01

    Neonatal hypoxic-ischemic injury (HI) results in widespread cerebral encephalopathy and affects structures that are essential for neurocognitive function, such as the hippocampus. The dentate gyrus contains a reservoir of neural stem and progenitor cells (NSPCs) that are critical for postnatal development and normal adult function of the hippocampus, and may also facilitate the recovery of function after injury. Using a neonatal mouse model of mild-to-moderate HI and immunohistochemical analysis of NSPC development markers, we asked whether these cells are vulnerable to HI and how they respond to both injury and hypothermic therapy. We found that cleaved caspase-3 labeling in the subgranular zone, where NSPCs are located, is increased by more than 30-fold after HI. The population of cells positive for both proliferating cell nuclear antigen and nestin (PCNA+Nes+), which represent primarily actively proliferating NSPCs, are acutely decreased by 68% after HI. The NSPC population expressing NeuroD1, a marker for NSPCs transitioning to become fate-committed neural progenitors, was decreased by 47%. One week after HI, there was a decrease in neuroblasts and immature neurons in the dentate gyrus, as measured by doublecortin (DCX) immunolabeling, and at the same time PCNA+Nes+ cell density was increased by 71%. NSPCs expressing Tbr2, which identifies a highly proliferative intermediate neural progenitor population, increased by 107%. Hypothermia treatment after HI partially rescues both the acute decrease in PCNA+Nes+ cell density at 1 day after injury and the chronic loss of DCX immunoreactivity and reduction in NeuroD1 cell density measured at 1 week after injury. Thus, we conclude that HI causes an acute loss of dentate gyrus NSPCs, and that hypothermia partially protects NSPCs from HI. PMID:26087836

  13. Sulfatide-Mediated Activation of Type II Natural Killer T Cells Prevents Hepatic Ischemic Reperfusion Injury In Mice

    PubMed Central

    Arrenberg, Philomena; Maricic, Igor; Kumar, Vipin

    2011-01-01

    Background & Aims Hepatic ischemic reperfusion injury (IRI) is a major complication of liver transplantation and resectional hepatic surgeries. Natural killer T (NKT) cells predominate in liver, where they recognize lipid antigens bound to CD1d molecules. Type I NKT cells utilize a semi-invariant T-cell receptor and react with α-galactosylceramide; type II NKT cells use diverse T-cell receptors. Some type II NKT cells recognize the self-glycolipid sulfatide. It is not clear whether or how these distinct NKT cell subsets mediate hepatocellular damage following IRI. Methods We examined the roles of type I and type II NKT cells in mice with partial hepatic, warm ischemia and reperfusion injury. Results Mice that lack type I NKT cells (Jα18−/−) were protected from hepatic IRI, indicated by reduced hepatocellular necrosis and serum levels of alanine aminotransferase. Sulfatide-mediated activation of type II NKT cells reduced IFN-γ secretion by type I NKT cells and prevented IRI. Protection from hepatic IRI by sulfatide-mediated inactivation of type I NKT cells was associated with significant reductions in hepatic recruitment of myeloid cell subsets, especially the CD11b+Gr-1int, Gr-1−, and NK cells. Conclusion In mice, subsets of NKT cells have opposing roles in hepatic IRI: type I NKT cells promote injury whereas sulfatide-reactive type II NKT cells protect against injury. CD1d activation of NKT cells is conserved from mice to humans, so strategies to modify these processes might be developed to treat patients with hepatic reperfusion injury. PMID:20950612

  14. Blocking lymphocyte trafficking with FTY720 prevents inflammation-sensitized hypoxic-ischemic brain injury in newborns.

    PubMed

    Yang, Dianer; Sun, Yu-Yo; Bhaumik, Siddhartha Kumar; Li, Yikun; Baumann, Jessica M; Lin, Xiaoyi; Zhang, Yujin; Lin, Shang-Hsuan; Dunn, R Scott; Liu, Chia-Yang; Shie, Feng-Shiun; Lee, Yi-Hsuan; Wills-Karp, Marsha; Chougnet, Claire A; Kallapur, Suhas G; Lewkowich, Ian P; Lindquist, Diana M; Murali-Krishna, Kaja; Kuan, Chia-Yi

    2014-12-01

    Intrauterine infection (chorioamnionitis) aggravates neonatal hypoxic-ischemic (HI) brain injury, but the mechanisms linking systemic inflammation to the CNS damage remain uncertain. Here we report evidence for brain influx of T-helper 17 (TH17)-like lymphocytes to coordinate neuroinflammatory responses in lipopolysaccharide (LPS)-sensitized HI injury in neonates. We found that both infants with histological chorioamnionitis and rat pups challenged by LPS/HI have elevated expression of the interleukin-23 (IL-23) receptor, a marker of early TH17 lymphocytes, in the peripheral blood mononuclear cells. Post-LPS/HI administration of FTY720 (fingolimod), a sphingosine-1-phosphate receptor agonist that blocks lymphocyte trafficking, mitigated the influx of leukocytes through the choroid plexus and acute induction of nuclear factor-κB signaling in the brain. Subsequently, the FTY720 treatment led to attenuated blood-brain barrier damage, fewer cluster of differentiation 4-positive, IL-17A-positive T-cells in the brain, less proinflammatory cytokine, and better preservation of growth and white matter functions. The FTY720 treatment also provided dose-dependent reduction of brain atrophy, rescuing >90% of LPS/HI-induced brain tissue loss. Interestingly, FTY720 neither opposed pure-HI brain injury nor directly inhibited microglia in both in vivo and in vitro models, highlighting its unique mechanism against inflammation-sensitized HI injury. Together, these results suggest that the dual hit of systemic inflammation and neonatal HI injury triggers early onset of the TH17/IL-17-mediated immunity, which causes severe brain destruction but responds remarkably to the therapeutic blockade of lymphocyte trafficking.

  15. Prognostic indicators of adverse renal outcome and death in acute kidney injury hospital survivors

    PubMed Central

    Hamzić-Mehmedbašić, Aida; Rašić, Senija; Balavac, Merima; Rebić, Damir; Delić-Šarac, Marina; Durak-Nalbantić, Azra

    2016-01-01

    Introduction: Data regarding prognostic factors of post-discharge mortality and adverse renal function outcome in acute kidney injury (AKI) hospital survivors are scarce and controversial. Objectives: We aimed to identify predictors of post-discharge mortality and adverse renal function outcome in AKI hospital survivors. Patients and Methods: The study group consisted of 84 AKI hospital survivors admitted to the tertiary medical center during 2-year period. Baseline clinical parameters, with renal outcome 3 months after discharge and 6-month mortality were evaluated. According survival and renal function outcome, patients were divided into two groups. Results: Patients who did not recover renal function were statistically significantly older (P < 0.007) with higher Charlson comorbidity index (CCI) score (P < 0.000) and more likely to have anuria and oliguria (P = 0.008) compared to those with recovery. Deceased AKI patients were statistically significantly older (P < 0.000), with higher CCI score (P < 0.000), greater prevalence of sepsis (P =0.004), higher levels of C-reactive protein (CRP) (P < 0.017) and ferritin (P < 0.051) and lower concentrations of albumin (P<0.01) compared to survivors. By multivariate analysis, independent predictors of adverse renal outcome were female gender (P =0.033), increasing CCI (P =0.000), presence of pre-existing chronic kidney disease (P =0.000) and diabetes mellitus (P =0.019) as well as acute decompensated heart failure (ADHF) (P =0.032), while protective factor for renal function outcome was higher urine output (P =0.009). Independent predictors of post-discharge mortality were female gender (P =0.04), higher CCI score (P =0.001) and sepsis (P =0.034). Conclusion: Female AKI hospital survivors with increasing burden of comorbidities, diagnosis of sepsis and ADHF seem to be at high-risk for poor post-discharge outcome. PMID:27471736

  16. Design, synthesis and biological evaluation of tricyclic diterpene derivatives as novel neuroprotective agents against ischemic brain injury.

    PubMed

    Wang, Ying-Ying; Gao, Yuan-Xue; Gao, Wei; Xu, Yuan; Xu, Ya-Zhou; Wang, Yun-Jie; Chang, Sai; Yu, Li-Gang; Zhang, Lu-Yong; Liao, Hong; Yang, Lian-Fang; Pang, Tao; Qiu, Wen-Wei

    2015-10-20

    Lead compound 7 has neuroprotective effects, and it was discovered by screening a small synthetic natural product-like (NPL) library. Based on the lead, a series of tricyclic diterpene derivatives was designed and synthesized, and their neuroprotective effects were further evaluated against glutamate-, oxygen and glucose deprivation (OGD)- and nutrient deprivation-induced neuronal injury using cell-based assays. To our delight, most of these synthetic compounds exhibited increased neuroprotective effects and blood-brain barrier (BBB) permeability without cellular toxicity. The most potent compound, compound 30, showed significantly improved neuroprotection against neuronal injury in primary neurons. Furthermore, compound 30 exhibited remarkable neuroprotection in transient middle cerebral artery occlusion (tMCAO) rats by reducing their infarct sizes and neurological deficit scores. A mechanistic exploration using in vitro and in vivo experiments showed that the neuroprotection of these compounds was at least partly mediated by improving the levels of glutathione (GSH), superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) protein. Therefore, these tricyclic diterpene derivatives could be used as promising leads for the development of a new type of neuroprotective agents against ischemic brain injury.

  17. A global transcriptomic view of the multifaceted role of glutathione peroxidase-1 in cerebral ischemic-reperfusion injury.

    PubMed

    Chen, Minghui Jessica; Wong, Connie H Y; Peng, Zhao Feng; Manikandan, Jayapal; Melendez, Alirio J; Tan, Theresa M; Crack, Peter J; Cheung, Nam Sang

    2011-03-15

    Transient cerebral ischemia often results in secondary ischemic/reperfusion injury, the pathogenesis of which remains unclear. This study provides a comprehensive, temporal description of the molecular events contributing to neuronal injury after transient cerebral ischemia. Intraluminal middle cerebral artery occlusion (MCAO) was performed to induce a 2-h ischemia with reperfusion. Microarray analysis was then performed on the infarct cortex of wild-type (WT) and glutathione peroxidase-1 (a major antioxidant enzyme) knockout (Gpx1(-/-)) mice at 8 and 24h postreperfusion to identify differential gene expression profile patterns and potential alternative injury cascades in the absence of Gpx1, a crucial antioxidant enzyme, in cerebral ischemia. Genes with at least ±1.5-fold change in expression at either time point were considered significant. Global transcriptomic analyses demonstrated that 70% of the WT-MCAO profile overlapped with that of Gpx1(-/-)-MCAO, and 28% vice versa. Critical analysis of the 1034 gene probes specific to the Gpx1(-/-)-MCAO profile revealed regulation of additional novel pathways, including the p53-mediated proapoptotic pathway and Fas ligand (CD95/Apo1)-mediated pathways; downplay of the Nrf2 antioxidative cascade; and ubiquitin-proteasome system dysfunction. Therefore, this comparative study forms the foundation for the establishment of screening platforms for target definition in acute cerebral ischemia intervention.

  18. A European Renal Best Practice (ERBP) position statement on the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines on Acute Kidney Injury: part 2: renal replacement therapy.

    PubMed

    Jörres, Achim; John, Stefan; Lewington, Andrew; ter Wee, Pieter M; Vanholder, Raymond; Van Biesen, Wim; Tattersall, James

    2013-12-01

    This paper provides an endorsement of the KDIGO guideline on acute kidney injury; more specifically, on the part that concerns renal replacement therapy. New evidence that has emerged since the publication of the KDIGO guideline was taken into account, and the guideline is commented on from a European perspective. Advice is given on when to start and stop renal replacement therapy in acute kidney injury; which modalities should be preferentially be applied, and in which conditions; how to gain access to circulation; how to measure adequacy; and which dose can be recommended.

  19. Association of renal injury with increased oxygen free radical activity and altered nitric oxide metabolism in chronic experimental hemosiderosis.

    PubMed

    Zhou, X J; Laszik, Z; Wang, X Q; Silva, F G; Vaziri, N D

    2000-12-01

    Chronic iron (Fe) overload is associated with a marked increase in renal tissue iron content and injury. It is estimated that 10% of the American population carry the gene for hemochromatosis and 1% actually suffer from iron overload. The mechanism of iron overload-associated renal damage has not been fully elucidated. Iron can accelerate lipid peroxidation leading to organelle membrane dysfunction and subsequent cell injury/death. Iron-catalyzed generation of reactive oxygen species (ROS) is responsible for initiating the peroxidatic reaction. We investigated the possible association of oxidative stress and its impact on nitric oxide (NO) metabolism in iron-overload-associated renal injury. Rats were randomized into Fe-loaded (given 0.5 g elemental iron/kg body weight as iron dextran; i.v.), Fe-depleted (given an iron-free diet for 20 weeks), and control groups. Renal histology, tissue expression of endothelial and inducible nitric oxide synthases (eNOS and iNOS), renal tissue expression of nitrotyrosine, plasma, and renal tissue lipid peroxidation product, malondialdehyde (MDA), and plasma and urinary NO metabolites (NOx) were examined. Iron overload was associated with mild proteinuria, tissue iron deposition together with significant glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Rare focal glomerulosclerosis and tubulointerstitial changes were noted in normal controls. No renal lesions were observed in Fe-depleted rats. Iron deposits were seen in glomeruli, proximal tubules, and interstitium. The iron staining in the distal tubules was negligible. Both plasma and renal tissue MDA and renal tissue nitrotyrosine were increased significantly in Fe-loaded rats compared with control rats. In contrast, Fe-depleted animals showed a marked reduction in plasma and renal tissue MDA and nitrotyrosine together with significant elevation of urinary NOx excretion. In addition, iron-overload was associated with up-regulation of renal eNOS and i

  20. Angiogenic response following renal ischemia reperfusion injury: new players.

    PubMed

    Pallet, N; Thervet, E; Timsit, M-O

    2014-06-01

    Ischemia-reperfusion (IR) injury can negatively influence the short- and long-term outcomes of kidney transplantation because it promotes acute tubular necrosis and tissue scarring and activates innate alloimmunity. The adaptive responses to IR are centrally involved in reducing tissue damage but can also be deleterious when they activate programmed cell death and inflammation. The HIF-1α-mediated angiogenic responses following IR at early and late stages are complex and poorly understood. The early stages of IR seem to be associated with an antiangiogenic response, whereas the hypoxia that follows IR at later stages may activate angiogenic factors such as vascular endothelial growth factor (VEGF) and may be beneficial by stabilizing the microvasculature and favoring local blood supply. In addition to HIF-1α, new players in angiogenesis, including mTOR and the unfolded protein response, may lead to innovative therapeutic strategies for treating patients with ischemia- and reperfusion-associated tissue inflammation and organ dysfunction. PMID:24950928

  1. 4-Hydroxychalcone Attenuates Hyperaldosteronism, Inflammation, and Renal Injury in Cryptochrome-Null Mice

    PubMed Central

    Qu, Qi; Dai, Bingguang; Yang, Bo; Li, Xuelian; Liu, Yimin; Zhang, Fuling

    2014-01-01

    In the present study, we aimed to investigate the preventive effects of 4-hydroxychalcone (4HCH) on resistant hypertension. We used cryptochrome-null mice, which characteristically show high plasma aldosterone levels, inflammation, and renal injury. The cryptochrome-null mice received high-salt treatment and were treated orally with 4HCH 10 mg/kg, 4HCH 20 mg/kg, and 4HCH 40 mg/kg, respectively. The salt administration in cryptochrome-null mice is able to induce an increase in systolic pressure which is associated with hyperaldosteronism, inflammation, and kidney injury. Treatment with 40 mg/kg 4HCH reduced systolic hypertension, serum IL-1β, and TNF-α levels and suppressed the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and renal injury. The impact of 4HCH on the hyperaldosteronism, inflammation, and kidney injury provides new insights for future development of therapeutic strategies in resistant hypertension. PMID:25003119

  2. Telomerase deficiency delays renal recovery in mice after ischemia reperfusion injury by impairing autophagy

    PubMed Central

    Cheng, Huifang; Fan, Xiaofeng; Lawson, William E.; Paueksakon, Paisit; Harris, Raymond C.

    2015-01-01

    The aged population suffers increased morbidity and higher mortality in response to episodes of acute kidney injury (AKI). Aging is associated with telomere shortening, and both telomerase reverse transcriptase (TerT) and RNA (TerC) are essential to maintain telomere length. To define a role of telomerase deficiency in susceptibility to AKI, we used ischemia/reperfusion injury in wild type mice or mice with either TerC or TerT deletion. Injury induced similar renal impairment at day 1 in each genotype, as assessed by azotemia, proteinuria, acute tubular injury score and apoptotic tubular epithelial cell index. However, either TerC or TerT knockout significantly delayed recovery compared to wild type mice. Electron microscopy showed increased autophagosome formation in renal tubular epithelial cells in wild type mice but a significant delay of their development in TerC and TerT knockout mice. There were also impeded increases in the expression of the autophagosome marker LC3 II, prolonged accumulation of the autophagosome protein P62, an increase of the cell cycle regulator p16, and greater activation of the mTOR pathway. The mTORC1 inhibitor, rapamycin, partially restored the ischemia/reperfusion-induced autophagy response, without a significant effect on either p16 induction or tubule epithelial cell proliferation. Thus, muting the maintenance of normal telomere length in mice impaired recovery from AKI, due to an increase in tubule cell senescence and impairment of mTOR-mediated autophagy. PMID:25760322

  3. Therapeutic assessment of mesenchymal stem cells delivered within a PEGylated fibrin gel following an ischemic injury.

    PubMed

    Ricles, Laura M; Hsieh, Pei-Ling; Dana, Nicholas; Rybalko, Viktoriya; Kraynak, Chelsea; Farrar, Roger P; Suggs, Laura J

    2016-09-01

    The intent of the current study was to investigate the therapeutic contribution of MSCs to vascular regeneration and functional recovery of ischemic tissue. We used a rodent hind limb ischemia model and intramuscularly delivered MSCs within a PEGylated fibrin gel matrix. Within this model, we demonstrated that MSC therapy, when delivered in PEGylated fibrin, results in significantly higher mature blood vessel formation, which allows for greater functional recovery of skeletal muscle tissue as assessed using force production measurements. We observed initial signs of vascular repair at early time points when MSCs were delivered without PEGylated fibrin, but this did not persist or lead to recovery of the tissue in the long-term. Furthermore, animals which were treated with PEGylated fibrin alone exhibited a greater number of mature blood vessels, but they did not arterialize and did not show improvements in force production. These results demonstrate that revascularization of ischemic tissue may be a necessary but not sufficient step to complete functional repair of the injured tissue. This work has implications on stem cell therapies for ischemic diseases and also potentially on how such therapies are evaluated. PMID:27318932

  4. Mycophenolate mofetil prevents high-fat diet-induced hypertension and renal glomerular injury in Dahl SS rats.

    PubMed

    Spradley, Frank T; De Miguel, Carmen; Hobbs, Janet; Pollock, David M; Pollock, Jennifer S

    2013-11-01

    We designed experiments to test the hypothesis that Dahl salt-sensitive (SS) rats are sensitive to high-fat diet (HFD)-induced hypertension and renal injury via an inflammatory mechanism. Twelve-week-old Dahl SS rats were maintained on a normal diet (ND; 14% fat), HFD (59% fat), or HFD supplemented with the lymphocyte immunosuppressive agent, mycophenolate mofetil (HFD + MMF; 30 mg/kg/day orally in diet), for a period of 4 weeks. Mean arterial pressure (MAP), metabolic parameters, T lymphocyte (CD3(+)) localization, and renal structural damage were assessed during the studies. Four weeks of HFD significantly elevated MAP and visceral adiposity without changing circulating levels of lipids or adipokines. Immunohistochemical analysis demonstrated that SS rats on HFD had significantly greater numbers of CD3(+) cells in renal glomerular and medullary areas compared to ND SS rats. Additionally, HFD led to increased glomerular injury, but did not alter renal medullary injury. Chronic MMF treatment in HFD-fed Dahl SS rats reduced MAP, visceral adiposity, infiltration of CD3(+) cells in the glomerulus, as well as glomerular injury. However, MMF treatment did not alter HFD-induced infiltration of CD3(+) cells in the renal medulla. In conclusion, Dahl SS rats are sensitized to HFD-induced hypertension and renal glomerular injury via infiltration of T lymphocytes.

  5. Isoflurane Preconditioning Induces Neuroprotection by Up-Regulation of TREK1 in a Rat Model of Spinal Cord Ischemic Injury

    PubMed Central

    Wang, Kun; Kong, Xiangang

    2016-01-01

    This study aimed to explore the neuroprotection and mechanism of isoflurane on rats with spinal cord ischemic injury. Total 40 adult male Sprague-Dawley rats were divided into the four groups (n=10). Group A was sham-operation group; group B was ischemia group; group C was isoflurane preconditioning group; group D was isoflurane preconditioning followed by ischemia treatment group. Then the expressions of TWIK-related K+ channel 1 (TREK1) in the four groups were detected by immunofluorescent assay, real time-polymerase chain reactions (RT-PCR) and western blot. The primary neurons of rats were isolated and cultured under normal and hypoxic conditions. Besides, the neurons under two conditions were transfected with green fluorescent protein (GFP)-TREK1 and lentivirual to overexpress and silence TREK1. Additionally, the neurons were treated with isoflurane or not. Then caspase-3 activity and cell cycle of neurons under normal and hypoxic conditions were detected. Furthermore, nicotinamide adenine dinucleotide hydrate (NADH) was detected using NAD+/NADH quantification colorimetric kit. Results showed that the mRNA and protein expressions of TREK1 increased significantly in group C and D. In neurons, when TREK1 silenced, isoflurane treatment improved the caspase-3 activity. In hypoxic condition, the caspase-3 activity and sub-G1 cell percentage significantly increased, however, when TREK1 overexpressed the caspase-3 activity and sub-G1 cell percentage decreased significantly. Furthermore, both isoflurane treatment and overexpression of TREK1 significantly decreased NADH. In conclusion, isoflurane-induced neuroprotection in spinal cord ischemic injury may be associated with the up-regulation of TREK1. PMID:27469140

  6. Apurinic/Apyrimidinic Endonuclease 1 Upregulation Reduces Oxidative DNA Damage and Protects Hippocampal Neurons from Ischemic Injury

    PubMed Central

    Leak, Rehana K.; Li, Peiying; Zhang, Feng; Sulaiman, Hassan H.; Weng, Zhongfang; Wang, Guohua; Stetler, R. Anne; Shi, Yejie; Cao, Guodong

    2015-01-01

    Abstract Aims: Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme that participates in base-excision repair of oxidative DNA damage and in the redox activation of transcription factors. We tested the hypothesis that APE1 upregulation protects neuronal structure and function against transient global cerebral ischemia (tGCI). Results: Upregulation of APE1 by low-dose proton irradiation (PI) or by transgene overexpression protected hippocampal CA1 neurons against tGCI-induced cell loss and reduced apurinic/apyrimidinic sites and DNA fragmentation. Conversely, APE1 knockdown attenuated the protection afforded by PI and ischemic preconditioning. APE1 overexpression inhibited the DNA damage response, as evidenced by lower phospho-histone H2A and p53-upregulated modulator of apoptosis levels. APE1 overexpression also partially rescued dendritic spines and attenuated the decrease in field excitatory postsynaptic potentials in hippocampal CA1. Presynaptic and postsynaptic markers were reduced after tGCI, and this effect was blunted in APE1 transgenics. The Morris water maze test revealed that APE1 protected against learning and memory deficits for at least 27 days post-injury. Animals expressing DNA repair-disabled mutant APE1 (D210A) exhibited more DNA damage than wild-type controls and were not protected against tGCI-induced cell loss. Innovation: This is the first study that thoroughly characterizes structural and functional protection against ischemia after APE1 upregulation by measuring synaptic markers, electrophysiological function, and long-term neurological deficits in vivo. Furthermore, disabling the DNA repair activity of APE1 was found to abrogate its protective impact. Conclusion: APE1 upregulation, either endogenously or through transgene overexpression, protects DNA, neuronal structures, synaptic function, and behavioral output from ischemic injury. Antioxid. Redox Signal. 22, 135–148. PMID:24180454

  7. Isoflurane Preconditioning Induces Neuroprotection by Up-Regulation of TREK1 in a Rat Model of Spinal Cord Ischemic Injury.

    PubMed

    Wang, Kun; Kong, Xiangang

    2016-09-01

    This study aimed to explore the neuroprotection and mechanism of isoflurane on rats with spinal cord ischemic injury. Total 40 adult male Sprague-Dawley rats were divided into the four groups (n=10). Group A was sham-operation group; group B was ischemia group; group C was isoflurane preconditioning group; group D was isoflurane preconditioning followed by ischemia treatment group. Then the expressions of TWIK-related K⁺ channel 1 (TREK1) in the four groups were detected by immunofluorescent assay, real time-polymerase chain reactions (RT-PCR) and western blot. The primary neurons of rats were isolated and cultured under normal and hypoxic conditions. Besides, the neurons under two conditions were transfected with green fluorescent protein (GFP)-TREK1 and lentivirual to overexpress and silence TREK1. Additionally, the neurons were treated with isoflurane or not. Then caspase-3 activity and cell cycle of neurons under normal and hypoxic conditions were detected. Furthermore, nicotinamide adenine dinucleotide hydrate (NADH) was detected using NAD+/NADH quantification colorimetric kit. Results showed that the mRNA and protein expressions of TREK1 increased significantly in group C and D. In neurons, when TREK1 silenced, isoflurane treatment improved the caspase-3 activity. In hypoxic condition, the caspase-3 activity and sub-G1 cell percentage significantly increased, however, when TREK1 overexpressed the caspase-3 activity and sub-G1 cell percentage decreased significantly. Furthermore, both isoflurane treatment and overexpression of TREK1 significantly decreased NADH. In conclusion, isoflurane-induced neuroprotection in spinal cord ischemic injury may be associated with the up-regulation of TREK1. PMID:27469140

  8. Intensity of Renal Support in Critically Ill Patients with Acute Kidney Injury

    PubMed Central

    2008-01-01

    BACKGROUND The optimal intensity of renal-replacement therapy in critically ill patients with acute kidney injury is controversial. METHODS We randomly assigned critically ill patients with acute kidney injury and failure of at least one nonrenal organ or sepsis to receive intensive or less intensive renal-replacement therapy. The primary end point was death from any cause by day 60. In both study groups, hemodynamically stable patients underwent intermittent hemodialysis, and hemodynamically unstable patients underwent continuous venovenous hemodiafiltration or sustained low-efficiency dialysis. Patients receiving the intensive treatment strategy underwent intermittent hemodialysis and sustained low-efficiency dialysis six times per week and continuous venovenous hemodiafiltration at 35 ml per kilogram of body weight per hour; for patients receiving the less-intensive treatment strategy, the corresponding treatments were provided thrice weekly and at 20 ml per kilogram per hour. RESULTS Baseline characteristics of the 1124 patients in the two groups were similar. The rate of death from any cause by day 60 was 53.6% with intensive therapy and 51.5% with less-intensive therapy (odds ratio, 1.09; 95% confidence interval, 0.86 to 1.40; P = 0.47). There was no significant difference between the two groups in the duration of renalreplacement therapy or the rate of recovery of kidney function or nonrenal organ failure. Hypotension during intermittent dialysis occurred in more patients randomly assigned to receive intensive therapy, although the frequency of hemodialysis sessions complicated by hypotension was similar in the two groups. CONCLUSIONS Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal

  9. Estrogen receptor agonists alleviate cardiac and renal oxidative injury in rats with renovascular hypertension.

    PubMed

    Özdemir Kumral, Zarife Nigâr; Kolgazi, Meltem; Üstünova, Savaş; Kasımay Çakır, Özgür; Çevik, Özge Dağdeviren; Şener, Göksel; Yeğen, Berrak Ç

    2016-01-01

    Although endogenous estrogen is known to offer cardiac and vascular protection, the involvement of estrogen receptors in mediating the protective effect of estrogen on hypertension-induced cardiovascular and renal injury is not fully explained. We aimed to investigate the effects of estrogen receptor (ER) agonists on oxidative injury, cardiovascular and renal functions of rats with renovascular hypertension (RVH). Female Sprague-Dawley rats were randomly divided as control and RVH groups, and RVH groups had either ovariectomy (OVX) or sham-OVX. Sham-OVX-RVH and OVX-RVH groups received either ERβ agonist diarylpropiolnitrile (1 mg/kg/day) or ERα agonist propyl pyrazole triol (1 mg/kg/day) for 6 weeks starting at the third week following the surgery. At the end of the 9(th) week, systolic blood pressures were recorded, cardiac functions were determined, and the contraction/relaxation responses of aortic rings were obtained. Serum creatinine levels, tissue malondialdehyde, glutathione, superoxide dismutase, catalase levels, and myeloperoxidase activity in heart and kidney samples were analyzed, and Na(+), K(+)-ATPase activity was measured in kidney samples. In both sham-OVX and OVX rats, both agonists reduced blood pressure and reversed the impaired contractile performance of the heart, while ERβ agonist improved renal functions in both the OVX and non-OVX rats. Both agonists reduced neutrophil infiltration, lipid peroxidation, and elevated antioxidant levels in the heart, but a more ERβ-mediated protective effect was observed in the kidney. Our data suggest that activation of ERβ might play a role in preserving the function of the stenotic kidney and delaying the progression of renal injury, while both receptors mediate similar cardioprotective effects. PMID:27399230

  10. A new model to predict acute kidney injury requiring renal replacement therapy after cardiac surgery

    PubMed Central

    Pannu, Neesh; Graham, Michelle; Klarenbach, Scott; Meyer, Steven; Kieser, Teresa; Hemmelgarn, Brenda; Ye, Feng; James, Matthew

    2016-01-01

    Background: Acute kidney injury after cardiac surgery is associated with adverse in-hospital and long-term outcomes. Novel risk factors for acute kidney injury have been identified, but it is unknown whether their incorporation into risk models substantially improves prediction of postoperative acute kidney injury requiring renal replacement therapy. Methods: We developed and validated a risk prediction model for acute kidney injury requiring renal replacement therapy within 14 days after cardiac surgery. We used demographic, and preoperative clinical and laboratory data from 2 independent cohorts of adults who underwent cardiac surgery (excluding transplantation) between Jan. 1, 2004, and Mar. 31, 2009. We developed the risk prediction model using multivariable logistic regression and compared it with existing models based on the C statistic, Hosmer–Lemeshow goodness-of-fit test and Net Reclassification Improvement index. Results: We identified 8 independent predictors of acute kidney injury requiring renal replacement therapy in the derivation model (adjusted odds ratio, 95% confidence interval [CI]): congestive heart failure (3.03, 2.00–4.58), Canadian Cardiovascular Society angina class III or higher (1.66, 1.15–2.40), diabetes mellitus (1.61, 1.12–2.31), baseline estimated glomerular filtration rate (0.96, 0.95–0.97), increasing hemoglobin concentration (0.85, 0.77–0.93), proteinuria (1.65, 1.07–2.54), coronary artery bypass graft (CABG) plus valve surgery (v. CABG only, 1.25, 0.64–2.43), other cardiac procedure (v. CABG only, 3.11, 2.12–4.58) and emergent status for surgery booking (4.63, 2.61–8.21). The 8-variable risk prediction model had excellent performance characteristics in the validation cohort (C statistic 0.83, 95% CI 0.79–0.86). The net reclassification improvement with the prediction model was 13.9% (p < 0.001) compared with the best existing risk prediction model (Cleveland Clinic Score). Interpretation: We have developed

  11. The Protective Effect of Remote Renal Preconditioning Against Hippocampal Ischemia Reperfusion Injury: Role of KATP Channels.

    PubMed

    Mehrjerdi, Fatemeh Zare; Aboutaleb, Nahid; Pazoki-Toroudi, Hamidreza; Soleimani, Mansoureh; Ajami, Marjan; Khaksari, Mehdi; Safari, Fatemeh; Habibey, Rouhollah

    2015-12-01

    Remote ischemic preconditioning (RIPC), which consists of several brief ischemia/reperfusion applied at the remote site of lethal ischemia reperfusion, can, through activating different mechanisms, increase the ability of the body's endogenous protection against prolonged ischemia/reperfusion. Recent studies have shown that RIPC has neuroprotective effects, but its mechanisms are not well elucidated. The present study aimed to determine whether activation of KATP channels in remote renal preconditioning decreases hippocampus damage induced by global cerebral ischemia. RIPC was induced by ischemia of the left renal artery (IPC); 24 h later, global cerebral ischemia reperfusion (IR) was induced by common carotid arteries occlusion. 5hydroxydecanoate (5HD) and glibenclamide (Gli) were injected before of IPC. The levels of malondialdehyde (MDA) and catalase (CAT) activity were assessed in hippocampus. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) was assessed to detect apoptotic cells in hippocampus. RIPC inhibited apoptosis by decreasing positive TUNEL cells (P < 0.05). KATP channels blocking with 5HD and Gli markedly increased apoptosis in hippocampal cells in RIPC group (P < 0.001). RIPC decreased MDA level and increased CAT activity in ischemic hippocampus (P < 0.01). Also, 5HD and Gli inhibited the effect of RIPC on MDA level and CAT activity (P < 0.05). The present study shows that RIPC can effectively attenuate programmed cell death, increase activity of CAT, and reduce MDA levels. Blocking of KATP channels inhibited the protective effects of RIPC. PMID:26254913

  12. Blood glucose fluctuation accelerates renal injury involved to inhibit the AKT signaling pathway in diabetic rats.

    PubMed

    Ying, Changjiang; Zhou, Xiaoyan; Chang, Zhenzhen; Ling, Hongwei; Cheng, Xingbo; Li, Wei

    2016-07-01

    Blood glucose fluctuation is associated with diabetic nephropathy. However, the mechanism by which blood glucose fluctuation accelerates renal injury is not fully understood. The aim of the present study was to assess the effects of blood glucose fluctuation on diabetic nephropathy in rats and investigate its underlying mechanism. Diabetes in the rats was induced by a high sugar, high-fat diet, and a single dose of STZ (35 mg/kg)-injected intraperitoneally. Unstable blood sugar models were induced by subcutaneous insulin injection and intravenous glucose injection alternately. Body weight, glycosylated hemoglobin A1c (HbAlc), blood urea nitrogen (BUN), serum creatinine (Scr), and Creatinine clearance (Ccr) were assessed. T-SOD activity and MDA level were measured by assay kit. Change in renal tissue ultrastructure was observed by light microscopy and electron microscopy. Phosphorylated ser/thr protein kinase (p-AKT) (phosphor-Ser473), phosphorylated glycogen synthase kinase-3 beta (p-GSK-3β) (phosphor-Ser9), Bcl-2-associated X protein (BAX), B cell lymphoma/leukemia 2 (BCL-2), and cleaved-cysteinyl aspartate-specific proteinase-3 (caspase-3) levels were detected by immunohistochemistry and Western blot. We observed that BUN and Scr were increased in diabetic rats, and Ccr was decreased. Furthermore, blood glucose fluctuations could exacerbate the Ccr changes. Renal tissue ultrastructure was also seriously injured by glucose variability in diabetic rats. In addition, glucose fluctuation increased the oxidative stress of renal tissue. Moreover, fluctuating blood glucose decreased p-AKT level and BCL-2, and increased p-GSK-3β, BAX, cleaved-caspase-3 levels, and ratio of BAX/BCL-2 in the kidneys of diabetic rats. In conclusion, these results suggest that blood glucose fluctuation accelerated renal injury is due, at least in part to its oxidative stress promoting and inhibiting the AKT signaling pathway in diabetic rats. PMID:26860515

  13. Preventing autoimmunity protects against the development of hypertension and renal injury.

    PubMed

    Mathis, Keisa W; Wallace, Kedra; Flynn, Elizabeth R; Maric-Bilkan, Christine; LaMarca, Babbette; Ryan, Michael J

    2014-10-01

    Several studies suggest a link between autoimmunity and essential hypertension in humans. However, whether autoimmunity can drive the development of hypertension remains unclear. The autoimmune disease systemic lupus erythematosus is characterized by autoantibody production, and the prevalence of hypertension is increased markedly in this patient population compared with normal healthy women. We hypothesized that preventing the development of autoimmunity would prevent the development of hypertension in a mouse model of lupus. Female lupus (NZBWF1) and control mice (NZW) were treated weekly with anti-CD20 or immunoglobulin G antibodies (both 10 mg/kg, IV) starting at 20 weeks of age for 14 weeks. Anti-CD20 therapy markedly attenuated lupus disease progression as evidenced by reduced CD45R+ B cells and lower double-stranded DNA autoantibody activity. In addition, renal injury in the form of urinary albumin, glomerulosclerosis, and tubulointerstitial fibrosis, as well as tubular injury (indicated by renal cortical expression of neutrophil gelatinase-associated lipocalin) was prevented by anti-CD20 therapy in lupus mice. Finally, lupus mice treated with anti-CD20 antibody did not develop hypertension. The protection against the development of hypertension was associated with lower renal cortical tumor necrosis factor-α expression, a cytokine that has been previously reported by us to contribute to the hypertension in this model, as well as renal cortical monocyte chemoattractant protein-1 expression and circulating T cells. These data suggest that the development of autoimmunity and the resultant increase in renal inflammation are an important underlying factor in the prevalent hypertension that occurs during systemic lupus erythematosus.

  14. Following specific podocyte injury captopril protects against progressive long term renal damage

    PubMed Central

    Zhou, Yu S; Ihmoda, Ihmoda A; Phelps, Richard G; Bellamy, Christopher OS; Turner, A Neil

    2015-01-01

    Background: Angiotensin converting enzyme inhibitors (ACEi) reduce proteinuria and preserve kidney function in proteinuric renal diseases. Their nephroprotective effect exceeds that attributable to lowering of blood pressure alone. This study examines the potential of ACEi to protect from progression of injury after a highly specific injury to podocytes in a mouse model. Methods: We created transgenic (Podo-DTR) mice in which graded specific podocyte injury could be induced by a single injection of diphtheria toxin. Transgenic and wild-type mice were given the ACEi captopril in drinking water, or water alone, commencing 24h after toxin injection. Kidneys were examined histologically at 8 weeks and injury assessed by observers blinded to experimental group. Results: After toxin injection, Podo-DTR mice developed acute proteinuria, and at higher doses transient renal impairment, which subsided within 3 weeks to be followed by a slow glomerular scarring process. Captopril treatment in Podo-DTR line 57 after toxin injection at 5ng/g body weight reduced proteinuria and ameliorated glomerular scarring, matrix accumulation and glomerulosclerosis almost to baseline (toxin: 17%; toxin + ACEi 10%, p<0.04; control 7% glomerular scarring). Podocyte counts were reduced after toxin treatment and showed no recovery irrespective of captopril treatment (7.1 and 7.3 podocytes per glomerular cross section in water and captopril-treated animals compared with 8.2 of wild-type controls, p<0.05). Conclusions: Observations in Podo-DTR mice support the hypothesis that continuing podocyte dysfunction is a key abnormality in proteinuric disease. Our model is ideal for studying strategies to protect the kidney from progressive injury following podocyte depletion. Demonstrable protective effects from captopril occur, despite indiscernible preservation or restoration of podocyte counts, at least after this degree of relatively mild injury. PMID:26629332

  15. Endoplasmic Reticulum Stress-Induced Autophagy Provides Cytoprotection from Chemical Hypoxia and Oxidant Injury and Ameliorates Renal Ischemia-Reperfusion Injury

    PubMed Central

    Chandrika, Bhavya B.; Yang, Cheng; Ou, Yang; Feng, Xiaoke; Muhoza, Djamali; Holmes, Alexandrea F.; Theus, Sue; Deshmukh, Sarika; Haun, Randy S.; Kaushal, Gur P.

    2015-01-01

    We examined whether endoplasmic reticulum (ER) stress-induced autophagy provides cytoprotection from renal tubular epithelial cell injury due to oxidants and chemical hypoxia in vitro, as well as from ischemia-reperfusion (IR) injury in vivo. We demonstrate that the ER stress inducer tunicamycin triggers an unfolded protein response, upregulates ER chaperone Grp78, and activates the autophagy pathway in renal tubular epithelial cells in culture. Inhibition of ER stress-induced autophagy accelerated caspase–3 activation and cell death suggesting a pro-survival role of ER stress-induced autophagy. Compared to wild-type cells, autophagy-deficient MEFs subjected to ER stress had enhanced caspase–3 activation and cell death, a finding that further supports the cytoprotective role of ER stress-induced autophagy. Induction of autophagy by ER stress markedly afforded cytoprotection from oxidants H2O2 and tert-Butyl hydroperoxide and from chemical hypoxia induced by antimycin A. In contrast, inhibition of ER stress-induced autophagy or autophagy-deficient cells markedly enhanced cell death in response to oxidant injury and chemical hypoxia. In mouse kidney, similarly to renal epithelial cells in culture, tunicamycin triggered ER stress, markedly upregulated Grp78, and activated autophagy without impairing the autophagic flux. In addition, ER stress-induced autophagy markedly ameliorated renal IR injury as evident from significant improvement in renal function and histology. Inhibition of autophagy by chloroquine markedly increased renal IR injury. These studies highlight beneficial impact of ER stress-induced autophagy in renal ischemia-reperfusion injury both in vitro and in vivo. PMID:26444017

  16. Endoplasmic Reticulum Stress-Induced Autophagy Provides Cytoprotection from Chemical Hypoxia and Oxidant Injury and Ameliorates Renal Ischemia-Reperfusion Injury.

    PubMed

    Chandrika, Bhavya B; Yang, Cheng; Ou, Yang; Feng, Xiaoke; Muhoza, Djamali; Holmes, Alexandrea F; Theus, Sue; Deshmukh, Sarika; Haun, Randy S; Kaushal, Gur P

    2015-01-01

    We examined whether endoplasmic reticulum (ER) stress-induced autophagy provides cytoprotection from renal tubular epithelial cell injury due to oxidants and chemical hypoxia in vitro, as well as from ischemia-reperfusion (IR) injury in vivo. We demonstrate that the ER stress inducer tunicamycin triggers an unfolded protein response, upregulates ER chaperone Grp78, and activates the autophagy pathway in renal tubular epithelial cells in culture. Inhibition of ER stress-induced autophagy accelerated caspase-3 activation and cell death suggesting a pro-survival role of ER stress-induced autophagy. Compared to wild-type cells, autophagy-deficient MEFs subjected to ER stress had enhanced caspase-3 activation and cell death, a finding that further supports the cytoprotective role of ER stress-induced autophagy. Induction of autophagy by ER stress markedly afforded cytoprotection from oxidants H2O2 and tert-Butyl hydroperoxide and from chemical hypoxia induced by antimycin A. In contrast, inhibition of ER stress-induced autophagy or autophagy-deficient cells markedly enhanced cell death in response to oxidant injury and chemical hypoxia. In mouse kidney, similarly to renal epithelial cells in culture, tunicamycin triggered ER stress, markedly upregulated Grp78, and activated autophagy without impairing the autophagic flux. In addition, ER stress-induced autophagy markedly ameliorated renal IR injury as evident from significant improvement in renal function and histology. Inhibition of autophagy by chloroquine markedly increased renal IR injury. These studies highlight beneficial impact of ER stress-induced autophagy in renal ischemia-reperfusion injury both in vitro and in vivo.

  17. CCR5 deficiency increased susceptibility to lipopolysaccharide-induced acute renal injury.

    PubMed

    Lee, Dong Hun; Park, Mi Hee; Hwang, Chul Ju; Hwang, Jae Yeon; Yoon, Hae Suk; Yoon, Do Young; Hong, Jin Tae

    2016-05-01

    C-C chemokine receptor 5 (CCR5) regulates leukocyte chemotaxis and activation, and its deficiency exacerbates development of nephritis. Therefore, we investigated the role of CCR5 during lipopolysaccharide (LPS)-induced acute kidney injury. CCR5-deficient (CCR5-/-) and wild-type (CCR5+/+) mice, both aged about 10 months, had acute renal injury induced by intraperitoneal injection of LPS (10 mg/kg). Compared with CCR5+/+ mice, CCR5-/- mice showed increased mortality and renal injury, including elevated creatinine and blood urea nitrogen levels, following LPS challenge. Compared to CCR5+/+ mice, CCR5-/- mice also exhibited greater increases in the serum concentrations of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β following LPS challenge. Furthermore, infiltration of macrophages and neutrophils, expression of intracellular adhesion molecule (ICAM)-1, and the number of apoptotic cells were more greatly increased by LPS treatment in CCR5-/- mice than in CCR5+/+ mice. The concentrations of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β were also significantly increased in the kidney of CCR5-/- mice after LPS challenge. Moreover, primary kidney cells from CCR5-/- mice showed greater increases in TNF-α production and p38 MAP kinase activation following treatment with LPS compared with that observed in the cells from CCR5+/+ mice. LPS-induced TNF-α production and apoptosis in the primary kidney cells from CCR5-/- mice were inhibited by treatment with p38 MAP kinase inhibitor. These results suggest that CCR5 deficiency increased the production of TNF-α following LPS treatment through increased activation of the p38 pathway in the kidney, resulting in renal apoptosis and leukocyte infiltration and led to exacerbation of LPS-induced acute kidney injury.

  18. Aggravation of post-ischemic liver injury by overexpression of insulin-like growth factor binding protein 3.

    PubMed

    Zhou, Lu; Koh, Hyoung-Won; Bae, Ui-Jin; Park, Byung-Hyun

    2015-01-01

    Insulin-like growth factor-1 (IGF-1) is known to inhibit reperfusion-induced apoptosis. IGF-binding protein-3 (IGFBP-3) is the major circulating carrier protein for IGF-1 and induces apoptosis. In this study, we determined if IGFBP-3 was important in the hepatic response to I/R. To deliver IGFBP-3, we used an adenovirus containing IGFBP-3 cDNA (AdIGFBP-3) or an IGFBP-3 mutant devoid of IGF binding affinity but retaining IGFBP-3 receptor binding ability (AdIGFBP-3(GGG)). Mice subjected to I/R injury showed typical patterns of hepatocellular damage. Protein levels of IGFBP-3 were increased after reperfusion and showed a positive correlation with the extent of liver injury. Prior injection with AdIGFBP-3 aggravated liver injury: serum aminotransferases, prothrombin time, proinflammatory cytokines, hepatocellular necrosis and apoptosis, and neutrophil infiltration were markedly increased compared to control mice. A decrease in antioxidant potential and an upregulation of NADPH oxidase might have caused these aggravating effects of IGFBP-3. Experiments using HepG2 cells and N-acetylcysteine-pretreated mice showed a discernible effect of IGFBP-3 on reactive oxygen species generation. Lastly, AdIGFBP-3 abolished the beneficial effects of ischemic preconditioning and hypothermia. Mice treated with AdIGFBP-3(GGG) exhibited effects similar to those of AdIGFBP-3, suggesting a ligand-independent effect of IGFBP-3. Our results suggest IGFBP-3 as an aggravating factor during hepatic I/R injury. PMID:26073647

  19. Diquat induces renal proximal tubule injury in glutathione reductase-deficient mice

    SciTech Connect

    Rogers, Lynette K. . E-mail: rogersl@ccri.net; Bates, Carlton M.; Welty, Stephen E.; Smith, Charles V.

    2006-12-15

    Reactive oxygen species (ROS) have been associated with many human diseases, and glutathione (GSH)-dependent processes are pivotal in limiting tissue damage. To test the hypothesis that Gr1{sup a1Neu} (Neu) mice, which do not express glutathione reductase (GR), would be more susceptible than are wild-type mice to ROS-mediated injury, we studied the effects of diquat, a redox cycling toxicant. Neu mice exhibited modest, dose- and time-dependent elevations in plasma alanine aminotransferase (ALT) activities, 126 {+-} 36 U/l at 2 h after 5 {mu}mol/kg of diquat, but no ALT elevations were observed in diquat-treated C3H/HeN mice for up to 6 h after 50 {mu}mol/kg of diquat. Histology indicated little or no hepatic necrosis in diquat-treated mice of either strain, but substantial renal injury was observed in diquat-treated Neu mice, characterized by brush border sloughing in the proximal tubules by 1 h and tubular necrosis by 2 h after doses of 7.5 {mu}mol/kg. Decreases in renal GSH levels were observed in the Neu mice by 2 h post dose (3.4 {+-} 0.4 vs 0.2 {+-} 0.0 {mu}mol/g tissue at 0 and 50 {mu}mol/kg, respectively), and increases in renal GSSG levels were observed in the Neu mice as early as 0.5 h after 7.5 {mu}mol/kg (105.5 {+-} 44.1 vs 27.9 {+-} 4.8 nmol/g tissue). Blood urea nitrogen levels were elevated by 2 h in Neu mice after doses of 7.5 {mu}mol/kg (Neu vs C3H, 32.8 {+-} 4.1 vs 17.9 {+-} 0.3 mg/dl). Diquat-induced renal injury in the GR-deficient Neu mice offers a useful model for studies of ROS-induced renal necrosis and of the contributions of GR in defense against oxidant-mediated injuries in vivo.

  20. Health status, renal function, and quality of life after multiorgan failure and acute kidney injury requiring renal replacement therapy

    PubMed Central

    Faulhaber-Walter, Robert; Scholz, Sebastian; Haller, Herrmann; Kielstein, Jan T; Hafer, Carsten

    2016-01-01

    Background Critically ill patients with acute kidney injury (AKI) in need of renal replacement therapy (RRT) may have a protracted and often incomplete rehabilitation. Their long-term outcome has rarely been investigated. Study design Survivors of the HANnover Dialysis OUTcome (HANDOUT) study were evaluated after 5 years for survival, health status, renal function, and quality of life (QoL). The HANDOUT study had examinded mortality and renal recovery of patients with AKI receiving either standard extendend or intensified dialysis after multi organ failure. Results One hundred fifty-six former HANDOUT participants were analyzed. In-hospital mortality was 56.4%. Five-year survival after AKI/RRT was 40.1% (86.5% if discharged from hospital). Main causes of death were cardiovascular complications and sepsis. A total of 19 survivors presented to the outpatient department of our clinic and had good renal recovery (mean estimated glomerular filtration rate 72.5±30 mL/min/1.73 m2; mean proteinuria 89±84 mg/d). One person required maintenance dialysis. Seventy-nine percent of the patients had a pathological kidney sonomorphology. The Charlson comorbidity score was 2.2±1.4 and adjusted for age 3.3±2.1 years. Numbers of comorbid conditions averaged 2.38±1.72 per patient (heart failure [52%] > chronic kidney disease/myocardial infarction [each 29%]). Median 36-item short form health survey (SF-36™) index was 0.657 (0.69 physical health/0.66 mental health). Quality-adjusted life-years after 5 years were 3.365. Conclusion Mortality after severe AKI is higher than short-term prospective studies show, and morbidity is significant. Kidney recovery as well as general health remains incomplete. Reduction of QoL is minor, and social rehabilitation is very good. Affectivity is heterogeneous, but most patients experience emotional well-being. In summary, AKI in critically ill patients leads to incomplete rehabilitation but acceptable QoL after 5 years. PMID:27284261

  1. Renal ischemia/reperfusion injury: functional tissue preservation by anti-activated {beta}1 integrin therapy.

    PubMed

    Molina, Ana; Ubeda, María; Escribese, María M; García-Bermejo, Laura; Sancho, David; Pérez de Lema, Guillermo; Liaño, Fernando; Cabañas, Carlos; Sánchez-Madrid, Francisco; Mampaso, Francisco

    2005-02-01

    Renal ischemia/reperfusion injury (IRI) is an important cause of acute renal failure. Cellular and molecular responses of the kidney to IRI are complex and not fully understood. beta1 integrins localize to the basal surface of tubular epithelium interacting with extracellular matrix components of the basal membrane, including collagen IV. Whether preservation of tubular epithelium integrity could be a therapeutic approach for IRI was assessed. The effects of HUTS-21 mAb administration, which recognizes an activation-dependent epitope of beta1 integrins, in a rat model of IRI were investigated. Preischemic HUTS-21 administration resulted in the preservation of renal functional and histopathologic parameters. Analyses of activated beta1 integrins expression and focal adhesion kinase phosphorylation suggest that its deactivation after IRI was prevented by HUTS-21 treatment. Moreover, HUTS-21 impaired the inflammatory response in vivo, as indicated by inhibition of proinflammatory mediators and the absence of infiltrating cells. Ex vivo adhesion assays using reperfused kidneys revealed that HUTS-21 induced a significant increase of epithelial cell attachment to collagen IV. In conclusion, the data provide evidence that HUTS-21 has a protective effect in renal IRI, preventing tubular epithelial cell detachment by preserving activated beta1 integrins functions.

  2. IL-11 Is Required for A1 Adenosine Receptor–Mediated Protection against Ischemic AKI

    PubMed Central

    Kim, Joo Yun; Kim, Mihwa; Ham, Ahrom; Brown, Kevin M.; Greene, Robert W.; D’Agati, Vivette D.

    2013-01-01

    A1 adenosine receptor activation ameliorates ischemic AKI through the induction of renal proximal tubular sphingosine kinase-1. However, systemic adverse effects may limit A1 adenosine receptor–based therapy for ischemic AKI, indicating a need to identify alternative therapeutic targets within this pathway. Here, we evaluated the function of renal proximal tubular IL-11, a clinically approved hematopoietic cytokine, in A1 adenosine receptor–mediated induction of sphingosine kinase-1 and renal protection. Treatment of human proximal tubule epithelial (HK-2) cells with a selective A1 adenosine receptor agonist, chloro-N(6)-cyclopentyladenosine (CCPA), induced the expression of IL-11 mRNA and protein in an extracellular signal–regulated kinase–dependent manner, and administration of CCPA in mice induced renal synthesis of IL-11. Pretreatment with CCPA protected against renal ischemia-reperfusion injury in wild-type mice, but not in IL-11 receptor–deficient mice. Administration of an IL-11–neutralizing antibody abolished the renal protection provided by CCPA. Similarly, CCPA did not induce renal IL-11 expression or protect against renal ischemia-reperfusion injury in mice lacking the renal proximal tubular A1 adenosine receptor. Finally, treatment with CCPA induced sphingosine kinase-1 in HK-2 cells and wild-type mice, but not in IL-11 receptor–deficient or renal proximal tubule A1 adenosine receptor–deficient mice. Taken together, these results suggest that induction of renal proximal tubule IL-11 is a critical intermediary in A1 adenosine receptor–mediated renal protection that warrants investigation as a novel therapeutic target for the treatment of ischemic AKI. PMID:23813214

  3. Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury.

    PubMed

    Estrela, Gabriel R; Wasinski, Frederick; Bacurau, Reury F; Malheiros, Denise M A C; Câmara, Niels O S; Araújo, Ronaldo C

    2014-09-01

    Cisplatin treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of creatinine and urea, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1β and TNF-α). The kinin B2 receptor has been associated with the inflammation process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the diabetic nephropathy status. To examine the role of the kinin B2 receptor in cisplatin-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with cisplatin. Additionally, WT mice were treated with a B2 receptor antagonist after cisplatin administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum creatinine and blood urea after cisplatin administration. Thus, our data suggest that the kinin B2 receptor is involved in cisplatin-induced acute kidney injury by mediating the necrotic process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by cisplatin therapy.

  4. Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury.

    PubMed

    Estrela, Gabriel R; Wasinski, Frederick; Bacurau, Reury F; Malheiros, Denise M A C; Câmara, Niels O S; Araújo, Ronaldo C

    2014-09-01

    Cisplatin treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of creatinine and urea, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1β and TNF-α). The kinin B2 receptor has been associated with the inflammation process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the diabetic nephropathy status. To examine the role of the kinin B2 receptor in cisplatin-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with cisplatin. Additionally, WT mice were treated with a B2 receptor antagonist after cisplatin administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum creatinine and blood urea after cisplatin administration. Thus, our data suggest that the kinin B2 receptor is involved in cisplatin-induced acute kidney injury by mediating the necrotic process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by cisplatin therapy. PMID:24975837

  5. Reduction of high-energy shock-wave-induced renal tubular injury by selenium.

    PubMed

    Strohmaier, W L; Lahme, S; Weidenbach, P M; Bichler, K H

    1999-10-01

    In shock-wave-induced renal injury cavitation-generated free radicals play an important role. Using an in vitro model with Madin-Darby canine kidney (MDCK) cells, we investigated the influence of selenium, a free radical scavenger, in shock-wave-induced tubular cell injury. Suspensions of MDCK cells (33 x 10(6) cells/ml) were placed in small containers (volume 1.1 ml) for shock wave exposure. Two groups of 12 containers each were examined: (1) control (no medication), (2) selenium (0.4 microg/ml nutrient medium). Six containers in each group were exposed to shock waves (impulse rate 256, frequency 60 Hz, generator voltage 18 kV), while the other six containers in each group served as a control. After shock wave exposure, the concentration of cellular enzymes such as lactate dehydrogenase (LDH), N-acetyl-beta-glucosaminidase (NAG), glutamate oxaloacetate transaminase (GOT) and glutamate lactate dehydrogenase (GLDH) in the nutrient medium was examined. Following shock wave exposure there was a significant rise in LDH, NAG, GOT and GLDH concentrations. Selenium reduced this enzyme leakage significantly. Thus we conclude that selenium protects renal tubular cells against shock-wave-induced injury. Since selenium is an essential part of glutathione peroxidase, this effect seems to be mediated by a reduction in reactive oxygen species. PMID:10550528

  6. Renal medullary Na-K-ATPase and hypoxic injury in perfused rat kidneys.

    PubMed

    Epstein, F H; Silva, P; Spokes, K; Brezis, M; Rosen, S

    1989-11-01

    We wished to see if chronic alterations in Na-K-ATPase activity in the medullary thick ascending limb would modify the susceptibility of its cells to the hypoxic injury produced by perfusion of the isolated kidney. Rats were fed a diet high (64%) or low (8%) in protein for three weeks. Renal medullary Na-K-ATPase was 75 +/- 12 U/mg protein/hr (mean +/- SE) in the high protein group and 44 +/- 3 in rats given low protein. After 90 minutes of perfusion, the kidneys of rats fed a high protein diet showed almost all mTAL cells near the inner medulla with severe damage (93 +/- 4.8%), whereas the same zone in perfused kidneys of rats on a low protein diet showed only 47 +/- 7.7% injury. In a similar fashion, damage to mTAL cells seen in perfused kidneys was greatly augmented by compensatory renal hypertrophy produced by removal of the contralateral kidney two weeks earlier, and by a diet high in potassium given for two weeks, procedures which also increased the activity of medullary Na-K-ATPase. The results suggest that the level of transport work of medullary cells mediated by Na-K-ATPase is a determinant of the vulnerability of mTAL cells to hypoxic injury.

  7. Effects of sodium citrate on salt sensitivity and kidney injury in chronic renal failure.

    PubMed

    Kim, Sejoong; Yang, Jin Young; Jung, Eun Sook; Lee, Jeonghwan; Heo, Nam Ju; Lee, Jae Wook; Na, Ki Young; Han, Jin Suk

    2014-12-01

    Metabolic acidosis, which is observed in salt-sensitive hypertension, is also associated with kidney injury. Alkali therapy in chronic renal failure (CRF) may ameliorate the progression of kidney disease; however, few studies have examined the effects of alkali therapy on salt sensitivity and kidney injury in CRF. We randomly administered standard diet (SD), sodium chloride with 20% casein diet (NACL), or sodium citrate with 20% casein diet (NACT) to Sprague-Dawley rats after a CRF or a sham operation. Four weeks after 5/6 nephrectomy, serum bicarbonate levels were higher in the NACT-treated group. On the pressure-natriuresis curve, NACT-treated CRF rats were more salt-resistant than NACL-treated CRF rats. Additionally, the NACT-treated CRF group showed less tubulointerstitial damage than the NACL-treated CRF group. The expression and immunoreactivity of NHE3 in the kidney in the NACT-treated CRF group were lower than those in the NACL-treated CRF group. We observed that dietary NACT as alkali therapy in CRF might improve the altered salt-sensitivity and ameliorate the progression of kidney injury compared to the NACL diet, which may be related to reduced renal NHE3 expression.

  8. Danhong injection attenuates cardiac injury induced by ischemic and reperfused neuronal cells through regulating arginine vasopressin expression and secretion.

    PubMed

    Yang, Mingzhu; Orgah, John; Zhu, Jie; Fan, Guanwei; Han, Jihong; Wang, Xiaoying; Zhang, Boli; Zhu, Yan

    2016-07-01

    Ischemic stroke is associated with cardiac myocyte vulnerability through some unknown mechanisms. Arginine vasopressin (AVP) may exert considerable function in the relationship of brain damage and heart failure. Danhong injection (DHI) can protect both stroke and heart failure patients with good efficacy in clinics. The aim of this study is to investigate the mechanism of DHI in heart and brain co-protection effects to determine whether AVP plays key role in this course. In the present study, we found that both the supernatant from oxygen-glucose deprivation (OGD) and reperfused primary rat neuronal cells (PRNCs) and AVP treatment caused significant reduction in cell viability and mitochondrial activity in primary rat cardiac myocytes (RCMs). Besides, DHI had the same protective effects with conivaptan, a dual vasopressin V1A and V2 receptor antagonist, in reducing the RCM damage induced by overdose AVP. DHI significantly decreased the injury of both PRNCs and RCMs. Meanwhile, the AVP level was elevated dramatically in OGD and reperfusion PRNCs, and DHI was able to decrease the AVP expression in the injured PRNCs. Therefore, our present results suggested that OGD and reperfusion PRNCs might induce myocyte injury by elevating the AVP expression in PRNCs. The ability of DHI to reinstate AVP level may be one of the mechanisms of its brain and heart co-protection effects.

  9. Mitochondrial Optic Atrophy (OPA) 1 Processing Is Altered in Response to Neonatal Hypoxic-Ischemic Brain Injury

    PubMed Central

    Baburamani, Ana A.; Hurling, Chloe; Stolp, Helen; Sobotka, Kristina; Gressens, Pierre; Hagberg, Henrik; Thornton, Claire

    2015-01-01

    Perturbation of mitochondrial function and subsequent induction of cell death pathways are key hallmarks in neonatal hypoxic-ischemic (HI) injury, both in animal models and in term infants. Mitoprotective therapies therefore offer a new avenue for intervention for the babies who suffer life-long disabilities as a result of birth asphyxia. Here we show that after oxygen-glucose deprivation in primary neurons or in a mouse model of HI, mitochondrial protein homeostasis is altered, manifesting as a change in mitochondrial morphology and functional impairment. Furthermore we find that the mitochondrial fusion and cristae regulatory protein, OPA1, is aberrantly cleaved to shorter forms. OPA1 cleavage is normally regulated by a balanced action of the proteases Yme1L and Oma1. However, in primary neurons or after HI in vivo, protein expression of YmelL is also reduced, whereas no change is observed in Oma1 expression. Our data strongly suggest that alterations in mitochondria-shaping proteins are an early event in the pathogenesis of neonatal HI injury. PMID:26393574

  10. Diffusion Tensor Imaging of White Matter Injury Caused by Prematurity-Induced Hypoxic-Ischemic Brain Damage

    PubMed Central

    Zhang, Fuyong; Liu, Chunli; Qian, Linlin; Hou, Haifeng; Guo, Zhengyi

    2016-01-01

    Background This investigation aimed to evaluate changes in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) of white matter injury (WMI) in preterm neonates with hypoxic-ischemic encephalopathy (HIE) using diffusion tension imaging (DTI). Material/Methods Thirty-eight neonates less than 37 weeks of gestation with leukoencephalopathy (as observation group) and 38 full-term infants with no leukoencephalopathy (as control group) were selected from the Neonatal Care Center in Taian Central Hospital from January 2012 to December 2013. A DTI scan was obtained within 1 week after birth. Results In the observation group, on both sides the ADC values in regions of interest (ROI) of white matter, lesions were greater and FA values were lower than in the control group. ADC and FA values in genu and splenum of corpus callosum were statistically different between the mild and severe injury groups (p<0.05). Conclusions This study demonstrates that DTI provides sensitive detection and early diagnosis of WMI in brains of premature infants with HIE. PMID:27338673

  11. Danhong injection attenuates cardiac injury induced by ischemic and reperfused neuronal cells through regulating arginine vasopressin expression and secretion.

    PubMed

    Yang, Mingzhu; Orgah, John; Zhu, Jie; Fan, Guanwei; Han, Jihong; Wang, Xiaoying; Zhang, Boli; Zhu, Yan

    2016-07-01

    Ischemic stroke is associated with cardiac myocyte vulnerability through some unknown mechanisms. Arginine vasopressin (AVP) may exert considerable function in the relationship of brain damage and heart failure. Danhong injection (DHI) can protect both stroke and heart failure patients with good efficacy in clinics. The aim of this study is to investigate the mechanism of DHI in heart and brain co-protection effects to determine whether AVP plays key role in this course. In the present study, we found that both the supernatant from oxygen-glucose deprivation (OGD) and reperfused primary rat neuronal cells (PRNCs) and AVP treatment caused significant reduction in cell viability and mitochondrial activity in primary rat cardiac myocytes (RCMs). Besides, DHI had the same protective effects with conivaptan, a dual vasopressin V1A and V2 receptor antagonist, in reducing the RCM damage induced by overdose AVP. DHI significantly decreased the injury of both PRNCs and RCMs. Meanwhile, the AVP level was elevated dramatically in OGD and reperfusion PRNCs, and DHI was able to decrease the AVP expression in the injured PRNCs. Therefore, our present results suggested that OGD and reperfusion PRNCs might induce myocyte injury by elevating the AVP expression in PRNCs. The ability of DHI to reinstate AVP level may be one of the mechanisms of its brain and heart co-protection effects. PMID:27107944

  12. Remote Ischemic Preconditioning for the Prevention of Contrast-Induced Acute Kidney Injury in Diabetics Receiving Elective Percutaneous Coronary Intervention

    PubMed Central

    Balbir Singh, Gillian; Ann, Soe Hee; Park, Jongha; Chung, Hyun Chul; Lee, Jong Soo; Kim, Eun-Sook; Choi, Jung Il; Lee, Jiho; Kim, Shin-Jae; Shin, Eun-Seok

    2016-01-01

    Objective Remote ischemic preconditioning (RIPC) induces transient episodes of ischemia by the occlusion of blood flow in non-target tissue, before a subsequent ischemia-reperfusion injury. When RIPC is applied before percutaneous coronary intervention (PCI), the kidneys may be protected against ischemia-reperfusion injury and subsequently contrast-induced acute kidney injury (CI-AKI). The aim of this study was to evaluate the efficacy of RIPC for the prevention of CI-AKI in patients with diabetes with pre-existing chronic kidney disease (CKD) undergoing elective PCI. Methods This randomized, double-blind, sham-controlled study enrolled patients with diabetes scheduled for elective PCI with eGFR ≤60 ml/min/1.73 m2 or urinary albumin creatinine ratio of >300 mg/g to receive either RIPC or the sham ischemic preconditioning. Results One hundred and two patients (68.9 ± 8.2 years old, 47.1% men) were included. Baseline eGFR, creatinine and serum NGAL was similar between RIPC and control groups (48.5 ± 12 ml/min vs. 46.6 ± 10 ml/min, p = 0.391; 1.42 ± 0.58 mg/dl vs. 1.41 ± 0.34 mg/dl, p = 0.924; and 136.0 ± 45.0 ng/ml vs. 137.6 ± 43.3 ng/ml, p = 0.961, respectively). CI-AKI occurred in 13.7% (14/102) of the total subjects, with both RIPC and control groups having an equal incidence of 13.7% (7/51). No significant differences were seen in creatinine, NGAL, cardiac enzymes (troponin T, CKMB) and hs-CRP between the groups post-procedure. Conclusions In this study, RIPC applied prior to elective PCI was not effective in preventing CI-AKI in patients with diabetes with pre-existing CKD. Trial Registration ClinicalTrials.gov NCT02329444 PMID:27723839

  13. Peroxisomal translocation of soluble epoxide hydrolase protects against ischemic stroke injury

    PubMed Central

    Nelson, Jonathan W; Zhang, Wenri; Alkayed, Nabil J; Koerner, Ines P

    2015-01-01

    Soluble epoxide hydrolase (sEH) contributes to cardiovascular disease, including stroke, although the exact mechanism remains unclear. While primarily a cytosolic enzyme, sEH can translocate into peroxisomes. The relevance of this for stroke injury is not understood. We tested the hypothesis that sEH-mediated injury is tied to the cytoplasmic localization. We found that a human sEH variant possessing increased affinity to peroxisomes reduced stroke injury in sEH-null mice, whereas infarcts were significantly larger when peroxisomal translocation of sEH was disrupted. We conclude that sEH contributes to stroke injury only when localized in the cytoplasm, while peroxisomal sEH may be protective. PMID:26126869

  14. MiR-592 Regulates the Induction and Cell Death-Promoting Activity of p75NTR in Neuronal Ischemic Injury

    PubMed Central

    Irmady, Krithi; Jackman, Katherine A.; Padow, Victoria A.; Shahani, Neelam; Martin, Laura Andres; Cerchietti, Leandro; Unsicker, Klaus; Iadecola, Costantino

    2014-01-01

    The neurotrophin receptor p75NTR has been implicated in mediating neuronal apoptosis after injury to the CNS. Despite its frequent induction in pathologic states, there is limited understanding of the mechanisms that regulate p75NTR expression after injury. Here, we show that after focal cerebral ischemia in vivo or oxygen–glucose deprivation in organotypic hippocampal slices or neurons, p75NTR is rapidly induced. A concomitant induction of proNGF, a ligand for p75NTR, is also observed. Induction of this ligand/receptor system is pathologically relevant, as a decrease in apoptosis, after oxygen–glucose deprivation, is observed in hippocampal neurons or slices after delivery of function-blocking antibodies to p75NTR or proNGF and in p75NTR and ngf haploinsufficient slices. Furthermore, a significant decrease in infarct volume was noted in p75NTR−/− mice compared with the wild type. We also investigated the regulatory mechanisms that lead to post-ischemic induction of p75NTR. We demonstrate that induction of p75NTR after ischemic injury is independent of transcription but requires active translation. Basal levels of p75NTR in neurons are maintained in part by the expression of microRNA miR-592, and an inverse correlation is seen between miR-592 and p75NTR levels in the adult brain. After cerebral ischemia, miR-592 levels fall, with a corresponding increase in p75NTR levels. Importantly, overexpression of miR-592 in neurons decreases the level of ischemic injury-induced p75NTR and attenuates activation of pro-apoptotic signaling and cell death. These results identify miR-592 as a key regulator of p75NTR expression and point to a potential therapeutic candidate to limit neuronal apoptosis after ischemic injury. PMID:24573298

  15. Methylene Blue Reduces Acute Cerebral Ischemic Injury via the Induction of Mitophagy.

    PubMed

    Di, Yao; He, Yun-Ling; Zhao, Tong; Huang, Xin; Wu, Kui-Wu; Liu, Shu-Hong; Zhao, Yong-Qi; Fan, Ming; Wu, Li-Ying; Zhu, Ling-Ling

    2015-05-19

    The treatment of stroke is limited by a short therapeutic window and a lack of effective clinical drugs. Methylene blue (MB) has been used in laboratories and clinics since the 1890s. Few studies have reported the neuroprotective role of MB in cerebral ischemia-reperfusion injury. However, whether and how MB protects against acute cerebral ischemia (ACI) injury was unclear. In this study, we investigated the effect of MB on this injury and revealed that MB protected against ACI injury by augmenting mitophagy. Using a rat middle cerebral artery occlusion (MCAO) model, we demonstrated that MB improved neurological function and reduced the infarct volume and necrosis after ACI injury. These improvements depended on the effect of MB on mitochondrial structure and function. ACI caused the disorder and disintegration of mitochondrial structure, while MB ameliorated the destruction of mitochondria. In addition, mitophagy was inhibited at 24 h after stroke and MB augmented mitophagy. In an oxygen-glucose deprivation (OGD) model in vitro, we further revealed that the elevation of mitochondrial membrane potential (MMP) by MB under OGD conditions mediated the augmented mitophagy. In contrast, exacerbating the decline of MMP during OGD abolished the MB-induced activation of mitophagy. Taken together, MB promotes mitophagy by maintaining the MMP at a relatively high level, which contributes to a decrease in necrosis and an improvement in neurological function, thereby protecting against ACI injury.

  16. Ischemic stroke after low-voltage electric injury in a diabetic and coagulopathic woman.

    PubMed

    Chen, Wei-Hsi; Chui, Chi; Lui, Chun-Chung; Yin, Hsin-Ling

    2012-11-01

    Electric injury is a common physical injury in daily life. Because of the low resistance of vascular tissue, vascular injury and thrombosis are frequently found in cases of high-voltage electric injury but are rarely reported in low-voltage conditions. We present the case of a diabetic woman who suffered symptomatic brainstem stroke after a short duration of 60 Hz/110 V alternate current electric contact with a home washer socket. A stroke risk factor survey did not reveal remarkable cardiac or vascular abnormality, except increased glycohemoglobin levels and decreased protein C activity. In contrast to a direct and adequate energy transfer in high-voltage electric injury, a pre-existing vasculohemostatic deficit, such as coagulopathy, has been proposed to provide a predisposition to thrombosis in low-voltage electric injury. Nevertheless, the findings in this patient remind the possibility of physical triggering factor for stroke occurrence in our environment as new technology and product generates rapidly enough for understanding their safety and biologic effect.

  17. Complement-dependent NADPH oxidase enzyme activation in renal ischemia/reperfusion injury.

    PubMed

    Simone, S; Rascio, F; Castellano, G; Divella, C; Chieti, A; Ditonno, P; Battaglia, M; Crovace, A; Staffieri, F; Oortwijn, B; Stallone, G; Gesualdo, L; Pertosa, G; Grandaliano, G

    2014-09-01

    NADPH oxidase plays a central role in mediating oxidative stress during heart, liver, and lung ischemia/reperfusion injury, but limited information is available about NADPH oxidase in renal ischemia/reperfusion injury. Our aim was to investigate the activation of NADPH oxidase in a swine model of renal ischemia/reperfusion damage. We induced renal ischemia/reperfusion in 10 pigs, treating 5 of them with human recombinant C1 inhibitor, and we collected kidney biopsies before ischemia and 15, 30, and 60 min after reperfusion. Ischemia/reperfusion induced a significant increase in NADPH oxidase 4 (NOX-4) expression at the tubular level, an upregulation of NOX-2 expression in infiltrating monocytes and myeloid dendritic cells, and 8-oxo-7,8-dihydro-2'-deoxyguanosine synthesis along with a marked upregulation of NADPH-dependent superoxide generation. This burden of oxidative stress was associated with an increase in tubular and interstitial expression of the myofibroblast marker α-smooth muscle actin (α-SMA). Interestingly, NOX-4 and NOX-2 expression and the overall NADPH oxidase activity as well as α-SMA expression and 8-oxo-7,8-dihydro-2'-deoxyguanosine synthesis were strongly reduced in C1-inhibitor-treated animals. In vitro, when we incubated tubular cells with the anaphylotoxin C3a, we observed an enhanced NADPH oxidase activity and α-SMA protein expression, which were both abolished by NOX-4 silencing. In conclusion, our findings suggest that NADPH oxidase is activated during ischemia/reperfusion in a complement-dependent manner and may play a potential role in the pathogenesis of progressive renal damage in this setting.

  18. Complement-dependent NADPH oxidase enzyme activation in renal ischemia/reperfusion injury.

    PubMed

    Simone, S; Rascio, F; Castellano, G; Divella, C; Chieti, A; Ditonno, P; Battaglia, M; Crovace, A; Staffieri, F; Oortwijn, B; Stallone, G; Gesualdo, L; Pertosa, G; Grandaliano, G

    2014-09-01

    NADPH oxidase plays a central role in mediating oxidative stress during heart, liver, and lung ischemia/reperfusion injury, but limited information is available about NADPH oxidase in renal ischemia/reperfusion injury. Our aim was to investigate the activation of NADPH oxidase in a swine model of renal ischemia/reperfusion damage. We induced renal ischemia/reperfusion in 10 pigs, treating 5 of them with human recombinant C1 inhibitor, and we collected kidney biopsies before ischemia and 15, 30, and 60 min after reperfusion. Ischemia/reperfusion induced a significant increase in NADPH oxidase 4 (NOX-4) expression at the tubular level, an upregulation of NOX-2 expression in infiltrating monocytes and myeloid dendritic cells, and 8-oxo-7,8-dihydro-2'-deoxyguanosine synthesis along with a marked upregulation of NADPH-dependent superoxide generation. This burden of oxidative stress was associated with an increase in tubular and interstitial expression of the myofibroblast marker α-smooth muscle actin (α-SMA). Interestingly, NOX-4 and NOX-2 expression and the overall NADPH oxidase activity as well as α-SMA expression and 8-oxo-7,8-dihydro-2'-deoxyguanosine synthesis were strongly reduced in C1-inhibitor-treated animals. In vitro, when we incubated tubular cells with the anaphylotoxin C3a, we observed an enhanced NADPH oxidase activity and α-SMA protein expression, which were both abolished by NOX-4 silencing. In conclusion, our findings suggest that NADPH oxidase is activated during ischemia/reperfusion in a complement-dependent manner and may play a potential role in the pathogenesis of progressive renal damage in this setting. PMID:25017967

  19. Amniotic Fluid Derived Stem Cells with a Renal Progenitor Phenotype Inhibit Interstitial Fibrosis in Renal Ischemia and Reperfusion Injury in Rats

    PubMed Central

    Oliveira Arcolino, Fanny; Carlon, Marianne Sylvia; Beckmann, Diego Vilibaldo; Pippi, Ney Luis; Luhers Graça, Dominguita; Levtchenko, Elena; Deprest, Jan; Toelen, Jaan

    2015-01-01

    Objectives Mesenchymal stem cells derived from human amniotic fluid (hAFSCs) are a promising source for cellular therapy, especially for renal disorders, as a subpopulation is derived from the fetal urinary tract. The purpose of this study was to evaluate if hAFSCs with a renal progenitor phenotype demonstrate a nephroprotective effect in acute ischemia reperfusion (I/R) model and prevent late stage fibrosis. Methods A total of 45 male 12-wk-old Wistar rats were divided into three equal groups;: rats subjected to I/R injury and treated with Chang Medium, rats subjected to I/R injury and treated with hAFSCs and sham-operated animals. In the first part of this study, hAFSCs that highly expressed CD24, CD117, SIX2 and PAX2 were isolated and characterized. In the second part, renal I/R injury was induced in male rats and cellular treatment was performed 6 hours later via arterial injection. Functional and histological analyses were performed 24 hours, 48 hours and 2 months after treatment using serum creatinine, urine protein to creatinine ratio, inflammatory and regeneration markers and histomorphometric analysis of the kidney. Statistical analysis was performed by analysis of variance followed by the Tukey’s test for multiple comparisons or by nonparametric Kruskal-Wallis followed by Dunn. Statistical significance level was defined as p <0.05. Results hAFSCs treatment resulted in significantly reduced serum creatinine level at 24 hours, less tubular necrosis, less hyaline cast formation, higher proliferation index, less inflammatory cell infiltration and less myofibroblasts at 48h. The treated group had less fibrosis and proteinuria at 2 months after injury. Conclusion hAFSCs contain a renal progenitor cell subpopulation that has a nephroprotective effect when delivered intra-arterially in rats with renal I/R injury, and reduces interstitial fibrosis on long term follow-up. PMID:26295710

  20. Mitochondria-targeted peptide SS-31 attenuates renal injury via an antioxidant effect in diabetic nephropathy.

    PubMed

    Hou, Yanjuan; Li, Shuangcheng; Wu, Ming; Wei, Jinying; Ren, Yunzhuo; Du, Chunyang; Wu, Haijiang; Han, Caili; Duan, Huijun; Shi, Yonghong

    2016-03-15

    Oxidative stress is implicated in the pathogenesis of diabetic kidney injury. SS-31 is a mitochondria-targeted tetrapeptide that can scavenge reactive oxygen species (ROS). Here, we investigated the effect and molecular mechanism of mitochondria-targeted antioxidant peptide SS-31 on injuries in diabetic kidneys and mouse mesangial cells (MMCs) exposed to high-glucose (HG) ambience. CD-1 mice underwent uninephrectomy and streptozotocin treatment prior to receiving daily intraperitoneal injection of SS-31 for 8 wk. The diabetic mice treated with SS-31 had alleviated proteinuria, urinary 8-hydroxy-2-deoxyguanosine level, glomerular hypertrophy, and accumulation of renal fibronectin and collagen IV. SS-31 attenuated renal cell apoptosis and expression of Bax and reversed the expression of Bcl-2 in diabetic mice kidneys. Furthermore, SS-31 inhibited expression of transforming-growth factor (TGF)-β1, Nox4, and thioredoxin-interacting protein (TXNIP), as well as activation of p38 MAPK and CREB and NADPH oxidase activity in diabetic kidneys. In vitro experiments using MMCs revealed that SS-31 inhibited HG-mediated ROS generation, apoptosis, expression of cleaved caspase-3, Bax/Bcl-2 ratio, and cytochrome c (cyt c) release from mitochondria. SS-31 normalized mitochondrial potential (ΔΨm) and ATP alterations, and inhibited the expression of TGF-β1, Nox4, and TXNIP, as well as activation of p38 MAPK and CREB and NADPH oxidase activity in MMCs under HG conditions. SS-31 treatment also could reverse the reduction of thioredoxin (TRX) biologic activity and upregulate expression of thioredoxin 2 (TRX2) in MMCs under HG conditions. In conclusion, this study demonstrates a protective effect of SS-31 against HG-induced renal injury via an antioxidant mechanism in diabetic nephropathy.

  1. Renal blood flow and acute kidney injury in septic shock: an arduous conflict that smolders intrarenally?

    PubMed

    Honore, Patrick M; Jacobs, Rita; De Waele, Elisabeth; Diltoer, Marc; Spapen, Herbert D

    2016-07-01

    Sepsis-induced acute kidney injury (SAKI) is traditionally viewed as a process driven by a reduced blood flow and prone to benefit from vasopressive support. In ovine hyperdynamic septic shock, Lankadeva et al. report a significant and flow-independent intrarenal perfusion and oxygenation "mismatch" jeopardizing the renal medulla that was aggravated by norepinephrine. Medullary and urinary oxygenation changed in parallel, suggesting that urinary oxygenation may act as a biomarker to predict SAKI. PMID:27312443

  2. Repair and regeneration of tracheal surface epithelium and submucosal glands in a mouse model of hypoxic-ischemic injury

    PubMed Central

    HEGAB, AHMED E.; NICKERSON, DEREK W.; HA, VI LUAN; DARMAWAN, DAPHNE O.; GOMPERTS, BRIGITTE N.

    2012-01-01

    Background and objective The heterotopic syngeneic tracheal transplant mouse model is an acute hypoxic-ischemic injury model that undergoes complete repair and regeneration. We hypothesized that the repair and regeneration process of the surface epithelium and submucosal glands would occur in a reproducible pattern that could be followed by the expression of specific markers of epithelial cell types. Methods We used the syngeneic heterotopic tracheal transplant model to develop a temporal and spatial map of cellular repair and regeneration by examining the tracheal grafts at post-transplant days 1, 3, 5, 7, 10 and 14. We used pulsed BrdU and immunofluorescent staining to identify and follow proliferating and repairing cell populations. Results We confirmed the reproducibility of the injury and repair in the model and we found a distinct sequence of reappearance of the various stem/ progenitor and differentiated cell populations of the tracheal surface epithelium and submucosal glands. In the initial phase, the basal and duct cells that survived the injury proliferated to re-epithelialize the basement membrane with K5 and K14 expressing cells. Then these cells proliferated further and differentiated to restore the function of the epithelium. During this repair process, TROP-2 marked all repairing submucosal gland tubules and ducts. Non-CCSP-expressing serous cells were found to differentiate 4–5 days before Clara, mucus and ciliated cells. Conclusions Improving our understanding of the reparative process of the airway epithelium will allow us to identify cell-specific mechanisms of repair that could be used as novel therapeutic approaches for abnormal repair leading to airway diseases. PMID:22617027

  3. Hydrogen sulfide protects the brain against ischemic reperfusion injury in a transient model of focal cerebral ischemia.

    PubMed

    Gheibi, Sevda; Aboutaleb, Nahid; Khaksari, Mehdi; Kalalian-Moghaddam, Hamid; Vakili, Abedin; Asadi, Yasin; Mehrjerdi, Fatemeh Zare; Gheibi, Azam

    2014-01-01

    Hydrogen sulfide (H(2)S), a well-known toxic gas, is regarded as endogenous neuromodulator and plays multiple roles in the central nervous system under physiological and pathological states, especially in secondary neuronal injury. Recent studies have shown relatively high concentrations of hydrogen sulfide (H(2)S) in the brain and also cytoprotective effects of endogenous and exogenous H(2)S in models of in vitro and in vivo ischemic injury. H(2)S protects neurons by functioning as an anti-oxidant, anti-inflammatory, and anti-apoptotic mediator and by improving neurological function. Moreover, it protects neurons from glutamate toxicity. Therefore, the present study aimed to determine whether H(2)S provides protection in transient focal cerebral ischemia. Focal ischemia was induced by 60-min middle cerebral artery occlusion (MCAO), followed by 23-h reperfusion. Saline as a vehicle and NaHS (H(2)S donor; 1 and 5 mg) were intraperitoneally injected (IP) at the beginning of ischemia. Infarct volume, brain edema, and apoptosis were assessed 24 h after MCAO.Treatment with NaHS at doses of 1 and 5 mg markedly reduced total infarct volumes by 29 and 51 %, respectively (P < 0.001). In addition, NaHS at doses of 1 and 5 mg reduced brain edema (P < 0.05) and inhibited apoptosis by decreasing positive TUNEL cells (P < 0.001).The present study shows that treatment with H(2)S reduces brain injuries and postischemic cerebral edema in a dose-dependent manner likely through the blocking programmed cell death.We propose that H(2)S might be a promising therapeutic target for stroke, although more researches are necessary to take into account the potential therapeutic effects of H(2)S in stroke patients.

  4. Impact of Seasonal Variant Temperatures and Laboratory Room Ambient Temperature on Mortality of Rats with Ischemic Brain Injury

    PubMed Central

    Gopalakrishanan, Sivakumar; Babu, Mg. Ramesh; Thangarajan, Rajesh; Punja, Dhiren; Jaganath, Vidyadhara Devarunda; Kanth, Akriti B.; Rao, Mohandas

    2016-01-01

    Introduction A popular rat model for hypoperfusion ischemic brain injury is bilateral common carotid artery occlusion (BCCAO). BCCAO surgery when performed in varying geographical locations and during different seasons of the year is reported to have variable mortality rates. Studies have also documented the diminishing influence of Ketamine-Xylazine (KT-XY) on thermoregulatory functions in rodents. Aim To explore the impact of seasonal variant temperatures and laboratory room ambient temperatures on mortality of rats following BCCAO surgery. Materials and Methods The study has two parts: 1 The first part is an analysis of a three year retrospective data to explore the association between the geographical season (hot summer and cold winter) induced laboratory room ambient temperature variations and the mortality rate in KT-XY anaesthetized BCCAO rats. 2. The second part investigated the effect of conditioned laboratory room ambient temperature (CAT) (23-250C) in KT-XY anaesthetized BCCAO group of rats. Rats were divided into 4 groups(n =8/group) as-Normal control, BCCAO and Sham BCCAO where they were all exposed to unconditioned ambient temperature (UCAT) during their surgery and postoperative care. And finally fourth group rats exposed to CAT during the BCCAO surgery and postoperative care. Results Pearson’s chi-square test indicates a significantly high association (p<0.006) between post-BCCAO mortality and hot season of the year. CAT during the hot season reduced the mortality rate (24% less) in post- BCCAO rats compared to the rats of UCAT. Conclusion Despite seasonal variations in temperature, conditioning the laboratory room ambient temperatures to 23–250C, induces hypothermia in KT-XY anaesthetized ischemic brain injured rodents and improves their survival rate. PMID:27190796

  5. Attenuation of Ischemic Liver Injury by Prostaglandin E1 Analogue, Misoprostol, and Prostaglandin I2 Analogue, OP-41483

    PubMed Central

    Totsuka, Eishi; Todo, Satoru; Zhu, Yue; Ishizaki, Naoki; Kawashima, Yoshiyuki; Jin, Maeng Bong; Urakami, Atsushi; Shimamura, Tsuyoshi; Starzl, Thomas E

    2010-01-01

    Background Prostaglandin has been reported to have protective effects against liver injury. Use of this agent in clinical settings, however, is limited because of drug-related side effects. This study investigated whether misoprostol, prostaglandin E1 analogue, and OP-41483, prostaglandin I2 analogue, which have fewer adverse effects with a longer half-life, attenuate ischemic liver damage. Study Design Thirty beagle dogs underwent 2 hours of hepatic vascular exclusion using venovenous bypass. Misoprostol was administered intravenously for 30 minutes before ischemia and for 3 hours after reperfusion. OP-41483 was administered intraportally for 30 minutes before ischemia (2 μg/kg/min) and for 3 hours after reperfusion (0.5 μg/kg/min). Animals were divided into five groups: untreated control group (n = 10); high-dose misoprostol (total 100 μg/kg) group (MP-H, n = 5); middle-dose misoprostol (50 μg/kg) group (MP-M, n = 5); low-dose misoprostol (25 μg/kg) group (MP-L, n = 5); and OP-41483 group (OP, n = 5). Animal survival, hepatic tissue blood flow (HTBF), liver function, and histology were analyzed. Results Two-week animal survival rates were 30% in control, 60% in MP-H, 100% in MP-M, 80% in MP-L, and 100% in OP. The treatments with prostaglandin analogues improved HTBF, and attenuated liver enzyme release, adenine nucleotrides degradation, and histologic abnormalities. In contrast to the MP-H animals that exhibited unstable cardiovascular systems, the MP-M, MP-L, and OP animals experienced only transient hypotension. Conclusions These results indicate that misoprostol and OP-41483 prevent ischemic liver damage, although careful dose adjustment of misoprostol is required to obtain the best protection with minimal side effects. PMID:9740185

  6. Reduction of zinc accumulation in mitochondria contributes to decreased cerebral ischemic injury by normobaric hyperoxia treatment in an experimental stroke model.

    PubMed

    Dong, Wen; Qi, Zhifeng; Liang, Jia; Shi, Wenjuan; Zhao, Yongmei; Luo, Yumin; Ji, Xunming; Liu, Ke Jian

    2015-10-01

    Cerebral ischemia interrupts oxygen supply to the affected tissues. Our previous studies have reported that normobaric hyperoxia (NBO) can maintain interstitial partial pressure of oxygen (pO2) in the penumbra of ischemic stroke rats at the physiological level, thus affording significant neuroprotection. However, the mechanisms that are responsible for the penumbra rescue by NBO treatment are not fully understood. Recent studies have shown that zinc, an important mediator of intracellular and intercellular neuronal signaling, accumulates in neurons and leads to ischemic neuronal injury. In this study, we investigate whether NBO could regulate zinc accumulation in the penumbra and prevent mitochondrial damage in penumbral tissue using a transient cerebral ischemic rat model. Our results showed that NBO significantly reduced zinc-staining positive cells and zinc-staining intensity in penumbral tissues, but not in the ischemic core. Moreover, ischemia-induced zinc accumulation in mitochondria, isolated from penumbral tissues, was greatly attenuated by NBO or a zinc-specific chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). NBO or TPEN administration stabilized the mitochondrial membrane potential in the penumbra after cerebral ischemia. Finally, ischemia-induced cytochrome c release from mitochondria in penumbral tissues was significantly reduced by NBO or TPEN treatment. These findings demonstrate a novel mechanism for NBO's neuroprotection, especially to penumbral tissues, providing further evidence for the potential clinical benefit of NBO for acute ischemic stroke.

  7. G-CSF administration to adult mice stimulates the proliferation of microglia but does not modify the outcome of ischemic injury.

    PubMed

    Bartolini, Alice; Vigliani, Maria-Claudia; Magrassi, Lorenzo; Vercelli, Alessandro; Rossi, Ferdinando

    2011-03-01

    Recent evidence suggests that adult bone marrow stem cells reduce tissue damage and promote repair following CNS ischemic injury. Since granulocyte-colony stimulating factor (G-CSF) mobilizes hematopoietic stem cells to the circulating compartment, here we tested whether administration of this drug modifies the outcome of a permanent occlusion of the middle cerebral artery in adult mice. To elucidate the behavior and fate of blood-borne cells in the ischemic brain, we produced chimeric animals, in which hematopoietic derivatives are genetically tagged. G-CSF administration enhances the proliferation of microglia in the uninjured CNS but has no effect on the amount of hematopoietic cells that infiltrate the ischemic tissue and on the size of the lesion. The blood-borne elements acquire different mesodermal identities but fail to adopt neural phenotypes, even though they occasionally fuse with Purkinje neurons. These results indicate that G-CSF treatment does not exert a significant beneficial effect on the ischemic injury. PMID:21111821

  8. Calpastatin overexpression prevents progression of S-1,2-dichlorovinyl-L-cysteine (DCVC)-initiated acute renal injury and renal failure (ARF) in diabetes

    SciTech Connect

    Dnyanmote, Ankur V.; Sawant, Sharmilee P.; Lock, Edward A.; Latendresse, John R.; Warbritton, Alan A.; Mehendale, Harihara M. . E-mail: mehendale@ulm.edu

    2006-09-01

    Previously we have shown that 90% of streptozotocin (STZ)-induced type-1 diabetic (DB) mice survive from acute renal failure (ARF) and death induced by a normally LD{sub 9} dose (75 mg/kg, i.p.) of the nephrotoxicant S-1,2-dichlorovinyl-L-cysteine (DCVC). This remarkable protection is due to a combination of slower progression of DCVC-initiated renal injury and increased compensatory nephrogenic tissue repair in the DB kidneys. BRDU immunohistochemistry revealed that the DB condition led to 4-fold higher number of proximal tubular cells (PTC) entering S-phase of cell cycle. In the present study, we tested the hypothesis that DB-induced augmentation of PTC into S-phase is accompanied by overexpression of the calpain-inhibitor calpastatin, which endogenously prevents the progression of DCVC-initiated renal injury mediated by the calpain escaping out of damaged PTCs. Immunohistochemical detection of renal calpain and its activity in the urine, over a time course after treatment with the LD{sub 9} dose of DCVC, indicated progressive increase in leakage of calpain into the extracellular spaces of the injured PTCs of the non-diabetic (NDB) kidneys as compared to the DB kidneys. Calpastatin expression was minimally detected in the NDB kidneys, using immunohistochemistry, over the time course. On the other hand, consistently higher number of tubules in the DB kidney showed calpastatin expression over the time course. The lower leakage of calpain in the DB kidneys was commensurate with constitutively higher expression of calpastatin in the S-phase-laden PTCs of these mice. To test the protective role of newly divided/dividing PTCs, DB mice were given the anti-mitotic agent colchicine (CLC) (2 mg/kg and 1.5 mg/kg, i.p., on days 8 and 10 after STZ injection) prior to challenge with a LD{sub 9} dose of DCVC, which led to 100% mortality by 48 h. Mortality was due to rapid progression of DCVC-initiated renal injury, suggesting that newly divided/dividing cells are instrumental

  9. Stanniocalcin-1 Protects a Mouse Model from Renal Ischemia-Reperfusion Injury by Affecting ROS-Mediated Multiple Signaling Pathways.

    PubMed

    Liu, Dajun; Shang, Huiping; Liu, Ying

    2016-01-01

    Stanniocalcin-1 (STC-1) protects against renal ischemia-reperfusion injury (RIRI). However, the molecular mechanisms remain widely unknown. STC-1 inhibits reactive oxygen species (ROS), whereas most ROS-mediated pathways are associated with ischemic injury. Therefore, to explore the mechanism, the effects of STC-1 on ROS-medicated pathways were studied. Non-traumatic vascular clamps were used to establish RIRI mouse models. The serum levels of STC-1, interleukin-6 (IL-6), interferon (IFN) γ, P53, and capase-3 were measured by ELISA kits. Superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by fluorescence spectrofluorometer. All these molecules changed significantly in a RIRI model mouse when compared with those in a sham control. Kidney cells were isolated from sham and model mice. STC-1 was overexpressed or knockout in these kidney cells. The molecules in ROS-medicated pathways were measured by real-time quantitative PCR and Western blot. The results showed that STC-1 is an effective ROS scavenger. The serum levels of STC-1, MDA and SOD activity were increased while the serum levels of IL-6, iIFN-γ, P53, and capase-3 were decreased in a model group when compared with a sham control (p < 0.05). Furthermore, the levels of STC-1,p53, phosphorylated mitogen-activated protein kinase kinase (p-MEKK-1), c-Jun N-terminal kinase (p-JNK), extracellular signal-regulated kinase (p-ERK), IkB kinase (p-IKK), nuclear factor (NF) κB, apoptosis signal-regulating kinase 1 (ASK-1) and caspase-3 changed significantly in kidney cells isolated from a RIRI model when compared to those isolated from a sham control (p < 0.05). Meanwhile, STC-1 overexpression or silence caused significant changes of the levels of these ROS-mediated molecules. Therefore, STC-1 maybe improve anti-inflammation, anti-oxidant and anti-apoptosis activities by affecting ROS-mediated pathways, especially the phospho-modifications of the respective proteins, resulting in the increase of SOD and

  10. Stanniocalcin-1 Protects a Mouse Model from Renal Ischemia-Reperfusion Injury by Affecting ROS-Mediated Multiple Signaling Pathways

    PubMed Central

    Liu, Dajun; Shang, Huiping; Liu, Ying

    2016-01-01

    Stanniocalcin-1 (STC-1) protects against renal ischemia-reperfusion injury (RIRI). However, the molecular mechanisms remain widely unknown. STC-1 inhibits reactive oxygen species (ROS), whereas most ROS-mediated pathways are associated with ischemic injury. Therefore, to explore the mechanism, the effects of STC-1 on ROS-medicated pathways were studied. Non-traumatic vascular clamps were used to establish RIRI mouse models. The serum levels of STC-1, interleukin-6 (IL-6), interferon (IFN) γ, P53, and capase-3 were measured by ELISA kits. Superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by fluorescence spectrofluorometer. All these molecules changed significantly in a RIRI model mouse when compared with those in a sham control. Kidney cells were isolated from sham and model mice. STC-1 was overexpressed or knockout in these kidney cells. The molecules in ROS-medicated pathways were measured by real-time quantitative PCR and Western blot. The results showed that STC-1 is an effective ROS scavenger. The serum levels of STC-1, MDA and SOD activity were increased while the serum levels of IL-6, iIFN-γ, P53, and capase-3 were decreased in a model group when compared with a sham control (p < 0.05). Furthermore, the levels of STC-1,p53, phosphorylated mitogen-activated protein kinase kinase (p-MEKK-1), c-Jun N-terminal kinase (p-JNK), extracellular signal-regulated kinase (p-ERK), IkB kinase (p-IKK), nuclear factor (NF) κB, apoptosis signal-regulating kinase 1 (ASK-1) and caspase-3 changed significantly in kidney cells isolated from a RIRI model when compared to those isolated from a sham control (p < 0.05). Meanwhile, STC-1 overexpression or silence caused significant changes of the levels of these ROS-mediated molecules. Therefore, STC-1 maybe improve anti-inflammation, anti-oxidant and anti-apoptosis activities by affecting ROS-mediated pathways, especially the phospho-modifications of the respective proteins, resulting in the increase of SOD and

  11. Administration of α-Galactosylceramide Improves Adenine-Induced Renal Injury

    PubMed Central

    Aguiar, Cristhiane Favero; Naffah-de-Souza, Cristiane; Castoldi, Angela; Corrêa-Costa, Matheus; Braga, Tárcio T; Naka, Érika L; Amano, Mariane T; Abate, Débora T R S; Hiyane, Meire I; Cenedeze, Marcos A; Filho, Alvaro Pacheco e Silva; Câmara, Niels O S

    2015-01-01

    Natural killer T (NKT) cells are a subset of lymphocytes that reacts to glycolipids presented by CD1d. Invariant NKT cells (iNKT) correspond to >90% of the total population of NKTs and reacts to α-galactosylceramide (αGalCer). αGalCer promotes a complex mixture of Th1 and Th2 cytokines, as interferon (IFN)-γ and interleukin (IL)-4. NKT cells and IFN-γ are known to participate in some models of renal diseases, but further studies are still necessary to elucidate their mechanisms. The aim of our study was to analyze the participation of iNKT cells in an experimental model of tubule-interstitial nephritis. We used 8-wk-old C57BL/6j, Jα18KO and IFN-γKO mice. They were fed a 0.25% adenine diet for 10 d. Both adenine-fed wild-type (WT) and Jα18KO mice exhibited renal dysfunction, but adenine-fed Jα18KO mice presented higher expression of kidney injury molecule-1 (KIM-1), tumor necrosis factor (TNF)-α and type I collagen. To analyze the role of activated iNKT cells in our model, we administered αGalCer in WT mice during adenine ingestion. After αGalCer injection, we observed a significant reduction in serum creatinine, proinflammatory cytokines and renal fibrosis. However, this improvement in renal function was not observed in IFN-γKO mice after αGalCer treatment and adenine feeding, illustrating that this cytokine plays a role in our model. Our findings may suggest that IFN-γ production is one of the factors contributing to improved renal function after αGalCer administration. PMID:26101952

  12. Neuroglobin is up-regulated by and protects neurons from hypoxic-ischemic injury.

    PubMed

    Sun, Y; Jin, K; Mao, X O; Zhu, Y; Greenberg, D A

    2001-12-18

    Globins are oxygen-binding heme proteins present in bacteria, protists, fungi, plants, and animals. Their functions have diverged widely in evolution, and include binding, transport, scavenging, detoxification, and sensing of gases like oxygen, nitric oxide, and carbon monoxide. Neuroglobin (Ngb) is a recently discovered monomeric globin with high affinity for oxygen and preferential localization to vertebrate brain. No function for Ngb is known, but its affinity for oxygen and its expression in cerebral neurons suggest a role in neuronal responses to hypoxia or ischemia. Here we report that Ngb expression is increased by neuronal hypoxia in vitro and focal cerebral ischemia in vivo, and that neuronal survival after hypoxia is reduced by inhibiting Ngb expression with an antisense oligodeoxynucleotide and enhanced by Ngb overexpression. Both induction of Ngb and its protective effect show specificity for hypoxia over other stressors. We conclude that hypoxia-inducible Ngb expression helps promote neuronal survival from hypoxic-ischemic insults.

  13. Increased Heme Levels in the Heart Lead to Exacerbated Ischemic Injury

    PubMed Central

    Sawicki, Konrad Teodor; Shang, Meng; Wu, Rongxue; Chang, Hsiang-Chun; Khechaduri, Arineh; Sato, Tatsuya; Kamide, Christine; Liu, Ting; Naga Prasad, Sathyamangla V; Ardehali, Hossein

    2015-01-01

    Background Heme is an essential iron-containing molecule for cardiovascular physiology, but in excess it may increase oxidative stress. Failing human hearts have increased heme levels, with upregulation of the rate-limiting enzyme in heme synthesis, δ-aminolevulinic acid synthase 2 (ALAS2), which is normally not expressed in cardiomyocytes. We hypothesized that increased heme accumulation (through cardiac overexpression of ALAS2) leads to increased oxidative stress and cell death in the heart. Methods and Results We first showed that ALAS2 and heme levels are increased in the hearts of mice subjected to coronary ligation. To determine the causative role of increased heme in the development of heart failure, we generated transgenic mice with cardiac-specific overexpression of ALAS2. While ALAS2 transgenic mice have normal cardiac function at baseline, their hearts display increased heme content, higher oxidative stress, exacerbated cell death, and worsened cardiac function after coronary ligation compared to nontransgenic littermates. We confirmed in cultured cardiomyoblasts that the increased oxidative stress and cell death observed with ALAS2 overexpression is mediated by increased heme accumulation. Furthermore, knoc