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Sample records for ischemic renal injury

  1. Chronic nicotine exposure exacerbates acute renal ischemic injury

    PubMed Central

    Grifoni, Samira; Clark, Jeb S.; Csongradi, Eva; Maric, Christine; Juncos, Luis A.

    2011-01-01

    Recent epidemiological reports showed that smoking has a negative impact on renal function and elevates the renal risk not only in the renal patient but perhaps also in the healthy population. Studies suggested that nicotine, a major tobacco alkaloid, links smoking to renal dysfunction. While several studies showed that smoking/chronic nicotine exposure exacerbates the progression of chronic renal diseases, its impact on acute kidney injury is virtually unknown. Here, we studied the effects of chronic nicotine exposure on acute renal ischemic injury. We found that chronic nicotine exposure increased the extent of renal injury induced by warm ischemia-reperfusion as evidenced by morphological changes, increase in plasma creatinine level, and kidney injury molecule-1 expression. We also found that chronic nicotine exposure elevated markers of oxidative stress such as nitrotyrosine as well as malondialdehyde. Interestingly, chronic nicotine exposure alone increased oxidative stress and injury in the kidney without morphological alterations. Chronic nicotine treatment not only increased reactive oxygen species (ROS) production and injury but also exacerbated oxidative stress-induced ROS generation through NADPH oxidase and mitochondria in cultured renal proximal tubule cells. The resultant oxidative stress provoked injury through JNK-mediated activation of the activator protein (AP)-1 transcription factor in vitro. This mechanism might exist in vivo as phosphorylation of JNK and its downstream target c-jun, a component of the AP-1 transcription factor, is elevated in the ischemic kidneys exposed to chronic nicotine. Our results imply that smoking may sensitize the kidney to ischemic insults and perhaps facilitates progression of acute kidney injury to chronic kidney injury. PMID:21511693

  2. Chronic nicotine exposure exacerbates acute renal ischemic injury.

    PubMed

    Arany, Istvan; Grifoni, Samira; Clark, Jeb S; Csongradi, Eva; Maric, Christine; Juncos, Luis A

    2011-07-01

    Recent epidemiological reports showed that smoking has a negative impact on renal function and elevates the renal risk not only in the renal patient but perhaps also in the healthy population. Studies suggested that nicotine, a major tobacco alkaloid, links smoking to renal dysfunction. While several studies showed that smoking/chronic nicotine exposure exacerbates the progression of chronic renal diseases, its impact on acute kidney injury is virtually unknown. Here, we studied the effects of chronic nicotine exposure on acute renal ischemic injury. We found that chronic nicotine exposure increased the extent of renal injury induced by warm ischemia-reperfusion as evidenced by morphological changes, increase in plasma creatinine level, and kidney injury molecule-1 expression. We also found that chronic nicotine exposure elevated markers of oxidative stress such as nitrotyrosine as well as malondialdehyde. Interestingly, chronic nicotine exposure alone increased oxidative stress and injury in the kidney without morphological alterations. Chronic nicotine treatment not only increased reactive oxygen species (ROS) production and injury but also exacerbated oxidative stress-induced ROS generation through NADPH oxidase and mitochondria in cultured renal proximal tubule cells. The resultant oxidative stress provoked injury through JNK-mediated activation of the activator protein (AP)-1 transcription factor in vitro. This mechanism might exist in vivo as phosphorylation of JNK and its downstream target c-jun, a component of the AP-1 transcription factor, is elevated in the ischemic kidneys exposed to chronic nicotine. Our results imply that smoking may sensitize the kidney to ischemic insults and perhaps facilitates progression of acute kidney injury to chronic kidney injury.

  3. Low-energy shock wave preconditioning reduces renal ischemic reperfusion injury caused by renal artery occlusion.

    PubMed

    Xue, Yuquan; Xu, Zhibin; Chen, Haiwen; Gan, Weimin; Chong, Tie

    2017-07-01

    To evaluate whether low energy shock wave preconditioning could reduce renal ischemic reperfusion injury caused by renal artery occlusion. The right kidneys of 64 male Sprague Dawley rats were removed to establish an isolated kidney model. The rats were then divided into four treatment groups: Group 1 was the sham treatment group; Group 2, received only low-energy (12 kv, 1 Hz, 200 times) shock wave preconditioning; Group 3 received the same low-energy shock wave preconditioning as Group 2, and then the left renal artery was occluded for 45 minutes; and Group 4 had the left renal artery occluded for 45 minutes. At 24 hours and one-week time points after reperfusion, serum inducible nitric oxide synthase (iNOS), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), creatinine (Cr), and cystatin C (Cys C) levels were measured, malondialdehyde (MDA) in kidney tissue was detected, and changes in nephric morphology were evaluated by light and electron microscopy. Twenty-four hours after reperfusion, serum iNOS, NGAL, Cr, Cys C, and MDA levels in Group 3 were significantly lower than those in Group 4; light and electron microscopy showed that the renal tissue injury in Group 3 was significantly lighter than that in Group 4. One week after reperfusion, serum NGAL, KIM-1, and Cys C levels in Group 3 were significantly lower than those in Group 4. Low-energy shock wave preconditioning can reduce renal ischemic reperfusion injury caused by renal artery occlusion in an isolated kidney rat model.

  4. Diannexin protects against renal ischemia reperfusion injury and targets phosphatidylserines in ischemic tissue.

    PubMed

    Wever, Kimberley E; Wagener, Frank A D T G; Frielink, Cathelijne; Boerman, Otto C; Scheffer, Gert J; Allison, Anthony; Masereeuw, Rosalinde; Rongen, Gerard A

    2011-01-01

    Renal ischemia/reperfusion injury (IRI) frequently complicates shock, renal transplantation and cardiac and aortic surgery, and has prognostic significance. The translocation of phosphatidylserines to cell surfaces is an important pro-inflammatory signal for cell-stress after IRI. We hypothesized that shielding of exposed phosphatidylserines by the annexin A5 (ANXA5) homodimer Diannexin protects against renal IRI. Protective effects of Diannexin on the kidney were studied in a mouse model of mild renal IRI. Diannexin treatment before renal IRI decreased proximal tubule damage and leukocyte influx, decreased transcription and expression of renal injury markers Neutrophil Gelatinase Associated Lipocalin and Kidney Injury Molecule-1 and improved renal function. A mouse model of ischemic hind limb exercise was used to assess Diannexin biodistribution and targeting. When comparing its biodistribution and elimination to ANXA5, Diannexin was found to have a distinct distribution pattern and longer blood half-life. Diannexin targeted specifically to the ischemic muscle and its affinity exceeded that of ANXA5. Targeting of both proteins was inhibited by pre-treatment with unlabeled ANXA5, suggesting that Diannexin targets specifically to ischemic tissues via phosphatidylserine-binding. This study emphasizes the importance of phosphatidylserine translocation in the pathophysiology of IRI. We show for the first time that Diannexin protects against renal IRI, making it a promising therapeutic tool to prevent IRI in a clinical setting. Our results indicate that Diannexin is a potential new imaging agent for the study of phosphatidylserine-exposing organs in vivo.

  5. Ameliorative Effect of Recombinant Human Erythropoietin and Ischemic Preconditioning on Renal Ischemia Reperfusion Injury in Rats

    PubMed Central

    Elshiekh, Mohammed; Kadkhodaee, Mehri; Seifi, Behjat; Ranjbaran, Mina; Ahghari, Parisa

    2015-01-01

    Background: Ischemia-reperfusion (IR) injury is one of the most common causes of renal dysfunction. There is increasing evidence about the role of the reactive oxygen species (ROS) in these injuries and endogenous antioxidants seem to have an important role in decreasing the renal tissue injury. Objectives: The aim of this study was to compare the effect of recombinant human erythropoietin (EPO) and ischemic preconditioning (IPC) on renal IR injury. Materials and Methods: Twenty four male Wistar rats were allocated into four experimental groups: sham-operated, IR, EPO + IR, and IPC + IR. Rats were underwent 50 minutes bilateral ischemia followed by 24 hours reperfusion. Erythropoietin (5000 IU/kg, i.p) was administered 30 minutes before onset of ischemia. Ischemic preconditioning was performed by three cycles of 3 minutes ischemia followed by 3 minutes reperfusion. Plasma concentrations of urea and creatinine were measured. Kidney samples were taken for reactive oxidative species (ROS) measurement including superoxide dismutase (SOD) activity, glutathione (GSH) contents, and malondialdehyde (MDA) levels. Results: Compared to the sham group, IR led to renal dysfunction as evidenced by significantly higher plasma urea and creatinine. Treatment with EPO or IPC decreased urea, creatinine, and renal MDA levels and increased SOD activity and GSH contents in the kidney. Conclusions: Pretreatment with EPO and application of IPC significantly ameliorated the renal injury induced by bilateral renal IR. However, both treatments attenuated renal dysfunction and oxidative stress in kidney tissues. There were no significant differences between pretreatment with EPO or application of IPC. PMID:26866008

  6. Renal Ischemia/Reperfusion Injury in Diabetic Rats: The Role of Local Ischemic Preconditioning

    PubMed Central

    Ozbilgin, Sule; Ozkardesler, Sevda; Akan, Mert; Boztas, Nilay; Ozbilgin, Mucahit; Ergur, Bekir Ugur; Derici, Serhan; Guneli, Mehmet Ensari; Meseri, Reci

    2016-01-01

    Background. The aim of this study was to evaluate the effects of local ischemic preconditioning using biochemical markers and histopathologically in the diabetic rat renal IR injury model. Methods. DM was induced using streptozotocin. Rats were divided into four groups: Group I, nondiabetic sham group (n = 7), Group II, diabetic sham group (n = 6), Group III, diabetic IR group (diabetic IR group, n = 6), and Group IV, diabetic IR + local ischemic preconditioning group (diabetic IR + LIPC group, n = 6). Ischemic renal injury was induced by clamping the bilateral renal artery for 45 min. 4 h following ischemia, clearance protocols were applied to assess biochemical markers and histopathologically in rat kidneys. Results. The histomorphologic total cell injury scores of the nondiabetic sham group were significantly lower than diabetic sham, diabetic IR, and diabetic IR + LIPC groups. Diabetic IR group scores were not significantly different than the diabetic sham group. But diabetic IR + LIPC group scores were significantly higher than the diabetic sham and diabetic IR groups. Conclusion. Local ischemic preconditioning does not reduce the risk of renal injury induced by ischemia/reperfusion in diabetic rat model. PMID:26925416

  7. Endoplasmic reticulum stress and its effects on renal tubular cells apoptosis in ischemic acute kidney injury.

    PubMed

    Xu, Yan; Guo, Min; Jiang, Wei; Dong, Hui; Han, Yafei; An, Xiao-Fei; Zhang, Jisheng

    2016-06-01

    Ischemia is the most frequent cause of acute kidney injury (AKI), which is characterized by apoptosis of renal tubular cell. A common result of ischemia in AKI is dysfunction of endoplasmic reticulum (ER), which causes the protein-folding capacity to lag behind the protein-folding load. The abundance of misfolded proteins stressed the ER and results in induction of the unfolded protein response (UPR). While the UPR is an adaptive response, over time it can result in apoptosis when cells are unable to recover quickly. Recent research suggests that ER stress is a major factor in renal tubular cell apoptosis resulting from ischemic AKI. Thus, ER stress may be an important new progression factor in the pathology of ischemic AKI. In this article, we review UPR signaling, describe pathology and pathophysiology mechanisms of ischemic AKI, and highlight the dual function of ER stress on renal tubular cell apoptosis.

  8. NQDI 1, an inhibitor of ASK1 attenuates acute ischemic renal injury by modulating oxidative stress and cell death.

    PubMed

    El Eter, Eman

    2013-09-01

    Apoptosis signal-regulating kinase 1 (ASK1) is among the signaling events that lead to postischemic cell death. Inhibition of ASK1 pathway protected hearts from ischemic damage. The present study evaluated the renal protective effects of NQDI 1, an inhibitor of ASK1, in an animal model of acute ischemic renal failure. Male Wistar rats were subjected to right nephrectomy and clamping of left renal pedicle for 45 min, or sham operation. The administration of NQDI 1 attenuated renal dysfunction and histological changes characteristic for renal ischemia/reperfusion injury (IRI). Apoptosis of renal tissues, as detected by TUNEL staining, was also reduced together with p53 protein expression, and renal levels of MDA and SOD with NQDI 1 administration and BCL2 was up regulated. In conclusion, inhibition of ASK1 is of therapeutic potential against acute ischemic renal injury. Its protective effects are mediated via inhibition of apoptosis and oxidative stress.

  9. Acute hepatic ischemic-reperfusion injury induces a renal cortical "stress response," renal "cytoresistance," and an endotoxin hyperresponsive state.

    PubMed

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

    2014-10-01

    Hepatic ischemic-reperfusion injury (HIRI) is considered a risk factor for clinical acute kidney injury (AKI). However, HIRI's impact on renal tubular cell homeostasis and subsequent injury responses remain ill-defined. To explore this issue, 30-45 min of partial HIRI was induced in CD-1 mice. Sham-operated or normal mice served as controls. Renal changes and superimposed injury responses (glycerol-induced AKI; endotoxemia) were assessed 2-18 h later. HIRI induced mild azotemia (blood urea nitrogen ∼45 mg/dl) in the absence of renal histologic injury or proteinuria, implying a "prerenal" state. However, marked renal cortical, and isolated proximal tubule, cytoprotective "stress protein" gene induction (neutrophil gelatinase-associated lipocalin, heme oxygenase-1, hemopexin, hepcidin), and increased Toll-like receptor 4 (TLR4) expression resulted (protein/mRNA levels). Ischemia caused release of hepatic heme-based proteins (e.g., cytochrome c) into the circulation. This corresponded with renal cortical oxidant stress (malondialdehyde increases). That hepatic derived factors can evoke redox-sensitive "stress protein" induction was implied by the following: peritoneal dialysate from HIRI mice, soluble hepatic extract, or exogenous cytochrome c each induced the above stress protein(s) either in vivo or in cultured tubule cells. Functional significance of HIRI-induced renal "preconditioning" was indicated by the following: 1) HIRI conferred virtually complete morphologic protection against glycerol-induced AKI (in the absence of hyperbilirubinemia) and 2) HIRI-induced TLR4 upregulation led to a renal endotoxin hyperresponsive state (excess TNF-α/MCP-1 gene induction). In conclusion, HIRI can evoke "renal preconditioning," likely due, in part, to hepatic release of pro-oxidant factors (e.g., cytochrome c) into the systemic circulation. The resulting renal changes can impact subsequent AKI susceptibility and TLR4 pathway-mediated stress.

  10. Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure.

    PubMed

    Johnson, D W; Pat, B; Vesey, D A; Guan, Z; Endre, Z; Gobe, G C

    2006-05-01

    Administration of human recombinant erythropoietin (EPO) at time of acute ischemic renal injury (IRI) inhibits apoptosis, enhances tubular epithelial regeneration, and promotes renal functional recovery. The present study aimed to determine whether darbepoetin-alfa (DPO) exhibits comparable renoprotection to that afforded by EPO, whether pro or antiapoptotic Bcl-2 proteins are involved, and whether delayed administration of EPO or DPO 6 h following IRI ameliorates renal dysfunction. The model of IRI involved bilateral renal artery occlusion for 45 min in rats (N = 4 per group), followed by reperfusion for 1-7 days. Controls were sham-operated. Rats were treated at time of ischemia or sham operation (T0), or post-treated (6 h after the onset of reperfusion, T6) with EPO (5000 IU/kg), DPO (25 mug/kg), or appropriate vehicle by intraperitoneal injection. Renal function, structure, and immunohistochemistry for Bcl-2, Bcl-XL, and Bax were analyzed. DPO or EPO at T0 significantly abrogated renal dysfunction in IRI animals (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.08 +/- 0.03 mmol/l vs EPO-IRI 0.04 +/- 0.01 mmol/l, P = 0.01). Delayed administration of DPO or EPO (T6) also significantly abrogated subsequent renal dysfunction (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.06 +/- 0.01 mmol/l vs EPO-IRI 0.03 +/- 0.03 mmol/l, P = 0.01). There was also significantly decreased tissue injury (apoptosis, P < 0.05), decreased proapoptotic Bax, and increased regenerative capacity, especially in the outer stripe of the outer medulla, with DPO or EPO at T0 or T6. These results reaffirm the potential clinical application of DPO and EPO as novel renoprotective agents for patients at risk of ischemic acute renal failure or after having sustained an ischemic renal insult.

  11. Ischemic postconditioning prevents renal ischemia reperfusion injury through the induction of heat shock proteins in rats.

    PubMed

    Guo, Qiongmei; Du, Xuefang; Zhao, Yanli; Zhang, Dong; Yue, Lihui; Wang, Zhenxian

    2014-12-01

    Ischemic postconditioning (IPo) attenuates ischemia‑reperfusion injuries (IRI) in various organs, of both animals and humans. This study tested the hypothesis that IPo attenuates renal IRI through the upregulation of heat shock protein (HSP)70, HSP27 and heme oxygenase‑1 (HO‑1, also known as HSP 32) expression. Adult Sprague Dawley rats were subjected to bilateral renal ischemia for 45 min followed by reperfusion for up to 48 h. One group of rats received IPo prior to restoring full perfusion. Another group was administered 100 mg/kg HSP inhibitor quercetin, injected intraperitoneally 1 h prior to ischemia. Control rats received sham operations. Renal IR resulted in severe morphological and pathological changes, with increased serum creatinine and blood urea nitrogen concentrations. IR resulted in increased inflammation by inducing plasma tumor necrosis factor‑α and renal nuclear factor kappa‑light‑chain‑enhancer of activated B cells expression. IR also increased lipid peroxidation, as indicated by elevated malondialdehyde content, reduced superoxide dismutase activity and increased renal apoptosis. Renal HSP70, HSP27 and HO‑1 mRNA and protein levels were increased by IR and further elevated by IPo. IPo attenuated these changes observed in pathology, lipid peroxidation, apoptosis and inflammation. Quercetin treatment abolished all the protective effects of IPo. In conclusion, this study showed that IPo can attenuate lipid peroxidation, apoptosis and inflammation as well as renal IRI by upregulating the expression of HSP70, HSP27 and HO‑1.

  12. Aliskiren reduced renal fibrosis in mice with chronic ischemic kidney injury--beyond the direct renin inhibition.

    PubMed

    Sun, Chiao-Yin; Cherng, Wen-Jin; Jian, Hui-Zhen; Hsu, Hsiang-Hao; Wu, I-Wen; Hsu, Heng-Jung; Wu, Mai-Szu

    2012-03-01

    Chronic renal ischemia leads to renal fibrosis and atrophy. Activation of the renin-angiotensin-aldosterone system is one of the main mechanisms driving chronic renal ischemic injury. The aim of the present study was to define the effect of aliskiren in chronic ischemia of the kidney. Two-kidney, one-clip mice were used to study chronic renal ischemia. Aliskiren significantly lowered the blood pressure in mice with renal artery constriction (92.1±1.1 vs. 81.0±1.8 mm Hg, P<0.05). Renin expression was significantly increased in ischemic kidneys when treated with aliskiren. In addition, (Pro)renin receptor expression was decreased by aliskiren in ischemic kidneys. Aliskiren treatment significantly increased klotho expression and reduced the expression of fibrogenic cystokines, caspase-3 and Bax in ischemic kidneys. Histological examination revealed that aliskiren significantly reduced the nephrosclerosis score (4.5±1.9 vs. 7.3±0.4, P<0.05). Immunofluorescence staining also showed that aliskiren decreased the deposition of interstitial collagen I in ischemic kidneys. In conclusion, direct renin inhibition significantly reduced renal fibrosis and apoptosis following chronic renal ischemia.

  13. Protective effect of insulin on ischemic renal injury in diabetes mellitus.

    PubMed

    Melin, Jan; Hellberg, Olof; Larsson, Erik; Zezina, Lilian; Fellström, Bengt C

    2002-04-01

    An exceptional susceptibility to unilateral renal ischemia/reperfusion (I/R) injury resulting in inflammation, fibrosis, atrophy of the kidney, and end-stage renal disease (ESRD) has been demonstrated in the diabetic rat. The aim of this study was to examine whether insulin treatment would reduce I/R injury in diabetic kidneys. Diabetes mellitus (DM) was induced in male Wistar rats by streptozotocin. I/R was achieved by clamping the left renal artery for 30 minutes. Treatment with long acting insulin was started 7 to 14 days before or one day after I/R. Short acting insulin was administrated 2 to 6 hours before the injury. Apoptosis was evaluated six hours after ischemia with the TUNEL-method. Four weeks after the clamping inulin clearance was measured and kidneys were removed for histopathological evaluation. In DM animals renal I/R caused massive induction of apoptosis in the renal medulla after six hours as well as inflammation, fibrosis, renal atrophy and anuria within four weeks. Treatment with long acting insulin before I/R resulted in decreased cell death and an almost complete protection of both renal function and histomorphology. Treatment with short acting insulin before I/R also decreased the loss of renal function. In contrast, insulin treatment after I/R did not protect the kidney from damage. This study shows that insulin treatment with a subsequent improved metabolic control before renal I/R protected kidneys from ESRD.

  14. IL-25 Elicits Innate Lymphoid Cells and Multipotent Progenitor Type 2 Cells That Reduce Renal Ischemic/Reperfusion Injury.

    PubMed

    Huang, Qingsong; Niu, Zhiguo; Tan, Jing; Yang, Jun; Liu, Yun; Ma, Haijun; Lee, Vincent W S; Sun, Shuming; Song, Xiangfeng; Guo, Minghao; Wang, Yiping; Cao, Qi

    2015-09-01

    IL-25 is an important immune regulator that can promote Th2 immune response-dependent immunity, inflammation, and tissue repair in asthma, intestinal infection, and autoimmune diseases. In this study, we examined the effects of IL-25 in renal ischemic/reperfusion injury (IRI). Treating IRI mice with IL-25 significantly improved renal function and reduced renal injury. Furthermore, IL-25 treatment increased the levels of IL-4, IL-5, and IL-13 in serum and kidney and promoted induction of alternatively activated (M2) macrophages in kidney. Notably, IL-25 treatment also increased the frequency of type 2 innate lymphoid cells (ILC2s) and multipotent progenitor type 2 (MPP(type2)) cells in kidney. IL-25-responsive ILC2 and MPP(type2) cells produced greater amounts of Th2 cytokines that associated with the induction of M2 macrophages and suppression of classically activated (M1) macrophages in vitro. Finally, adoptive transfer of ILC2s or MPP(type2) cells not only reduced renal functional and histologic injury in IRI mice but also induced M2 macrophages in kidney. In conclusion, our data identify a mechanism whereby IL-25-elicited ILC2 and MPP(type2) cells regulate macrophage phenotype in kidney and prevent renal IRI. Copyright © 2015 by the American Society of Nephrology.

  15. Induction of a laminin isoform and alpha(3)beta(1)-integrin in renal ischemic injury and repair in vivo.

    PubMed

    Zuk, Anna; Matlin, Karl S

    2002-11-01

    Ischemic injury to the kidney, a major cause of acute renal failure, leads to the detachment and loss of numerous tubular epithelial cells. Integrin-laminin interactions may promote regeneration of the damaged epithelium by influencing kidney epithelial cell adhesion and differentiation. Laminins are major structural components of basement membranes. Of the various laminin isoforms, laminin-5 is of particular interest because of its proposed role in the healing of skin wounds. In this study, we investigate the expression of laminin-5 in rat kidney after unilateral ischemia. Using a polyclonal antibody generated against laminin-5, we find that immunostaining is confined to the basement membranes of collecting ducts in the papilla and the major and minor calyces in normal kidney. With injury and regeneration, however, immunostaining becomes much more intense and widespread in basement membranes along the nephron. Immunoblotting of ischemic kidney extracts reveals significantly increased expression of a polypeptide of approximately 220 kDa, possibly corresponding to a precursor of one of the three laminin-5 chains. Immunoblotting and immunostaining also demonstrate significantly increased expression and altered localization of the alpha(3)-integrin subunit, a receptor for laminin-5. These results indicate that there is induction of a laminin isoform, possibly laminin-5, and alpha(3)beta(1)-integrin in the ischemic kidney and may implicate this receptor-ligand combination in the pathogenesis of acute renal failure and/or repair of the injured kidney epithelium.

  16. The ischemic/nephrotoxic acute kidney injury and the use of renal biomarkers in clinical practice.

    PubMed

    Andreucci, Michele; Faga, Teresa; Pisani, Antonio; Perticone, Maria; Michael, Ashour

    2017-04-01

    The term Acute Renal Failure (ARF) has been replaced by the term Acute Kidney Injury (AKI). AKI indicates an abrupt (within 24-48h) decrease in Glomerular Filtraton Rate, due to renal damage, that causes fluid and metabolic waste retention and alteration of electrolyte and acid-base balance. The renal biomarkers of AKI are substances or processes that are indicators of normal or impaired function of the kidney. The most used renal biomarker is still serum creatinine that is inadequate for several reasons, one of which is its inability to differentiate between hemodynamic changes of renal function ("prerenal azotemia") from intrinsic renal failure or obstructive nephropathy. Cystatin C is no better in this respect. After the description of the pathophysiology of "prerenal azotemia" and of Acute Kidney Injury (AKI) due to ischemia or nephrotoxicity, the renal biomarkers are listed and described: urinary NAG, urinary and serum KIM-1, serum and urinary NGAL, urinary IL-18, urinary L-FABP, serum Midkine, urinary IGFBP7 and TIMP2, urinary α-GST and π-GST, urinary ɣGT and AP, urinary β2M, urinary RBP, serum and urinary miRNA. All have been shown to appear much earlier than the rise of serum Creatinine. Some of them have been demonstrated to predict the clinical outcomes of AKI, such as the need for initiation of dialysis and mortality.

  17. 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.

  18. Inhibition of poly(ADP-ribose) polymerase attenuates ischemic renal injury in rats.

    PubMed

    Martin, D R; Lewington, A J; Hammerman, M R; Padanilam, B J

    2000-11-01

    The enzyme, poly(ADP-ribose) polymerase (PARP), effects repair of DNA after ischemia-reperfusion (I/R) injury to cells in nerve and muscle tissue. However, its activation in severely damaged cells can lead to ATP depletion and death. We show that PARP expression is enhanced in damaged renal proximal tubules beginning at 6-12 h after I/R injury. Intraperitoneal administration of PARP inhibitors, benzamide or 3-amino benzamide, after I/R injury accelerates the recovery of normal renal function, as assessed by monitoring the levels of plasma creatinine and blood urea nitrogen during 6 days postischemia. PARP inhibition leads to increased cell proliferation at 1 day postinjury as assessed by proliferating cell nuclear antigen and improves the histopathological appearance of kidneys examined at 7 days postinjury. Furthermore, inhibition of PARP increases levels of ATP measured at 24 h postischemia compared with those in vehicle-treated animals. Our data indicate that PARP activation is a part of the cascade of molecular events that occurs after I/R injury in the kidney. Although caution is advised, transient inhibition of PARP postischemia may constitute a novel therapy for acute renal failure.

  19. Acute unilateral ischemic renal injury induces progressive renal inflammation, lipid accumulation, histone modification, and "end-stage" kidney disease.

    PubMed

    Zager, Richard A; Johnson, Ali C M; Becker, Kirsten

    2011-12-01

    There is an emerging concept in clinical nephrology that acute kidney injury (AKI) can initiate chronic kidney disease (CKD). However, potential mechanisms by which this may occur remain elusive. Hence, this study tested the hypotheses that 1) AKI triggers progressive activation of selected proinflammatory genes, 2) there is a relative failure of compensatory anti-inflammatory gene expression, 3) proinflammatory lipid accumulation occurs, 4) these changes correspond with "gene-activating" histone acetylation, and 5) in concert, progressive renal disease results. CD-1 mice were subjected to 30 min of unilateral renal ischemia. Assessments were made 1 day, 1 wk, or 3 wk later. Results were contrasted to those observed in uninjured contralateral kidneys or in kidneys from normal mice. Progressive renal injury occurred throughout the 3-wk postischemic period, as denoted by stepwise increases in neutrophil gelatinase-associated lipocalin gene induction and ongoing histologic damage. By 3 wk postischemia, progressive renal disease was observed (massive tubular dropout; 2/3rds reduction in renal weight). These changes corresponded with progressive increases in proinflammatory cytokine/chemokine gene expression (MCP-1, TNF-α, TGF-β1), a relative failure of anti-inflammatory enzyme/cytokine (heme oxygenase-1; IL-10) upregulation, and progressive renal lipid (cholesterol/triglyceride) loading. Stepwise increases in collagen III mRNA and collagen deposition (Sirius red staining) indicated a progressive profibrotic response. Postischemic dexamethasone treatment significantly preserved renal mass, indicating functional significance of the observed proinflammatory state. Progressive gene-activating H3 acetylation was observed by ELISA, rising from 5% at baseline to 75% at 3 wk. This was confirmed by chromatin immunoprecipitation assay of target genes. In sum, these results provide experimental support for the clinical concept that AKI can trigger CKD, this is partially

  20. Acute Ipsilateral Renal Dysfunction after Partial Nephrectomy in Patients with a Contralateral Kidney: Spectrum Score to Unmask Ischemic Injury.

    PubMed

    Zhang, Zhiling; Zhao, Juping; Dong, Wen; Aguilar Palacios, Diego; Remer, Erick M; Li, Jianbo; Demirjian, Sevag; Zabell, Joseph; Campbell, Steven C

    2016-10-01

    Acute ischemic injury in the operated kidney after partial nephrectomy (PN) is often masked by a functional contralateral kidney; however, there is no practical method to assess this and its prognostic significance has not been defined. We propose a spectrum score to reflect the degree of ischemic insult in the ipsilateral kidney and study its relationship to subsequent functional recovery. From 2007 to 2014, 243 patients with a functional contralateral kidney underwent PN with necessary studies for detailed analysis of function and parenchymal mass before and after surgery in the ipsilateral kidney. Based on split function and percent parenchymal mass preserved in the ipsilateral kidney, we determined: serum creatinine (SCr)ideal-peak: expected peak SCr presuming no ischemic injury; and SCrworstcase-peak: expected peak SCr presuming temporary complete nonfunction of the ipsilateral kidney. The acute ipsilateral renal dysfunction spectrum score was defined: (observed peak SCr - SCrideal-peak)/(SCrworstcase-peak - SCrideal-peak). Subsequent functional recovery was defined: (percent function preserved)/(percent mass saved). PN. Factors associated with spectrum score and relationship between spectrum score and subsequent functional recovery were evaluated by linear regression. Median duration of warm ischemia (n=152) was 21min (interquartile range [IQR] = 15-27) and hypothermia (n=91) 26min (IQR=23-30). Median parenchymal mass preservation was 83% (IQR=74-91%). Warm ischemia and longer ischemia duration associated with higher spectrum score (both p<0.05). Increased spectrum score (<25%, 25-50%, 50-75%, and >75% quartiles) had decreased functional recovery (98%, 94%, 90%, and 89%, respectively, p<0.001). However, this trend was not observed in the hypothermia cohort. On multivariable analysis spectrum score and ischemia type significantly associated with functional recovery (both p<0.01), while age and comorbidities failed to associate (p=0.3-0.7). Acute ipsilateral

  1. NK Cell Regulatory Property is Involved in the Protective Role of MSC-Derived Extracellular Vesicles in Renal Ischemic Reperfusion Injury.

    PubMed

    Zou, Xiangyu; Gu, Di; Zhang, Guangyuan; Zhong, Liang; Cheng, Zhongliang; Liu, Guohua; Zhu, Yingjian

    2016-11-01

    Immunomodulation has been regarded as an important therapeutic aspect of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) in renal ischemic reperfusion injury (IRI), and the specific mechanism still unclear. Here, we attempt to test the function of human MSC-EVs on renal IRI by targeting the natural killer (NK) cells and to investigate the possible mechanism. Data indicated that EVs decreased NK cells in spleen and ischemic kidney. Both the EVs and antibody-dependent depletion of NK cells displayed a protective role in IRI rats. Moreover, the splenectomy model was established to evaluate the role of spleen in this process. It showed that the NK cell regulatory ability and renal protective effects by EVs still exist without spleen, which is unlike MSC properties published previously. Further, the down-regulation of chemokines in injured kidney and the delivery of RNAs through EVs in vitro were also observed. Through the microRNA array test, various inflammation-related microRNAs highly expressed in MSC-EVs compared with fibroblast EVs were tested. Thus, these results indicated that MSC-EVs could ameliorate renal ischemic reperfusion injury by decreasing NK cells and the spleen is not necessary in this process. The regulation of chemokines in injured kidney was the other factor, and the transfer of various microRNAs in the MSC-EVs may be involved. This provides direction for future clinical applications.

  2. Nitric oxide protects against ischemic acute renal failure through the suppression of renal endothelin-1 overproduction.

    PubMed

    Kurata, Hayato; Takaoka, Masanori; Kubo, Yasuhiro; Katayama, Tomoaki; Tsutsui, Hidenobu; Takayama, Junji; Matsumura, Yasuo

    2004-11-01

    To elucidate the role of nitric oxide in the pathogenesis of ischemic acute renal failure, we investigated the effects of FK409, a spontaneous nitric oxide donor, and N(G)-nitro-L-arginine methyl ester, a non-selective nitric oxide synthase inhibitor, on ischemia/reperfusion-induced renal injury and endothelin-1 overproduction in post-ischemic kidneys. Ischemic acute renal failure was induced by occlusion of the left renal artery and vein for 45 minutes followed by reperfusion, 2 weeks after contralateral nephrectomy. At 24 hours after reperfusion, renal function in untreated acute renal failure rats markedly decreased and histological examination revealed severe renal damage of the kidney. Increases in renal endothelin-1 contents were evident in the acute renal failure rats at 2 and 24 hours after reperfusion, respectively. Pretreatment with FK409 (1 or 3 mg/kg, intravenously) dose-dependently ameliorated renal injuries and suppressed the elevation of endothelin-1 content induced by ischemia/reperfusion. In contrast, N(G)-nitro-L-arginine methyl ester (1 or 10 mg/kg, intravenously) pretreatment dose-dependently aggravated renal injuries of acute renal failure rats, and the effect is accompanied by further increase in the renal endothelin-1 contents. These results suggest that both exogenous and endogenous nitric oxide have protective effects against ischemia/reperfusion-induced renal dysfunction and tissue damage, probably through the suppression of endothelin-1 overproduction in post-ischemic kidneys.

  3. Role of Cystathionine Gamma-Lyase in Immediate Renal Impairment and Inflammatory Response in Acute Ischemic Kidney Injury

    PubMed Central

    Markó, Lajos; Szijártó, István A.; Filipovic, Milos R.; Kaßmann, Mario; Balogh, András; Park, Joon-Keun; Przybyl, Lukasz; N’diaye, Gabriele; Krämer, Stephanie; Anders, Juliane; Ishii, Isao; Müller, Dominik N.; Gollasch, Maik

    2016-01-01

    Hydrogen sulfide (H2S) is known to act protectively during renal ischemia/reperfusion injury (IRI). However, the role of the endogenous H2S in acute kidney injury (AKI) is largely unclear. Here, we analyzed the role of cystathionine gamma-lyase (CTH) in acute renal IRI using CTH-deficient (Cth−/−) mice whose renal H2S levels were approximately 50% of control (wild-type) mice. Although levels of serum creatinine and renal expression of AKI marker proteins were equivalent between Cth−/− and control mice, histological analysis revealed that IRI caused less renal tubular damage in Cth−/− mice. Flow cytometric analysis revealed that renal population of infiltrated granulocytes/macrophages was equivalent in these mice. However, renal expression levels of certain inflammatory cytokines/adhesion molecules believed to play a role in IRI were found to be lower after IRI only in Cth−/− mice. Our results indicate that the systemic CTH loss does not deteriorate but rather ameliorates the immediate AKI outcome probably due to reduced inflammatory responses in the kidney. The renal expression of CTH and other H2S-producing enzymes was markedly suppressed after IRI, which could be an integrated adaptive response for renal cell protection. PMID:27273292

  4. Silencing of hypoxia-inducible factor-1α gene attenuates chronic ischemic renal injury in two-kidney, one-clip rats.

    PubMed

    Wang, Zhengchao; Zhu, Qing; Li, Pin-Lan; Dhaduk, Romesh; Zhang, Fan; Gehr, Todd W; Li, Ningjun

    2014-05-15

    Overactivation of hypoxia-inducible factor (HIF)-1α is implicated as a pathogenic factor in chronic kidney diseases (CKD). However, controversy exists regarding the roles of HIF-1α in CKD. Additionally, although hypoxia and HIF-1α activation are observed in various CKD and HIF-1α has been shown to stimulate fibrogenic factors, there is no direct evidence whether HIF-1α is an injurious or protective factor in chronic renal hypoxic injury. The present study determined whether knocking down the HIF-1α gene can attenuate or exaggerate kidney damage using a chronic renal ischemic model. Chronic renal ischemia was induced by unilaterally clamping the left renal artery for 3 wk in Sprague-Dawley rats. HIF-1α short hairpin (sh) RNA or control vectors were transfected into the left kidneys. Experimental groups were sham+control vector, clip+control vector, and clip+HIF-1α shRNA. Enalapril was used to normalize blood pressure 1 wk after clamping the renal artery. HIF-1α protein levels were remarkably increased in clipped kidneys, and this increase was blocked by shRNA. Morphological examination showed that HIF-1α shRNA significantly attenuated injury in clipped kidneys: glomerular injury indices were 0.71 ± 0.04, 2.50 ± 0.12, and 1.34 ± 0.11, and the percentage of globally damaged glomeruli was 0.02, 34.3 ± 5.0, and 6.3 ± 1.6 in sham, clip, and clip+shRNA groups, respectively. The protein levels of collagen and α-smooth muscle actin also dramatically increased in clipped kidneys, but this effect was blocked by HIF-1α shRNA. In conclusion, long-term overactivation of HIF-1α is a pathogenic factor in chronic renal injury associated with ischemia/hypoxia.

  5. Acute bile duct ligation ameliorates ischemic renal failure.

    PubMed

    Jeyarajah, D Rohan; Kielar, Mariusz L; Zhou, Xin J; Zhang, Ying; Lu, Christopher Y

    2003-01-01

    Biliary obstruction affects the renal response to ischemia and also elicits a hepatic cytokine response. Using a murine model, we now test the hypothesis that these hepatic cytokines help determine the outcome of ischemic acute renal failure. C3H/HEN mice were subjected to bile duct ligation 24 h (ABDL) or 7 days (CBDL) prior to induction of acute ischemic renal failure (ARF). Serum creatinine (Scr), cytokine mRNA abundance, and renal histology were studied 24 h after renal ischemia. ABDL prior to ARF resulted in amelioration of renal injury (Scr 0.7 +/- 0.1 mg/dl compared to 2.5 +/- 0.1 mg/dl in sham/ARF group, (mean +/- SE, n = 11/group). CBDL exacerbated renal injury. Increased hepatic mRNA for interleukin-10 (IL10) and interleukin-1 receptor antagonist (IL1RA) was detected in the ABDL/ARF group but not in the CBDL/ARF group. These data suggest that hepatic production of IL10 and IL1RA in response to ABDL ameliorates ischemic ARF, an effect that is lost after several days of BDL. Our data support the concept that hepatic cytokines modulate renal injury. This adds a new dimension in our understanding of renal injury in the setting of hepatic disease. Copyright 2003 S. Karger AG, Basel

  6. 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

  7. Renal Hypoxia and Dysoxia After Reperfusion of the Ischemic Kidney

    PubMed Central

    Legrand, Matthieu; Mik, Egbert G; Johannes, Tanja; Payen, Didier; Ince, Can

    2008-01-01

    Ischemia is the most common cause of acute renal failure. Ischemic-induced renal tissue hypoxia is thought to be a major component in the development of acute renal failure in promoting the initial tubular damage. Renal oxygenation originates from a balance between oxygen supply and consumption. Recent investigations have provided new insights into alterations in oxygenation pathways in the ischemic kidney. These findings have identified a central role of microvascular dysfunction related to an imbalance between vasoconstrictors and vasodilators, endothelial damage and endothelium–leukocyte interactions, leading to decreased renal oxygen supply. Reduced microcirculatory oxygen supply may be associated with altered cellular oxygen consumption (dysoxia), because of mitochondrial dysfunction and activity of alternative oxygen-consuming pathways. Alterations in oxygen utilization and/or supply might therefore contribute to the occurrence of organ dysfunction. This view places oxygen pathways’ alterations as a potential central player in the pathogenesis of acute kidney injury. Both in regulation of oxygen supply and consumption, nitric oxide seems to play a pivotal role. Furthermore, recent studies suggest that, following acute ischemic renal injury, persistent tissue hypoxia contributes to the development of chronic renal dysfunction. Adaptative mechanisms to renal hypoxia may be ineffective in more severe cases and lead to the development of chronic renal failure following ischemia-reperfusion. This paper is aimed at reviewing the current insights into oxygen transport pathways, from oxygen supply to oxygen consumption in the kidney and from the adaptation mechanisms to renal hypoxia. Their role in the development of ischemia-induced renal damage and ischemic acute renal failure are discussed. PMID:18488066

  8. Meclofenamate elicits a nephropreventing effect in a rat model of ischemic acute kidney injury by suppressing indoxyl sulfate production and restoring renal organic anion transporters

    PubMed Central

    Saigo, Chika; Nomura, Yui; Yamamoto, Yuko; Sagata, Masataka; Matsunaga, Rika; Jono, Hirofumi; Nishi, Kazuhiko; Saito, Hideyuki

    2014-01-01

    Indoxyl sulfate (IS), a putative low-molecular weight uremic toxin, is excreted in the urine under normal kidney function, but is retained in the circulation and tissues during renal dysfunction in acute kidney injury and chronic kidney disease. IS, which is one of the most potent inducers of oxidative stress in the kidney and cardiovascular system, is enzymatically produced in the liver from indole by cytochrome P450-mediated hydroxylation to indoxyl, followed by sulfotransferase-mediated sulfate conjugation. We used rat liver S9 fraction to identify inhibitors of IS production. After testing several compounds, including phytochemical polyphenols, we identified meclofenamate as a potent inhibitor of IS production with an apparent IC50 value of 1.34 μM. Ischemia/reperfusion (I/R) of rat kidney caused a marked elevation in the serum IS concentration 48 hours after surgery. However, intravenous administration of meclofenamate (10 mg/kg) significantly suppressed this increase in the serum level of IS. Moreover, IS concentrations in both kidney and liver were dramatically elevated by renal I/R treatment, but this increase was blocked by meclofenamate. Serum creatinine and blood urea nitrogen were markedly elevated in rats after renal I/R treatment, but these increases were significantly restored by administration of meclofenamate. Renal expression of both basolateral membrane-localized organic anion transporters rOAT1 and rOAT3 was downregulated by I/R treatment. However, expression of rOAT1 and rOAT3 recovered after administration of meclofenamate, which is associated with the inhibition of I/R-evoked elevation of prostaglandin E2. Our results suggest that meclofenamate inhibits hepatic sulfotransferase-mediated production of IS, thereby suppressing serum and renal accumulation of IS. Meclofenamate also prevents the prostaglandin E2-dependent downregulation of rOAT1 and rOAT3 expression. In conclusion, meclofenamate was found to elicit a nephropreventive effect in

  9. Remote Ischemic Conditioning and Renal Protection.

    PubMed

    Giannopoulos, Georgios; Vrachatis, Dimitrios A; Panagopoulou, Vasiliki; Vavuranakis, Manolis; Cleman, Michael W; Deftereos, Spyridon

    2017-07-01

    Over the course of the last 2 decades, the concept of remote ischemic conditioning (RIC) has attracted considerable research interest, because RIC, in most of its embodiments offers an inexpensive way of protecting tissues against ischemic damage inflicted by a number of medical conditions or procedures. Acute kidney injury (AKI) is a common side effect in the context of various medical procedures, and RIC has been suggested as a means of reducing its incidence. Outcomes regarding kidney function have been reported in numerous studies that evaluated the effects of RIC in a variety of settings (eg, cardiac surgery, interventions requiring intravenous administration of contrast media). Although several individual studies have implied a beneficial effect of RIC in preserving kidney function, 3 recently published randomized controlled trials evaluating more than 1000 patients each (Effect of Remote Ischemic Preconditioning in the Cardiac Surgery, Remote Ischaemic Preconditioning for Heart Surgery, and ERICCA) were negative. However, AKI or any other index of renal function was not a stand-alone primary end point in any of these trials. On the other hand, a range of meta-analyses (each including thousands of participants) have reported mixed results, with the most recent among them showing benefit from RIC, pinpointing at the same time a number of shortcomings in published studies, adversely affecting the quality of available data. The present review provides a critical appraisal of the current state of this field of research. It is the opinion of the authors of this review that there is a clear need for a common clinical trial framework for ischemic conditioning studies. If the current babel of definitions, procedures, outcomes, and goals persists, it is most likely that soon ischemic conditioning will be "yesterday's news" with no definitive conclusions having been reached in terms of its real clinical utility.

  10. Hyperoxia-induced preconditioning against renal ischemic injury is mediated by reactive oxygen species but not related to heat shock proteins 70 and 32.

    PubMed

    Wahhabaghai, Hannaneh; Heidari, Reza; Zeinoddini, Atefeh; Soleyman-Jahi, Saeed; Golmanesh, Leila; Rasoulian, Bahram; Akbari, Hassan; Foadoddoni, Mohsen; Esmailidehaj, Mansour

    2015-06-01

    Pre-exposure of rats to normobaric hyperoxia (O2 ≥ 95%) may induce late preconditioning against renal ischemia-reperfusion (IR) injury. In this study we investigated probable mechanisms of IR injury such as the role of reactive oxygen species (ROS), renal antioxidant agents, and heat shock proteins (HSP) 32 and 70 during delayed hyperoxia-preconditioning (HO). Fifty-two rats were divided into 7 groups: (A) IR, (B) HO + IR, (C) mercaptopropionyl glycine (MPG) + HO + IR, (D) MPG + IR, (E) HO + sham, (F) MPG + sham, and (G) sham. Rats in the following study groups (group B, C and E) were kept in a normobaric hyperoxic environment for 4 h/day for 6 consecutive days, after which they were subjected to 40 minutes of ischemia; animals in the control group (group A, D, F, and G) were kept in a normoxic cage. At the end of the preconditioning period, 24 hours of reperfusion was performed. Renal function was assessed by measuring serum creatinine (Cr), blood urea nitrogen (BUN), and creatinine clearance (CLCr). Induction of the antioxidant system was evaluated by measuring renal catalase (CAT) and superoxide dismutase (SOD) activities and glutathione (GSH) and malondialdehyde (MDA) content. The role of ROS was investigated by use of MPG (a ROS scavenger). HSP32 & 70 mRNA and protein also were determined. The hyperoxia-preconditioned IR group (B) had a lower plasma Cr and BUN and greater CLCr compared with the IR group (A) (P ≤ .016). Administration of MPG led to an increase in plasma Cr and BUN and a decrease in CLCr in group C compared with the hyperoxia-preconditioned group B (P ≤ .004). The hyperoxia-preconditioned IR group had a greater CAT activity and GSH level compared with the IR group A (P ≤ .007), whereas the administration of MPG did not change the GSH level but led to a decrease in CAT activity in group D compared with group B (P < .001). SOD activity did not change in hyperoxia-preconditioned ischemic rats compared with ischemic rats. Hyperoxia

  11. Delayed ischemic preconditioning contributes to renal protection by upregulation of miR-21

    PubMed Central

    Xu, Xialian; Kriegel, Alison J.; Liu, Yong; Usa, Kristie; Mladinov, Domagoj; Liu, Hong; Fang, Yi; Ding, Xiaoqiang; Liang, Mingyu

    2013-01-01

    Delayed ischemic preconditioning effectively protects kidneys from ischemia-reperfusion injury but the mechanism underlying renal protection remains poorly understood. Here we examined the in vivo role of microRNA miR-21 in the renal protection conferred by delayed ischemic preconditioning in mice. A 15 minute renal ischemic preconditioning significantly increased the expression of miR-21 by 4 hours and substantially attenuated ischemia-reperfusion injury induced 4 days later. A locked nucleic acid-modified anti-miR-21 given at the time of ischemic preconditioning knocked down miR-21 and significantly exacerbated subsequent ischemia-reperfusion injury in the mouse kidney. Knockdown of miR-21 resulted in significant upregulation of programmed cell death protein 4, a pro-apoptotic target gene of miR-21, and substantially increased tubular cell apoptosis. Hypoxia inducible factor-1α in the kidney was activated after ischemic preconditioning and blockade of its activity with a decoy abolished the up-regulation of miR-21 in cultured human renal epithelial cells treated with the inducer cobalt chloride. In the absence of ischemic preconditioning, knockdown of miR-21 alone did not significantly affect ischemia-reperfusion injury in the mouse kidney. Thus, upregulation of miR-21 contributes to the protective effect of delayed ischemic preconditioning against subsequent renal ischemia-reperfusion injury. PMID:22785173

  12. Preventive mechanisms of agmatine against ischemic acute kidney injury in rats.

    PubMed

    Sugiura, Takahiro; Kobuchi, Shuhei; Tsutsui, Hidenobu; Takaoka, Masanori; Fujii, Toshihide; Hayashi, Kentaro; Matsumura, Yasuo

    2009-01-28

    The excitation of renal sympathetic nervous system plays an important role in the development of ischemic acute kidney injury in rats. Recently, we found that agmatine, an adrenaline alpha(2)/imidazoline I(1)-receptor agonist, has preventive effects on ischemic acute kidney injury by suppressing the enhanced renal sympathetic nerve activity during renal ischemia and by decreasing the renal venous norepinephrine overflow after reperfusion. In the present study, we investigated preventive mechanisms of agmatine against ischemic acute kidney injury in rats. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after the contralateral nephrectomy. Pretreatment with efaroxan (30 mumol/kg, i.v.), an alpha(2)/I(1)-receptor antagonist, abolished the suppressive effects of agmatine on the enhanced renal sympathetic nerve activity during renal ischemia and on the elevated norepinephrine overflow after reperfusion, and eliminated the preventing effects of agmatine on the ischemia/reperfusion-induced renal dysfunction and histological damage. On the other hand, pretreatment with yohimbine (6 mumol/kg, i.v.), an alpha(2)-receptor antagonist, eliminated the preventing effects of agmatine on the ischemia/reperfusion-induced renal injury and norepinephrine overflow, without affecting the lowering effect of agmatine on renal sympathetic nerve activity. These results indicate that agmatine prevents the ischemic renal injury by sympathoinhibitory effect probably via I(1) receptors in central nervous system and by suppressing the norepinephrine overflow through alpha(2) or I(1) receptors on sympathetic nerve endings.

  13. [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.

  14. Red propolis ameliorates ischemic-reperfusion acute kidney injury.

    PubMed

    da Costa, Marcus Felipe Bezerra; Libório, Alexandre Braga; Teles, Flávio; Martins, Conceição da Silva; Soares, Pedro Marcos Gomes; Meneses, Gdayllon C; Rodrigues, Francisco Adelvane de Paulo; Leal, Luzia Kalyne Almeida Moreira; Miron, Diogo; Silva, Aline Holanda; Martins, Alice Maria Costa

    2015-08-15

    Acute kidney injury (AKI) remains a great problem in clinical practice. Renal ischemia/reperfusion (I/R) injury is a complex pathophysiological process. Propolis is a natural polyphenol-rich resinous substance collected by honeybees from a variety of plant sources that has anti-inflammatory and anti-oxidative properties. Red propolis (RP) protection in renal I/R injury was investigated. Male Wistar rats underwent unilateral nephrectomy and contralateral renal I/R (60 min). Rats were divided into four groups: (1) sham group, (2) RP group (sham-operated rats treated with RP), 3) IR group (rats submitted to ischemia) and (4) IR-RP (rats treated with RP before ischemia). At 48 h after reperfusion, renal function was assessed and kidneys were removed for analysis. I/R increased plasma levels of creatinine and reduced creatinine clearance (CrCl), and RP provided protection against this renal injury. Red propolis significantly improves oxidative stress parameters when compared with the IR group. Semiquantitative assessment of the histological lesions showed marked structural damage in I/R rats compared with the IR-RP rats. RP attenuates I/R-induced endothelial nitric oxide-synthase down regulation and increased heme-oxygenase expression in renal tissue. Red propolis protects kidney against acute ischemic renal failure and this protection is associated with reduced oxidative stress and eNOS and heme-oxygenase up regulation. Copyright © 2015 Elsevier GmbH. All rights reserved.

  15. Vitamin D deficiency aggravates ischemic acute kidney injury in rats

    PubMed Central

    de Bragança, Ana Carolina; Volpini, Rildo A; Canale, Daniele; Gonçalves, Janaína G; Shimizu, Maria Heloisa M; Sanches, Talita R; Seguro, Antonio C; Andrade, Lúcia

    2015-01-01

    Vitamin D deficiency (VDD) increases the risk of death in hospitalized patients. Renal ischemia/reperfusion injury (IRI) induces acute kidney injury (AKI), which activates cell cycle inhibitors, including p21, a cyclin-dependent kinase inhibitor and genomic target of 25-hydroxyvitamin D, which is in turn a potent immunomodulator with antiproliferative effects. In this study, we assess the impact of VDD in renal IRI. Wistar rats were divided into groups, each evaluated for 30 days: control (receiving a standard diet); VDD (receiving a vitamin D-free diet); IRI (receiving a standard diet and subjected to 45-min bilateral renal ischemia on day 28); and VDD + IRI (receiving a vitamin D-free diet and subjected to 45-min bilateral renal ischemia on day 28). At 48 h after IRI, animals were euthanized; blood, urine, and kidney tissue samples were collected. Compared with IRI rats, VDD + IRI rats showed a more severe decrease in glomerular filtration rate, greater urinary protein excretion, a higher kidney/body weight ratio and lower renal aquaporin 2 expression, as well as greater morphological damage, characterized by increased interstitial area and tubular necrosis. Our results suggest that the severity of tubular damage in IRI may be associated with downregulation of vitamin D receptors and p21. VDD increases renal inflammation, cell proliferation and cell injury in ischemic AKI. PMID:25780095

  16. Delivery of interleukin-10 via injectable hydrogels improves renal outcomes and reduces systemic inflammation following ischemic acute kidney injury in mice.

    PubMed

    Soranno, Danielle E; Rodell, Christopher B; Altmann, Christopher; Duplantis, Jane; Andres-Hernando, Ana; Burdick, Jason A; Faubel, Sarah

    2016-08-01

    Injectable hydrogels can be used to deliver drugs in situ over a sustained period of time. We hypothesized that sustained delivery of interleukin-10 (IL-10) following acute kidney injury (AKI) would mitigate the local and systemic proinflammatory cascade induced by AKI and reduce subsequent fibrosis. Wild-type C57BL/6 mice underwent ischemia-reperfusion AKI with avertin anesthesia. Three days later, mice were treated with either hyaluronic acid injectable hydrogel with or without IL-10, or IL-10 suspended in saline, injected under the capsule of the left kidney, or hydrogel with IL-10 injected subcutaneously. Untreated AKI served as controls. Serial in vivo optical imaging tracked the location and degradation of the hydrogel over time. Kidney function was assessed serially. Animals were killed 28 days following AKI and the following were evaluated: serum IL-6, lung inflammation, urine neutrophil gelatinase-associated lipocalin, and renal histology for fibroblast activity, collagen type III deposition and fibrosis via Picrosirius Red staining and second harmonic imaging. Our model shows persistent systemic inflammation, and renal inflammation and fibrosis 28 days following AKI. The hydrogels are biocompatible and reduced serum IL-6 and renal collagen type III 28 days following AKI even when delivered without IL-10. Treatment with IL-10 reduced renal and systemic inflammation, regardless of whether the IL-10 was delivered in a sustained manner via the injectable hydrogel under the left kidney capsule, as a bolus injection via saline under the left kidney capsule, or via the injectable hydrogel subcutaneously. Injectable hydrogels are suitable for local drug delivery following renal injury, are biocompatible, and help mitigate local and systemic inflammation. Copyright © 2016 the American Physiological Society.

  17. Ischemic brain injury in cerebral amyloid angiopathy

    PubMed Central

    van Veluw, Susanne J; Greenberg, Steven M

    2016-01-01

    Cerebral amyloid angiopathy (CAA) is a common form of cerebral small vessel disease and an important risk factor for intracerebral hemorrhage and cognitive impairment. While the majority of research has focused on the hemorrhagic manifestation of CAA, its ischemic manifestations appear to have substantial clinical relevance as well. Findings from imaging and pathologic studies indicate that ischemic lesions are common in CAA, including white-matter hyperintensities, microinfarcts, and microstructural tissue abnormalities as detected with diffusion tensor imaging. Furthermore, imaging markers of ischemic disease show a robust association with cognition, independent of age, hemorrhagic lesions, and traditional vascular risk factors. Widespread ischemic tissue injury may affect cognition by disrupting white-matter connectivity, thereby hampering communication between brain regions. Challenges are to identify imaging markers that are able to capture widespread microvascular lesion burden in vivo and to further unravel the etiology of ischemic tissue injury by linking structural magnetic resonance imaging (MRI) abnormalities to their underlying pathophysiology and histopathology. A better understanding of the underlying mechanisms of ischemic brain injury in CAA will be a key step toward new interventions to improve long-term cognitive outcomes for patients with CAA. PMID:25944592

  18. Spectroscopic monitoring of kidney tissue ischemic injury

    NASA Astrophysics Data System (ADS)

    Fitzgerald, Jason T.; Michalopoulou, Andromachi P.; Troppmann, Christoph; Demos, Stavros G.

    2004-07-01

    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.

  19. 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.

  20. 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.

  1. The role of renal sympathetic nerves in ischemia reperfusion injury.

    PubMed

    Lambert, Elisabeth; Schlaich, Markus

    2017-05-01

    Decreased blood flow supply to the kidneys known as renal ischemia/reperfusion is a common occurrence during various clinical and surgical settings. This remains highly concerning as it is a major cause of acute kidney injury (AKI). The kidneys have a rich supply of efferent and afferent sympathetic nerves playing a crucial physiological role in regulation of renal function. Studies in animal models of renal ischemia/reperfusion injury have indicated that very early during an ischemic event, the sympathetic nerves are activated and in concert with decreased nitric oxide availability, increased angiotensin II and several other molecules results in renal damage. Renal sympathetic inhibition or denervation seems to prevent or decrease some of the renal damage induced by ischemia/reperfusion injury but the evidence at present is based on animal studies and remains to be confirmed in the clinical setting. Remote ischemic preconditioning (IPC) has gained a lot of interest as a strategy to limit ischemia/reperfusion damage with some recent evidence suggesting that intact sympathetic nerves may be relevant in mediating protective effects. In this article, we review the experimental studies and emerging clinical studies that have investigated the role of sympathetic nerves following ischemia/reperfusion injury and studies exploring the role of sympathetic nerves in IPC and preventing tissue dysfunction induced by renal ischemia/reperfusion. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. 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

  3. Effect of first myocardial ischemic event on renal function.

    PubMed

    Eijkelkamp, Wouter B A; de Graeff, Pieter A; van Veldhuisen, Dirk J; van Dokkum, Richard P E; Gansevoort, Ronald T; de Jong, Paul E; de Zeeuw, Dick; Hillege, Hans L

    2007-07-01

    Effects of cardiovascular dysfunction on renal function have been poorly characterized. Therefore, we investigated the relation between a first ischemic cardiac event and long-term renal function changes in the general population from the PREVEND study. We studied 6,360 subjects with a total follow-up duration of 27.017 subject-years. The estimated mean proportional increase in serum creatinine after a first ischemic cardiac event was 3.1% compared with 0.4% per year of follow-up in subjects without such an event (p = 0.005). This represented a significantly larger decrease in estimated glomerular filtration rate after the event in subjects with an event versus the decrease in subjects without a first ischemic cardiac event (2.2 vs 0.5 ml/min/1.73 m(2)/year of follow-up, p = 0.006). In multivariate analysis with adjustment for renal risk factors, this event showed an independent association with serum creatinine change. In conclusion, a first ischemic cardiac event appears to enhance the natural decrease in renal function. Because even mild renal dysfunction should be considered a major cardiovascular risk factor after myocardial infarction, increased renal function loss after an ischemic cardiac event could add to the risk for subsequent cardiovascular morbidity, thus closing a vicious circle.

  4. The Study of Pentoxifylline Drug Effects on Renal Apoptosis and BCL-2 Gene Expression Changes Following Ischemic Reperfusion Injury in Rat

    PubMed Central

    Hashemi, Mehrdad

    2014-01-01

    Ischemia Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. In this study, the effect of pentoxyfylline on BCL-2 gene expression changes and cell injury in kidney of rat following Ischemia Reperfusion were evaluated. In this experimental study, 20 male wistar rats with average weight of 250-300 g were selected and then were accidently divided them on two tenth group of control and treatment groups. In the control group, celiotomy was performed by ventral midline incision. The left kidney was isolated, and then both the renal artery and vein were obstructed. After 60 minutes of warm ischemia, vessel obstruction resolved and the right kidney was removed. 72 hours after reperfusion, tissue samples were taken from left kidney for Tunel assay. We used quantitative real time PCR for detection of BCL-2 gene expression in treated groups and then compared them to control samples. In the treatment group, the cell death changes, showed lower level than the control group. The results also showed the BCL-2 gene expression was declined in ischemia group as campared to PNT drug group. The pentoxyfylline might have a role in control of apoptosis result from Ischemia- reperfusion and quantitative real-time PCR can be used as a direct method for detection BCL-2 gene expression in tested samples and normal samples. PMID:24734070

  5. DNA repair in ischemic acute kidney injury.

    PubMed

    Pressly, Jeffrey D; Park, Frank

    2017-04-01

    Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury leading to an induction of oxidative stress, cellular dysfunction, and loss of renal function. DNA damage, including oxidative base modifications and physical DNA strand breaks, is a consequence of renal IRI. Like many other organs in the body, a redundant and highly conserved set of endogenous repair pathways have evolved to selectively recognize the various types of cellular DNA damage and combat its negative effects on cell viability. Severe damage to the DNA, however, can trigger cell death and elimination of the injured tubular epithelial cells. In this minireview, we summarize the state of the current field of DNA damage and repair in the kidney and provide some expected and, in some cases, unexpected effects of IRI on DNA damage and repair in the kidney. These findings may be applicable to other forms of acute kidney injury and could provide new opportunities for renal research.

  6. Renal tubule cell repair following acute renal injury.

    PubMed

    Humes, H D; Lake, E W; Liu, S

    1995-01-01

    Experimental data suggests the recovery of renal function after ischemic or nephrotoxic acute renal failure is due to a replicative repair process dependent upon predominantly paracrine release of growth factors. These growth factors promote renal proximal tubule cell proliferation and a differentiation phase dependent on the interaction between tubule cells and basement membrane. These insights identify the molecular basis of renal repair and ischemic and nephrotoxic acute renal failure, and may lead to potential therapeutic modalities that accelerate renal repair and lessen the morbidity and mortality associated with these renal disease processes. In this regard, there is a prominent vasoconstrictor response of the renal vasculature during the postischemic period of developing acute renal failure. The intravenous administration of pharmacologic doses of atrial natriuretic factor (ANF) in the postischemic period have proven efficacious by altering renal vascular resistance, so that renal blood flow and glomerular filtration rate improve. ANF also appears to protect renal tubular epithelial integrity and holds significant promise as a therapeutic agent in acute renal failure. Of equal or greater promise are the therapeutic interventions targeting the proliferative reparative zone during the postischemic period. The exogenous administration of epidermal growth factor or insulin-like growth factor-1 in the postischemic period have effectively decreased the degree of renal insufficiency as measured by the peak serum creatinine and has hastened renal recovery as measured by the duration of time required to return the baseline serum creatinine values. A similarly efficacious role for hepatocyte growth factor has also been recently demonstrated.

  7. Effects of a stable prostacyclin analog on experimental ischemic acute renal failure.

    PubMed Central

    Tobimatsu, M; Ueda, Y; Saito, S; Tsumagari, T; Konomi, K

    1988-01-01

    The effect of OP-41483, a stable prostacyclin (PGI2) analog, on ischemic acute renal failure (ARF) was investigated in dogs. Administration of OP-41483 for three days after ischemia significantly increased renal cortical blood flow (RCBF) when compared with dogs treated with the saline vehicle. In the OP-41483-treated group, serum creatinine levels remained relatively low during postoperative days 1-3 and mean survival time was prolonged. Injection of a silicone rubber vascular casting compound (Microfil) revealed increased numbers of visible renal cortical glomeruli and microvessels compared to the saline vehicle group. Histologic sections showed only very limited tubular necrosis, whereas sections of kidneys treated with saline showed extensive tubular necrosis. In conclusion, this stable prostacyclin analog provided a significant degree of protection for the kidneys from ischemic injury and may be useful in a clinical setting. Images Figs. 3A-D. Figs. 4A-D. PMID:3291800

  8. [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.

  9. Thrombolysis in Chinese Ischemic Stroke Patients with Renal Dysfunction

    PubMed Central

    Lo, Wai Ting; Cheung, Chi Yuen; Li, Chung Ki; Chau, Ka Foon; Fong, Wing Chi

    2015-01-01

    Background Current data concerning the relationship between renal function and clinical outcome among stroke patients treated with intravenous thrombolytic therapy are conflicting. Our aim is to analyze whether the clinical outcome of Chinese ischemic stroke patients treated with thrombolytic therapy is affected by the presence of renal dysfunction. Methods Chinese patients who received intravenous thrombolytic therapy for acute ischemic stroke were recruited. Renal dysfunction was defined as an estimated glomerular filtration rate (eGFR) <90 ml/min/1.73 m2. The primary outcome was independent function (modified Rankin Scale, mRS, 0-2) at 3 months, while secondary outcomes included early improvement of the National Institute of Health Stroke Scale (NIHSS) score of ≥4 points at 24 h, symptomatic intracerebral hemorrhage (ICH) within 36 h of treatment and 30-day mortality. Results A total of 199 patients were recruited, of whom 51.3% had renal dysfunction. There were no significant differences in functional independence at 3 months, NIHSS improvement at 24 h post-thrombolysis and 30-day mortality between patients with or without renal dysfunction. Multivariate analysis showed that eGFR as a continuous variable was not an independent risk factor for symptomatic ICH. Conclusion Chinese ischemic stroke patients with renal dysfunction who received thrombolytic therapy had clinical outcomes similar to those without renal dysfunction. PMID:26019713

  10. Homocysteine in Renal Injury

    PubMed Central

    Long, Yanjun; Nie, Jing

    2016-01-01

    Background Homocysteine (Hcy) is an intermediate of methionine metabolism. Hyperhomocysteinemia (HHcy) can result from a deficiency in the enzymes or vitamin cofactors required for Hcy metabolism. Patients with renal disease tend to be hyperhomocysteinemic, particularly as renal function declines, although the underlying cause of HHcy in renal disease is not entirely understood. Summary HHcy is considered a risk or pathogenic factor in the progression of chronic kidney disease (CKD) as well as the cardiovascular complications. Key Messages In this review, we summarize both clinical and experimental findings that reveal the contribution of Hcy as a pathogenic factor to the development of CKD. In addition, we discuss several important mechanisms mediating the pathogenic action of Hcy in the kidney, such as local oxidative stress, endoplasmic reticulum stress, inflammation and hypomethylation. PMID:27536696

  11. Metabolic Syndrome and Renal Injury

    PubMed Central

    Sheen, Yi-Jing; Sheu, Wayne Huey-Herng

    2011-01-01

    Both metabolic syndrome (MetS) and chronic kidney disease (CKD) are major global health issues. Current clinical markers used to reflect renal injury include albuminuria and estimated glomerular filtration rate (eGFR). Given the same eGFR level, urine albumin might be a better risk marker to predict progression of CKD and future development of cardiovascular diseases (CVDs). Serum Cystatin C is emerging as a new biomarker for early detection of renal injury associated with MetS and cardiovascular risk. In addition to each component, MetS per se influences the incidence and prognosis of renal injury and the odds ratios increased with the increase in the number of metabolic abnormalities. Hyperinsulinemia, activation of rennin-angiotensin-aldosterone system, increase of oxidative stress, and inflammatory cytokines are proposed to be the plausible biological link between MetS and CKD. Weight control, stick control of blood pressure, glucose, and lipids disorders may lead to lessening renal injury and even the subsequent CVD. PMID:21461396

  12. Protection of retinal function by sulforaphane following retinal ischemic injury.

    PubMed

    Ambrecht, Lindsay A; Perlman, Jay I; McDonnell, James F; Zhai, Yougang; Qiao, Liang; Bu, Ping

    2015-09-01

    Sulforaphane, a precursor of glucosinolate in cruciferous vegetables such as broccoli and cauliflower, has been shown to protect brain ischemic injury. In this study, we examined the effect of systemic administration of sulforaphane on retinal ischemic reperfusion injury. Intraocular pressure was elevated in two groups of C57BL/6 mice (n = 8 per group) for 45 min to induce retinal ischemic reperfusion injury. Following retinal ischemic reperfusion injury, vehicle (1% DMSO saline) or sulforaphane (25 mg/kg/day) was administered intraperitoneally daily for 5 days. Scotopic electroretinography (ERG) was used to quantify retinal function prior to and one-week after retinal ischemic insult. Retinal morphology was examined one week after ischemic insult. Following ischemic reperfusion injury, ERG a- and b-wave amplitudes were significantly reduced in the control mice. Sulforaphane treatment significantly attenuated ischemic-induced loss of retinal function as compared to vehicle treated mice. In vehicle treated mice, ischemic reperfusion injury produced marked thinning of the inner retinal layers, but the thinning of the inner retinal layers appeared significantly less with sulforaphane treatment. Thus, sulforaphane may be beneficial in the treatment of retinal disorders with ischemic reperfusion injury. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Early interleukin 6 production by leukocytes during ischemic acute kidney injury is regulated by TLR4

    PubMed Central

    Chen, Jianlin; Hartono, John R.; John, Reji; Bennett, Michael; Zhou, Xin Jin; Wang, Yanxia; Wu, Qingqing; Winterberg, Pamela D.; Nagami, Glenn T.; Lu, Christopher Y.

    2012-01-01

    Although leukocytes infiltrate the kidney during ischemic acute kidney injury (AKI) and release interleukin 6 (IL6), their mechanism of activation is unknown. Here, we tested whether Toll-like receptor 4 (TLR4) on leukocytes mediated this activation by interacting with high-mobility group protein B1 (HMGB1) released by renal cells as a consequence of ischemic kidney injury. We constructed radiation-induced bone marrow chimeras using C3H/HeJ and C57BL/10ScNJ strains of TLR4 (−/−) mice and their respective TLR4 (+/+) wild-type counterparts and studied them at 4 h after an ischemic insult. Leukocytes adopted from TLR4 (+/+) mice infiltrated the kidneys of TLR4 (−/−) mice, and TLR4 (−/−) leukocytes infiltrated the kidneys of TLR4 (+/+) mice but caused little functional renal impairment in each case. Maximal ischemic AKI required both radiosensitive leukocytes and radioresistant renal parenchymal and endothelial cells from TLR4 (+/+) mice. Only TLR4 (−/−) leukocytes produced IL6 in vivo and in response to HMGB1 in vitro. Thus, following infiltration of the injured kidney, leukocytes produce IL6 when their TLR4 receptors interact with HMGB1 released by injured renal cells. This underscores the importance of TLR4 in the pathogenesis of ischemic AKI. PMID:21633411

  14. Effect of remote ischemic preconditioning on renal dysfunction after complex valvular heart surgery: a randomized controlled trial.

    PubMed

    Choi, Yong Seon; Shim, Jae Kwang; Kim, Jong Chan; Kang, Kyu-Sik; Seo, Yong Han; Ahn, Ki-Ryang; Kwak, Young Lan

    2011-07-01

    Acute kidney injury after cardiac surgery with cardiopulmonary bypass is closely related to systemic inflammatory reactions and oxidative stresses. Remote ischemic preconditioning is a systemic protective strategy whereby brief limb ischemia confers systemic protection against prolonged ischemia and inflammatory reactions in distant organs. This study investigated whether remote ischemic preconditioning provides systemic protective effect on kidneys that are not directly exposed to ischemia-reperfusion injury during complex valvular heart surgery. Seventy-six adult patients undergoing complex valvular heart surgery were randomly assigned to either remote ischemic preconditioning group (n = 38) or control group (n = 38). Remote ischemic preconditioning consisted of 3 10-minute cycles of lower limb ischemia and reperfusion with an automated cuff inflator. Primary end points were comparisons of biomarkers of renal injury including serum creatinine, cystatin C and neutrophil gelatinase-associated lipocalin, and incidence of acute kidney injury. Secondary end points were comparisons of myocardial enzyme release and pulmonary parameters. There were no significant differences in serum levels of biomarkers of renal injury between groups throughout the study period. The incidence of acute kidney injury did not differ between groups. Creatine kinase isoenzyme MB at 24 hours after surgery was lower, and intensive care unit stay was shorter in the remote ischemic preconditioning group than in the control group. In patients undergoing complex valvular heart surgery, remote ischemic preconditioning did not reduce degree of renal injury or incidence of acute kidney injury whereas it did reduce myocardial injury and intensive care unit stay. Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

  15. Long-term Effects of Remote Ischemic Preconditioning on Kidney Function in High-risk Cardiac Surgery Patients: Follow-up Results from the RenalRIP Trial.

    PubMed

    Zarbock, Alexander; Kellum, John A; Van Aken, Hugo; Schmidt, Christoph; Küllmar, Mira; Rosenberger, Peter; Martens, Sven; Görlich, Dennis; Meersch, Melanie

    2017-05-01

    In a multicenter, randomized trial, the authors enrolled patients at high-risk for acute kidney injury as identified by a Cleveland Clinic Foundation score of 6 or more. The authors enrolled 240 patients at four hospitals and randomized them to remote ischemic preconditioning or control. The authors found that remote ischemic preconditioning reduced acute kidney injury in high-risk patients undergoing cardiac surgery. The authors now report on the effects of remote ischemic preconditioning on 90-day outcomes. In this follow-up study of the RenalRIP trial, the authors examined the effect of remote ischemic preconditioning on the composite endpoint major adverse kidney events consisting of mortality, need for renal replacement therapy, and persistent renal dysfunction at 90 days. Secondary outcomes were persistent renal dysfunction and dialysis dependence in patients with acute kidney injury. Remote ischemic preconditioning significantly reduced the occurrence of major adverse kidney events at 90 days (17 of 120 [14.2%]) versus control (30 of 120 [25.0%]; absolute risk reduction, 10.8%; 95% CI, 0.9 to 20.8%; P = 0.034). In those patients who developed acute kidney injury after cardiac surgery, 2 of 38 subjects in the remote ischemic preconditioning group (5.3%) and 13 of 56 subjects in the control group (23.2%) failed to recover renal function at 90 days (absolute risk reduction, 17.9%; 95% CI, 4.8 to 31.1%; P = 0.020). Acute kidney injury biomarkers were also increased in patients reaching the major adverse kidney event endpoint compared to patients who did not. Remote ischemic preconditioning significantly reduced the 3-month incidence of a composite endpoint major adverse kidney events consisting of mortality, need for renal replacement therapy, and persistent renal dysfunction in high-risk patients undergoing cardiac surgery. Furthermore, remote ischemic preconditioning enhanced renal recovery in patients with acute kidney injury.

  16. Fyn in Neurodevelopment and Ischemic Brain Injury

    PubMed Central

    Knox, Renatta; Jiang, Xiangning

    2016-01-01

    The Src Family kinases (SFKs) are nonreceptor protein tyrosine kinases that are implicated in many normal and pathological processes in the nervous system. The SFKs Fyn, Src, Yes, Lyn and Lck are expressed in the brain. This review will focus on Fyn, as Fyn mutant mice have striking phenotypes in the brain and Fyn has been shown to be involved in ischemic brain injury in adult rodents, and with our work, in neonatal animals. An understanding of Fyn’s role in neurodevelopment and disease will allow researchers to target pathological pathways while preserving protective ones. PMID:25720756

  17. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial.

    PubMed

    Zarbock, Alexander; Schmidt, Christoph; Van Aken, Hugo; Wempe, Carola; Martens, Sven; Zahn, Peter K; Wolf, Britta; Goebel, Ulrich; Schwer, Christian I; Rosenberger, Peter; Haeberle, Helene; Görlich, Dennis; Kellum, John A; Meersch, Melanie

    2015-06-02

    No interventions have yet been identified to reduce the risk of acute kidney injury in the setting of cardiac surgery. To determine whether remote ischemic preconditioning reduces the rate and severity of acute kidney injury in patients undergoing cardiac surgery. In this multicenter trial, we enrolled 240 patients at high risk for acute kidney injury, as identified by a Cleveland Clinic Foundation score of 6 or higher, between August 2013 and June 2014 at 4 hospitals in Germany. We randomized them to receive remote ischemic preconditioning or sham remote ischemic preconditioning (control). All patients completed follow-up 30 days after surgery and were analyzed according to the intention-to-treat principle. Patients received either remote ischemic preconditioning (3 cycles of 5-minute ischemia and 5-minute reperfusion in one upper arm after induction of anesthesia) or sham remote ischemic preconditioning (control), both via blood pressure cuff inflation. The primary end point was the rate of acute kidney injury defined by Kidney Disease: Improving Global Outcomes criteria within the first 72 hours after cardiac surgery. Secondary end points included use of renal replacement therapy, duration of intensive care unit stay, occurrence of myocardial infarction and stroke, in-hospital and 30-day mortality, and change in acute kidney injury biomarkers. Acute kidney injury was significantly reduced with remote ischemic preconditioning (45 of 120 patients [37.5%]) compared with control (63 of 120 patients [52.5%]; absolute risk reduction, 15%; 95% CI, 2.56%-27.44%; P = .02). Fewer patients receiving remote ischemic preconditioning received renal replacement therapy (7 [5.8%] vs 19 [15.8%]; absolute risk reduction, 10%; 95% CI, 2.25%-17.75%; P = .01), and remote ischemic preconditioning reduced intensive care unit stay (3 days [interquartile range, 2-5]) vs 4 days (interquartile range, 2-7) (P = .04). There was no significant effect of remote ischemic

  18. Influence of age and vitamin E on post-ischemic acute renal failure.

    PubMed

    Shimizu, Maria Heloisa Massola; Araujo, Magali; Borges, Sergio Murilo Mello; de Tolosa, Erasmo Magalhães C; Seguro, Antonio Carlos

    2004-05-01

    The aging process causes progressive deterioration in kidney structure and function. Aberrant generation of reactive oxygen species has been implicated in both age-related and ischemia-related tissue injury. Vitamin E (VE), one of the most powerful and effective exogenous antioxidants, prevents lipid peroxidation and protects against the effects of oxidative stress. The objective of this study was to determine the influence of age and VE on post-ischemic acute renal failure (ARF). Young adult, middle-aged and aged male Wistar rats were maintained on three different 30-day diets: Normal, VE absent and VE supplemented. On day 30, urinary protein and serum cholesterol and VE were measured. On day 31, rats were subjected to 60' clamping of the left renal artery plus right nephrectomy. Inulin clearance (InCl) was performed 48 h after renal ischemia. Malondialdehyde (MDA) was measured in the cortex of normal and 48-h post-ischemic kidneys. Urinary protein and serum cholesterol were higher in aged rats than in other rats. With aging, InCl decreased progressively. Vitamin E deficiency aggravated ARF. In middle-aged and aged rats, VE supplementation protected against ARF. In the absence of VE, MDA increased with age. In conclusion, our data suggest that ARF becomes more severe with age and that ischemia/reperfusion injury is exacerbated when antioxidant-scavenging ability of the kidney is impaired by VE deficiency. Supplementation with VE is essential for protecting aging kidneys against ischemic ARF.

  19. 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.

  20. 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

  1. Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney

    PubMed Central

    Leemans, Jaklien C.; Stokman, Geurt; Claessen, Nike; Rouschop, Kasper M.; Teske, Gwendoline J.D.; Kirschning, Carsten J.; Akira, Shizuo; van der Poll, Tom; Weening, Jan J.; Florquin, Sandrine

    2005-01-01

    TLRs are conserved pattern recognition receptors that detect motifs of pathogens and host material released during injury. For unknown reasons, renal TLR2 mRNA is mainly expressed by tubular cells and is enhanced upon renal ischemia/reperfusion (I/R) injury. We evaluated the role of TLR2 in I/R injury using TLR2–/– and TLR2+/+ mice, TLR2 antisense oligonucleotides, and chimeric mice deficient in leukocyte or renal TLR2. Tubular cells needed TLR2 to produce significant cytokine and chemokine amounts upon ischemia in vitro. TLR2 played a proinflammatory and detrimental role in vivo after I/R injury, as reflected by a reduction in the amount of local cytokines and chemokines, leukocytes, and the level of renal injury and dysfunction in TLR2–/– mice compared with controls. Analysis of chimeric mice suggested that TLR2 expressed on renal parenchyma plays a crucial role in the induction of inflammation and injury. TLR2-antisense treatment protected mice from renal dysfunction, neutrophil influx, and tubular apoptosis after I/R injury compared with nonsense treatment. In summary, we identified renal-associated TLR2 as an important initiator of inflammatory responses leading to renal injury and dysfunction in I/R injury. These data imply that TLR2 blockade could provide a basis for therapeutic strategies to treat or prevent renal ischemic injury. PMID:16167081

  2. [Ischemic rhabdomyolysis and acute renal failure].

    PubMed

    Madrazo Delgado, M; Uña Orejón, R; Redondo Calvo, F J; Criado Jiménez, A

    2007-01-01

    Rhabdomyolysis is a clinical syndrome characterized by the breakdown and later necrosis of skeletal muscle, leading to the release of various intracellular components into the blood stream. The clinical expression of rhabdomyolysis ranges from asymptomatic to severe forms involving multiorgan failure with electrolyte imbalance, respiratory distress syndrome, acute renal failure and disseminated intravascular coagulation. Diagnosis is based on a finding of elevated serum levels of components that are normally found within the muscle cell, chiefly muscle enzymes and myoglobin. Acute kidney failure, one of the main consequences of rhabdomyolysis, occurs in 4% to 33% of cases. Treatment requires prompt volume replacement with crystalloids. In spite of successful resuscitation and prophylaxis against myoglobulin-induced renal failure, 1 out of every 3 patients develops kidney damage and requires continuous replacement therapy.

  3. Increased hematocrit mitigates ischemic renal damage in the splenectomized dog.

    PubMed

    Bell, R D; Mandal, A K

    1989-03-01

    Splenectomy (SPLX) prevents ischemic acute tubular necrosis (ATN) and peritubular capillary (PTC) congestion. This study attempts to reverse the protective effect of splenectomy in the ischemic model of ATN by increasing hematocrit before inducing ATN. Sham-SPLX, SPLX, and SPLX dogs given packed red cells to elevate hematocrit by 30% (SPLX-high hematocrit) received bilateral renal artery obstruction (RAO) for 120 minutes. Renal function was tested for 6 days post-RAO. Hematocrit in the SPLX-high hematocrit group was greater (p less than .05) than the SPLX-RAO group but did not differ from the non-SPLX group. All groups had different (p less than .05) serum creatinine levels for 48 hours post-RAO, and untreated animals differed from all the others at 144 hours. Serum creatinine was highest in untreated, lowest in SPLX-high hematocrit, and intermediate in noninfused SPLX animals. The same pattern was observed in blood urea nitrogen, creatinine clearance and renal histopathology. Fractional excretion of sodium in the SPLX groups was six times that in the intact animals (p less than .05), irrespective of hematocrit level. We conclude that increased hematocrit is protective in ischemic ATN, and does not promote PTC congestion or ATN in the SPLX animal. In addition, the protective effect of splenectomy may be mediated, in part, by mechanism(s) that alter sodium transport or osmolar excretion.

  4. Influence of remote ischemic conditioning and tramadol hydrochloride on oxidative stress in kidney ischemia/reperfusion injury in rats.

    PubMed

    Oliveira, Rita de Cássia Silva de; Brito, Marcus Vinicius Henriques; Ribeiro, Rubens Fernando Gonçalves; Oliveira, Leonam Oliver Durval; Monteiro, Andrew Moraes; Brandão, Fernando Mateus Viegas; Cavalcante, Lainy Carollyne da Costa; Gouveia, Eduardo Henrique Herbster; Henriques, Higor Yuri Bezerra

    2017-03-01

    To evaluate the effects of tramadol hydrochloride associated to remote ischemic perconditioning on oxidative stress. Twenty five male rats (Wistar) underwent right nephrectomy and were distributed into five groups: Sham group (S); Ischemia/Reperfusion group (I/R) with 30 minutes of renal ischemia; Remote ischemic perconditioning group (Per) with three cycles of 10 minutes of I/R performed during kidney ischemia; Tramadol group (T) treated with tramadol hydrochloride (40mg/kg); remote ischemic perconditioning + Tramadol group (Per+T) with both treatments. Oxidative stress was assessed after 24 hours of reperfusion. Statistical differences were observed in MDA levels between I/R group with all groups (p<0.01), in addition there was difference between Tramadol with Sham, Per and Per+T groups (p<0.05), both in plasma and renal tissue. Remote ischemic perconditioning was more effective reducing renal ischemia-reperfusion injury than administration of tramadol or association of both treatments.

  5. Poly-IC preconditioning protects against cerebral and renal ischemia-reperfusion injury.

    PubMed

    Packard, Amy E B; Hedges, Jason C; Bahjat, Frances R; Stevens, Susan L; Conlin, Michael J; Salazar, Andres M; Stenzel-Poore, Mary P

    2012-02-01

    Preconditioning induces ischemic tolerance, which confers robust protection against ischemic damage. We show marked protection with polyinosinic polycytidylic acid (poly-IC) preconditioning in three models of murine ischemia-reperfusion injury. Poly-IC preconditioning induced protection against ischemia modeled in vitro in brain cortical cells and in vivo in models of brain ischemia and renal ischemia. Further, unlike other Toll-like receptor (TLR) ligands, which generally induce significant inflammatory responses, poly-IC elicits only modest systemic inflammation. Results show that poly-IC is a new powerful prophylactic treatment that offers promise as a clinical therapeutic strategy to minimize damage in patient populations at risk of ischemic injury.

  6. Ischemia reperfusion injury, ischemic conditioning and diabetes mellitus.

    PubMed

    Lejay, Anne; Fang, Fei; John, Rohan; Van, Julie A D; Barr, Meredith; Thaveau, Fabien; Chakfe, Nabil; Geny, Bernard; Scholey, James W

    2016-02-01

    Ischemia/reperfusion, which is characterized by deficient oxygen supply and subsequent restoration of blood flow, can cause irreversible damages to tissue. Mechanisms contributing to the pathogenesis of ischemia reperfusion injury are complex, multifactorial and highly integrated. Extensive research has focused on increasing organ tolerance to ischemia reperfusion injury, especially through the use of ischemic conditioning strategies. Of morbidities that potentially compromise the protective mechanisms of the heart, diabetes mellitus appears primarily important to study. Diabetes mellitus increases myocardial susceptibility to ischemia reperfusion injury and also modifies myocardial responses to ischemic conditioning strategies by disruption of intracellular signaling responsible for enhancement of resistance to cell death. The purpose of this review is twofold: first, to summarize mechanisms underlying ischemia reperfusion injury and the signal transduction pathways underlying ischemic conditioning cardioprotection; and second, to focus on diabetes mellitus and mechanisms that may be responsible for the lack of effect of ischemic conditioning strategies in diabetes.

  7. Xanthine oxidase inhibition attenuates ischemic-reperfusion lung injury

    SciTech Connect

    Lynch, M.J.; Grum, C.M.; Gallagher, K.P.; Bolling, S.F.; Deeb, G.M.; Morganroth, M.L.

    1988-05-01

    Ischemic-reperfusion lung injury is a factor potentially limiting the usefulness of distant organ procurement for heart-lung transplantation. Toxic oxygen metabolites are considered a major etiologic factor in reperfusion injury. Although oxygen-free radicals may be generated by many mechanisms, we investigated the role of xanthine oxidase in this injury process by using lodoxamide, a xanthine oxidase inhibitor, to inhibit ischemic-reperfusion injury in an isolated rat lung model. Isolated rat lungs were perfused with physiologic salt solution (PSS) osmotically stabilized with Ficoll until circulating blood elements were nondetectable in the pulmonary venous effluent. Lungs were rendered ischemic by interrupting ventilation and perfusion for 2 hr at 37/sup 0/C. After the ischemic interval, the lungs were reperfused with whole blood and lung injury was determined by measuring the accumulation of /sup 125/I-bovine serum albumin in lung parenchyma and alveolar lavage fluid as well as by gravimetric measurements. Lung effluent was collected immediately pre- and postischemia for analysis of uric acid by high-pressure liquid chromatography. Lodoxamide (1 mM) caused significant attenuation of postischemic lung injury. Uric acid levels in the lung effluent confirmed inhibition of xanthine oxidase. Protection from injury was not complete, however, implying that additional mechanisms may contribute to ischemic-reperfusion injury in the lung.

  8. Effects of hypertonic saline solution associated to remote ischemic perconditioning in kidney ischemia/reperfusion injury in rats.

    PubMed

    Brito, Marcus Vinicius Henriques; Yasojima, Edson Yuzur; Percário, Sandro; Ribeiro, Rubens Fernando Gonçalves; Cavalcante, Lainy Carollyne da Costa; Monteiro, Andrew Moraes; Couteiro, Rodrigo Paracampo; Rodrigues, Ivone Aline da Silva; Santos, Hellen Aparecida Geyer Dos

    2017-03-01

    To evaluate the effects of hypertonic saline solution associated to remote ischemic perconditioning in renal ischemia/reperfusion injury in rats. Twenty five male rats (Wistar) underwent right nephrectomy and were distributed into five groups: Sham group (S); Ischemia/Reperfusion group (I/R) with 30 minutes of renal ischemia; Remote ischemic perconditioning group (Per) with three cycles of 10 minutes of I/R performed during kidney ischemia; Hypertonic saline solution group (HSS) treated with hypertonic saline solution (4ml/kg); remote ischemic perconditioning + Hypertonic saline solution group (Per+HSS) with both treatments. After reperfusion, blood samples were collected for BUN and creatinine serum levels analyzes. TBARS were evaluated in plasma and renal tissue to assess oxidative stress. Kidney histopathological examination were performed. Per+HSS group showed a lower degree of renal dysfunction in relation to I/R group, whereas the technique of remote ischemic perconditioning isolated or associated with saline solution significantly reduced oxidative stress and histological damage. Remote ischemic perconditioning associated or not to saline solution promoted reduction of acute renal injury induced by ischemia/reperfusion.

  9. MicroRNA-24 Antagonism Prevents Renal Ischemia Reperfusion Injury

    PubMed Central

    Lorenzen, Johan M.; Kaucsar, Tamas; Schauerte, Celina; Schmitt, Roland; Rong, Song; Hübner, Anika; Scherf, Kristian; Fiedler, Jan; Martino, Filippo; Kumarswamy, Regalla; Kölling, Malte; Sörensen, Inga; Hinz, Hebke; Heineke, Joerg; van Rooij, Eva; Haller, Hermann

    2014-01-01

    Ischemia-reperfusion (I/R) injury of the kidney is a major cause of AKI. MicroRNAs (miRs) are powerful regulators of various diseases. We investigated the role of apoptosis-associated miR-24 in renal I/R injury. miR-24 was upregulated in the kidney after I/R injury of mice and in patients after kidney transplantation. Cell-sorting experiments revealed a specific miR-24 enrichment in renal endothelial and tubular epithelial cells after I/R induction. In vitro, anoxia/hypoxia induced an enrichment of miR-24 in endothelial and tubular epithelial cells. Transient overexpression of miR-24 alone induced apoptosis and altered functional parameters in these cells, whereas silencing of miR-24 ameliorated apoptotic responses and rescued functional parameters in hypoxic conditions. miR-24 effects were mediated through regulation of H2A histone family, member X, and heme oxygenase 1, which were experimentally validated as direct miR-24 targets through luciferase reporter assays. In vitro, adenoviral overexpression of miR-24 targets lacking miR-24 binding sites along with miR-24 precursors rescued various functional parameters in endothelial and tubular epithelial cells. In vivo, silencing of miR-24 in mice before I/R injury resulted in a significant improvement in survival and kidney function, a reduction of apoptosis, improved histologic tubular epithelial injury, and less infiltration of inflammatory cells. miR-24 also regulated heme oxygenase 1 and H2A histone family, member X, in vivo. Overall, these results indicate miR-24 promotes renal ischemic injury by stimulating apoptosis in endothelial and tubular epithelial cell. Therefore, miR-24 inhibition may be a promising future therapeutic option in the treatment of patients with ischemic AKI. PMID:24854275

  10. 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

  11. [Effects of mycophenolate mofetil in ischemic acute renal failure in rats].

    PubMed

    Chávez-Velásquez, M; Pons, H; Medina, M; Quiroz, Y; Parra, G; Herrera, J

    2007-01-01

    Mycophenolate mofetil (MMF) is a purine synthesis inhibitor commonly used as immunosupresive agent in transplantation. Kidney grafts undergo more or less prolonged cold ischemia after harvesting which results in variable degrees of ischemia reperfusion injury. To determine whether the inhibition of early events of cellular infiltration may influence the severity of damage induced by ischemic acute renal failure, 45 Sprague Dawley rats were given MMF at a dose of 20mg/kg/day (MMF-rats) by gavage 2 days before (pre-MMF group, n=15) or after (post-MMF group, n=15) clamping the left renal artery for 40 minutes followed by rigt-sided nephrectomy. (control group, n=15) received vehicle. Serum Creatinine (Screat) was measured daily in all groups. On the 2nd post-ischemic day Screat was significantly lower (p=0.001) in pre-MMF group compared with post-MMF group and control group (4 +/- 2mg/dl post-MMF group vs 1.7 +/- 1.2 mg/dl pre-MMF group, control group 5+/-2, p< 0.05). Kidney biopsies shown that the histologic damage was 54 +/- 28% in post-MMF group vs 34+/- 22% in pre-MMF group and 61 +/- 25% in control group (pre-MMF vs post-MMF, p NS). On the 5th day post-ischemic, MMF-rats showed more severe tubulointerstitial necrosis (pre-MMF group: 17 +/- 20 %, post-MMF group: 33 +/- 27%) than controls (4 +/- 5%). The severity of ATN was significantly higher in post-MMF group compared with controls (p=0.01). Tubulointersticial T-lymphocyte (T CD 5) and monocyte (ED 1) infiltration evaluated on the 2nd post-ischemic day was less intense in group I (T CD5: 3 +/- 3, ED 1: 10 +/- 9, cel/mm2) compared to post-MMF group (T CD 5: 10 +/- 4, ED 1: 55 +/- 40) and to control group (T CD 5: 10+/- 4, ED 1: 64 +/- 46). However, on the 5th post-ischemia day, ED 1 infiltration was significantly higher in post-MMF group (24 +/- 18%) compared to pre-MMF group (5 +/- 5, p NS) and also in pre-MMF group vs control group (31 +/- 33, p< 0.05). Our results suggest that MMF given before a renal ischemic

  12. Renal Cortical Lactate Dehydrogenase: A Useful, Accurate, Quantitative Marker of In Vivo Tubular Injury and Acute Renal Failure

    PubMed Central

    Zager, Richard A.; Johnson, Ali C. M.; Becker, Kirsten

    2013-01-01

    Studies of experimental acute kidney injury (AKI) are critically dependent on having precise methods for assessing the extent of tubular cell death. However, the most widely used techniques either provide indirect assessments (e.g., BUN, creatinine), suffer from the need for semi-quantitative grading (renal histology), or reflect the status of residual viable, not the number of lost, renal tubular cells (e.g., NGAL content). Lactate dehydrogenase (LDH) release is a highly reliable test for assessing degrees of in vitro cell death. However, its utility as an in vivo AKI marker has not been defined. Towards this end, CD-1 mice were subjected to graded renal ischemia (0, 15, 22, 30, 40, or 60 min) or to nephrotoxic (glycerol; maleate) AKI. Sham operated mice, or mice with AKI in the absence of acute tubular necrosis (ureteral obstruction; endotoxemia), served as negative controls. Renal cortical LDH or NGAL levels were assayed 2 or 24 hrs later. Ischemic, glycerol, and maleate-induced AKI were each associated with striking, steep, inverse correlations (r, −0.89) between renal injury severity and renal LDH content. With severe AKI, >65% LDH declines were observed. Corresponding prompt plasma and urinary LDH increases were observed. These observations, coupled with the maintenance of normal cortical LDH mRNA levels, indicated the renal LDH efflux, not decreased LDH synthesis, caused the falling cortical LDH levels. Renal LDH content was well maintained with sham surgery, ureteral obstruction or endotoxemic AKI. In contrast to LDH, renal cortical NGAL levels did not correlate with AKI severity. In sum, the above results indicate that renal cortical LDH assay is a highly accurate quantitative technique for gauging the extent of experimental acute ischemic and toxic renal injury. That it avoids the limitations of more traditional AKI markers implies great potential utility in experimental studies that require precise quantitation of tubule cell death. PMID:23825563

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

    PubMed

    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.

  14. 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. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Acute kidney injury, hyperbilirubinemia, and ischemic skin necrosis due to massive sulindac overdose.

    PubMed

    Vaughn, John L; Shah, Kejal V; Ghossein, Maroun M; Meyer, William L; Kirkpatrick, Robert B

    2015-01-01

    Sulindac is a long-acting nonsteroidal anti-inflammatory drug (NSAID) widely used for the management of osteoarthritis, rheumatoid arthritis, ankylosing sponydlitis, and acute gouty arthritis. Reports of sulindac toxicity in the literature are rare. We report the case of a 22-year old male with a history of bipolar disorder who was brought to the emergency department after ingesting approximately 15 g of sulindac in a suicide attempt. He was found to have acute kidney injury and hyperbilirubinemia. Despite aggressive fluid resuscitation, his renal function progressively worsened requiring the initiation of hemodialysis. Ten days following ingestion of sulindac, he began to develop ischemic skin changes with a gangrenous appearance in his hands and feet. He continued to receive supportive treatment, and his acute kidney injury, hyperbillirubinemia, and ischemic skin necrosis eventually resolved. Clinicians should be aware of this long-acting NSAID and its ability to cause prolonged multisystem organ dysfunction.

  16. The neuroprotective roles of BDNF in hypoxic ischemic brain injury

    PubMed Central

    CHEN, AI; XIONG, LI-JING; TONG, YU; MAO, MENG

    2013-01-01

    Hypoxia-ischemia (H/I) brain injury results in various degrees of damage to the body, and the immature brain is particularly fragile to oxygen deprivation. Hypothermia and erythropoietin (EPO) have long been known to be neuroprotective in ischemic brain injury. Brain-derived neurotrophic factor (BDNF) has recently been recognized as a potent modulator capable of regulating a wide repertoire of neuronal functions. This review was based on studies concerning the involvement of BDNF in the protection of H/I brain injury following a search in PubMed between 1995 and December, 2011. We initially examined the background of BDNF, and then focused on its neuroprotective mechanisms against ischemic brain injury, including its involvement in promoting neural regeneration/cognition/memory rehabilitation, angiogenesis within ischemic penumbra and the inhibition of the inflammatory process, neurotoxicity, epilepsy and apoptosis. We also provided a literature overview of experimental studies, discussing the safety and the potential clinical application of BDNF as a neuroprotective agent in the ischemic brain injury. PMID:24648914

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

    PubMed

    Grahammer, Florian; Haenisch, Nora; Steinhardt, Frederic; Sandner, Lukas; Sander, 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

    2014-07-08

    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.

  18. 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

  19. 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

  20. A Double Blind Randomized Clinical Trial of Remote Ischemic Conditioning in Live Donor Renal Transplantation.

    PubMed

    Nicholson, Michael L; Pattenden, Clare J; Barlow, Adam D; Hunter, James P; Lee, Gwyn; Hosgood, Sarah A

    2015-08-01

    Ischemic conditioning involves the delivery of short cycles of reversible ischemic injury in order to induce protection against subsequent more prolonged ischemia. This randomized controlled trial was designed to determine the safety and efficacy of remote ischemic conditioning (RC) in live donor kidney transplantation.This prospective randomized clinical trial, 80 patients undergoing live donor kidney transplantation were randomly assigned in a 1:1 ratio to either RC or to a control group. RC consisted of cycles of lower limb ischemia induced by an arterial tourniquet cuff placed around the patient's thigh. In the RC treatment group, the cuff was inflated to 200 mm Hg or systolic pressure +25 mm Hg for 4 cycles of 5 min ischemia followed by 5 min reperfusion. In the control group, the blood pressure cuff was inflated to 25 mm Hg. Patients and medical staff were blinded to treatment allocation. The primary end-point was renal function measured by estimated glomerular filtration rate (eGFR) at 1 and 3 months posttransplant.Donor and recipient demographics were similar in both groups (P < 0.05). There were no significant differences in eGFR at 1 month (control 52 ± 14 vs RC 54 ± 17 mL/min; P = 0.686) or 3 months (control 50 ± 14 vs RC 49 ± 18 mL/min; P = 0.678) between the control and RC treatment groups. The RC technique did not cause any serious adverse effects.RC, using the protocol described here, did not improve renal function after live donor kidney transplantation.

  1. Sex differences in ischemia/reperfusion-induced acute kidney injury are dependent on the renal sympathetic nervous system.

    PubMed

    Tanaka, Ryosuke; Tsutsui, Hidenobu; Ohkita, Mamoru; Takaoka, Masanori; Yukimura, Tokihito; Matsumura, Yasuo

    2013-08-15

    Resistance to ischemic acute kidney injury has been shown to be higher in female rats than in male rats. We found that renal venous norepinephrine overflow after reperfusion played important roles in the development of ischemic acute kidney injury. In the present study, we investigated whether sex differences in the pathogenesis of ischemic acute kidney injury were derived from the renal sympathetic nervous system using male and female Sprague-Dawley rats. Ischemia/reperfusion-induced acute kidney injury was achieved by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function was impaired after reperfusion in both male and female rats; however, renal dysfunction and histological damage were more severe in male rats than in female rats. Renal venous plasma norepinephrine levels after reperfusion were markedly elevated in male rats, but were not in female rats. These sex differences were eliminated by ovariectomy or treatment with tamoxifen, an estrogen receptor antagonist, in female rats. Furthermore, an intravenous injection of hexamethonium (25mg/kg), a ganglionic blocker, 5 min before ischemia suppressed the elevation in renal venous plasma norepinephrine levels after reperfusion, and attenuated renal dysfunction and histological damage in male rats, and ovariectomized and tamoxifen-treated female rats, but not in intact females. Thus, the present findings confirmed sex differences in the pathogenesis of ischemic acute kidney injury, and showed that the attenuation of ischemia/reperfusion-induced acute kidney injury observed in intact female rats may be dependent on depressing the renal sympathetic nervous system with endogenous estrogen.

  2. Targeting MMP-2 to treat ischemic heart injury.

    PubMed

    Hughes, Bryan G; Schulz, Richard

    2014-07-01

    Matrix metalloproteinase (MMPs) are long understood to be involved in remodeling of the extracellular matrix. However, over the past decade, it has become clear that one of the most ubiquitous MMPs, MMP-2, has numerous intracellular targets in cardiac myocytes. Notably, MMP-2 proteolyzes components of the sarcomere, and its intracellular activity contributes to ischemia-reperfusion injury of the heart. Together with the well documented role played by MMPs in the myocardial remodeling that occurs following myocardial infarction, this has led to great interest in targeting MMPs to treat cardiac ischemic injury. In this review we will describe the expanding understanding of intracellular MMP-2 biology, and how this knowledge may lead to improved treatments for ischemic heart injury. We also critically review the numerous preclinical studies investigating the effects of MMP inhibition in animal models of myocardial infarction and ischemia-reperfusion injury, as well as the recent clinical trials that are part of the effort to translate these results into clinical practice. Acknowledging the disappointing results of past clinical trials of MMP inhibitors for other diseases, we discuss the need for carefully designed preclinical and clinical studies to avoid mistakes that have been previously made. We conclude that inhibition of MMPs, and in particular MMP-2, shows promise as a therapy to prevent the progression from ischemic injury to heart failure. However, it is critical that the full breadth of MMP-2 biology be taken into account as such therapies are developed.

  3. Investigation of reperfusion injury and ischemic preconditioning in microsurgery.

    PubMed

    Wang, Wei Zhong

    2009-01-01

    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 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 and preconditioning-induced protection in the fields relevant to microsurgery.

  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. Renal Vein Injury During Percutaneous Nephrolithotomy Procedure.

    PubMed

    Mahmood, Sarwar Noori; Toffeq, Hewa Mahmood

    2016-01-01

    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.

  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. Nitrite-mediated renal vasodilatation is increased during ischemic conditions via cGMP-independent signaling.

    PubMed

    Liu, Ming; Zollbrecht, Christa; Peleli, Maria; Lundberg, Jon O; Weitzberg, Eddie; Carlström, Mattias

    2015-07-01

    The kidney is vulnerable to hypoxia, and substantial efforts have been made to ameliorate renal ischemic injury secondary to pathological conditions. Stimulation of the nitrate-nitrite-nitric oxide pathway is associated with renal and cardiovascular protection in disease models, but less is known about the vascular effects during renal ischemia. This study was aimed at investigating the vascular effects of nitrite in the kidney during normoxic and ischemic conditions. Using a multiwire myograph system, we assessed nitrite-mediated relaxation (10(-9)-10(-4)mol/L) in isolated and preconstricted renal interlobar arteries from C57BL/6 mice under normal conditions (pO2 13kPa; pH 7.4) and with low oxygen tension and low pH to mimic ischemia (pO2 3kPa; pH 6.6). Xanthine oxidoreductase expression was analyzed by quantitative PCR, and production of reactive nitrogen species was measured by DAF-FM DA fluorescence. During normoxia significant vasodilatation (15±3%) was observed only at the highest concentration of nitrite, which was dependent on NO-sGC-cGMP signaling. The vasodilatory responses to nitrite were greatly sensitized and enhanced during hypoxia with low pH, demonstrating significant dilatation (11±1%) already in the physiological range (10(-8)mol/L), with a maximum response of 27±2% at 10(-4) mol/L. In contrast to normoxia, and to that observed with a classical NO donor (DEA NONOate), this sensitization was independent of sGC-cGMP signaling. Moreover, inhibition of various enzymatic systems reported to reduce nitrite in other vascular beds, i.e., aldehyde oxidase (raloxifene), aldehyde dehydrogenase (cyanamide), and NO synthase (L-NAME), had no effect on the nitrite response. However, inhibition of xanthine oxidoreductase (XOR; febuxostat or allopurinol) abolished the sensitized response to nitrite during hypoxia and acidosis. In conclusion, in contrast to normoxia, nitrite exerted potent vasorelaxation during ischemic conditions already at physiological

  9. Renal injury due to hepatic hydatid disease.

    PubMed

    Altay, Mustafa; Unverdi, Selman; Altay, Fatma Aybala; Ceri, Mevlüt; Akay, Hatice; Ozer, Hüseyin; Kiraç, Halil; Denizli, Nazim; Yilmaz, Bilal; Güvence, Necmettin; Duranay, Murat

    2010-08-01

    Many studies on renal hydatid disease have been reported in the literature, and the disease process appears to be well defined. However, renal injury without direct renal invasion remains poorly understood. The present study aims to define the frequency and the property of the renal involvement in hydatid disease. Eighty patients older than 18 years and diagnosed with liver echinococcosis were included in the study. The echinococcosis was diagnosed by the haemagglutination test and abdominal ultrasonography. Twenty-four-hour protein excretion was measured for patients who had elevated serum creatinine levels or whose urinalyses were positive for haematuria or proteinuria. Subsequently, renal biopsy was performed, and the specimens were examined by light microscopy and immunofluorescence staining. Haematuria was detected in 11 patients (13.75%), and proteinuria was detected in nine patients (11.25%). Percutaneous renal biopsy was applied to nine patients who gave signed consents to undergo the test. We detected four immunoglobulin A nephritis (together with tubulointerstitial nephritis in one patient), one membranoproliferative glomerulonephritis, one immunoglobulin M nephritis together with mesangiocapillary glomerulonephritis, one membranous glomerulonephritis, one amyloidosis and one tubulointerstitial nephritis. Renal hydatid cyst was detected only in four patients (5%). Hydatid disease, which affects the kidney, is not rare, and we suggest that urinalysis and, if indicated, renal biopsy should be performed for hepatic hydatid disease diagnosis.

  10. Renal oxygenation in acute renal ischemia-reperfusion injury.

    PubMed

    Abdelkader, Amany; Ho, Julie; Ow, Connie P C; Eppel, Gabriela A; Rajapakse, Niwanthi W; Schlaich, Markus P; Evans, Roger G

    2014-05-01

    Tissue hypoxia has been demonstrated, in both the renal cortex and medulla, during the acute phase of reperfusion after ischemia induced by occlusion of the aorta upstream from the kidney. However, there are also recent clinical observations indicating relatively well preserved oxygenation in the nonfunctional transplanted kidney. To test whether severe acute kidney injury can occur in the absence of widespread renal tissue hypoxia, we measured cortical and inner medullary tissue Po2 as well as total renal O2 delivery (Do2) and O2 consumption (Vo2) during the first 2 h of reperfusion after 60 min of occlusion of the renal artery in anesthetized rats. To perform this experiment, we used a new method for measuring kidney Do2 and Vo2 that relies on implantation of fluorescence optodes in the femoral artery and renal vein. We were unable to detect reductions in renal cortical or inner medullary tissue Po2 during reperfusion after ischemia localized to the kidney. This is likely explained by the observation that Vo2 (-57%) was reduced by at least as much as Do2 (-45%), due to a large reduction in glomerular filtration (-94%). However, localized tissue hypoxia, as evidence by pimonidazole adduct immunohistochemistry, was detected in kidneys subjected to ischemia and reperfusion, particularly in, but not exclusive to, the outer medulla. Thus, cellular hypoxia, particularly in the outer medulla, may still be present during reperfusion even when reductions in tissue Po2 are not detected in the cortex or inner medulla.

  11. 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

  12. Protein methionine oxidation augments reperfusion injury in acute ischemic stroke

    PubMed Central

    Gu, Sean X.; Blokhin, Ilya O.; Wilson, Katina M.; Dhanesha, Nirav; Doddapattar, Prakash; Grumbach, Isabella M.; Chauhan, Anil K.; Lentz, Steven R.

    2016-01-01

    Reperfusion injury can exacerbate tissue damage in ischemic stroke, but little is known about the mechanisms linking ROS to stroke severity. Here, we tested the hypothesis that protein methionine oxidation potentiates NF-κB activation and contributes to cerebral ischemia/reperfusion injury. We found that overexpression of methionine sulfoxide reductase A (MsrA), an antioxidant enzyme that reverses protein methionine oxidation, attenuated ROS-augmented NF-κB activation in endothelial cells, in part, by protecting against the oxidation of methionine residues in the regulatory domain of calcium/calmodulin-dependent protein kinase II (CaMKII). In a murine model, MsrA deficiency resulted in increased NF-κB activation and neutrophil infiltration, larger infarct volumes, and more severe neurological impairment after transient cerebral ischemia/reperfusion injury. This phenotype was prevented by inhibition of NF-κB or CaMKII. MsrA-deficient mice also exhibited enhanced leukocyte rolling and upregulation of E-selectin, an endothelial NF-κB–dependent adhesion molecule known to contribute to neurovascular inflammation in ischemic stroke. Finally, bone marrow transplantation experiments demonstrated that the neuroprotective effect was mediated by MsrA expressed in nonhematopoietic cells. These findings suggest that protein methionine oxidation in nonmyeloid cells is a key mechanism of postischemic oxidative injury mediated by NF-κB activation, leading to neutrophil recruitment and neurovascular inflammation in acute ischemic stroke. PMID:27294204

  13. Renal dysfunction and chronic kidney disease in ischemic stroke and transient ischemic attack: A population-based study.

    PubMed

    Hayden, Derek; McCarthy, Christine; Akijian, Layan; Callaly, Elizabeth; Ní Chróinín, Danielle; Horgan, Gillian; Kyne, Lorraine; Duggan, Joseph; Dolan, Eamon; O' Rourke, Killian; Williams, David; Murphy, Sean; O'Meara, Yvonne; Kelly, Peter J

    2017-10-01

    Background and purpose The prevalence of chronic kidney disease (estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m(2) for ≥3 months, chronic kidney disease (CKD)) in ischemic stroke and transient ischemic attack (TIA) is unknown, as estimates have been based on single-point estimates of renal function. Studies investigating the effect of renal dysfunction (eGFR < 60 mL/min per 1.73 m(2), renal dysfunction) on post-stroke outcomes are limited to hospitalized cohorts and have provided conflicting results. Methods We investigated rates, determinants and outcomes of renal dysfunction in ischemic stroke and TIA in the North Dublin Population Stroke Study. We also investigate the persistence of renal dysfunction in 90-day survivors to determine the prevalence of CKD. Ascertainment included hot and cold pursuit using multiple overlapping sources. Survival analysis was performed using Kaplan-Meier survival curves and Cox proportional hazards modeling. Results In 547 patients (ischemic stroke in 76.4%, TIA in 23.6%), the mean eGFR at presentation was 63.7 mL/min/1.73 m(2) (SD 22.1). Renal dysfunction was observed in 44.6% (244/547). Among 90-day survivors, 31.2% (139/446) met criteria for CKD. After adjusting for age and stroke severity, eGFR < 45 mL/min/1.73 m(2) (hazard ratio 2.53, p = 0.01) independently predicted 28-day fatality but not at two years. Poor post-stroke functional outcome (Modified Rankin Scale 3-5) at two years was more common in those with renal dysfunction (52.5% vs. 20.6%, p < 0.001). After adjusting for age, stroke severity and pre-stroke disability, renal dysfunction (OR 2.17, p = 0.04) predicted poor functional outcome. Conclusion Renal dysfunction and CKD are common in ischemic stroke and TIA. Renal dysfunction is associated with considerable post-stroke morbidity and mortality. Further studies are needed to investigate if modifiable mechanisms underlie these associations.

  14. Loss of matrix metalloproteinase-8 is associated with worsened recovery after ischemic kidney injury.

    PubMed

    Basu, Rajit K; Donaworth, Emily; Siroky, Brian; Devarajan, Prasad; Wong, Hector R

    2015-04-01

    Acute kidney injury (AKI) leads to chronic kidney disease. The mechanisms involved with recovery from AKI are poorly understood and molecular mediators responsible for healing and restoration of kidney function are understudied. We previously discovered differential expression of matrix metalloproteinase-8 (MMP-8) mRNA and protein in patients with severe sepsis associated AKI versus sepsis without AKI. Here, we demonstrate the involvement of MMP-8 in purely ischemic AKI. Mice subjected to 30 min of bilateral renal ischemia developed increased plasma creatinine and MMP-8 expression within 24 h versus sham controls. After an initial surge and subsequent return toward baseline, both kidney MMP-8 expression and activity exhibited a late increase (Days 5-7 post-ischemia reperfusion) in mice subjected to AKI. Neutrophil infiltration of the kidney was significantly higher after AKI in wild-type mice than in MMP-8 null mice, starting at 4 days. Additionally, MMP-8 null mice subjected to AKI demonstrated a persistent histopathologic and functional injury and worsened health (greater overall weight loss) versus wild-type cohorts after seven days. Taken together, our findings suggest that MMP-8 is involved with restoration of baseline kidney health after ischemic kidney injury and that a potential mechanism involves the interaction of MMP-8 and neutrophil recruitment to the site of injury.

  15. 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.

  16. Mechanisms of gender-linked ischemic brain injury

    PubMed Central

    Liu, Mingyue; Dziennis, Suzan; Hurn, Patricia D.; Alkayed, Nabil J.

    2010-01-01

    Biological sex is an important determinant of stroke risk and outcome. Women are protected from cerebrovascular disease relative to men, an observation commonly attributed to the protective effect of female sex hormones, estrogen and progesterone. However, sex differences in brain injury persist well beyond the menopause and can be found in the pediatric population, suggesting that the effects of reproductive steroids may not completely explain sexual dimorphism in stroke. We review recent advances in our understanding of sex steroids (estradiol, progesterone and testosterone) in the context of ischemic cell death and neuroprotection. Understanding the molecular and cell-based mechanisms underlying sex differences in ischemic brain injury will lead to a better understanding of basic mechanisms of brain cell death and is an important step toward designing more effective therapeutic interventions in stroke. PMID:19531872

  17. 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

  18. Oxidant Mechanisms in Renal Injury and Disease.

    PubMed

    Ratliff, Brian B; Abdulmahdi, Wasan; Pawar, Rahul; Wolin, Michael S

    2016-07-20

    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. 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. 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. 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.

  19. 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

  20. MRI patterns of global hypoxic-ischemic injury in adults.

    PubMed

    Muttikkal, Thomas J Eluvathingal; Wintermark, Max

    2013-07-01

    To assess MRI patterns and associated clinical outcome in adults with global hypoxic-ischemic injury. In order to identify the patients with evidence of global hypoxic-ischemic injury, we retrospectively searched our radiology information system for reports of brain MRI studies from 01/01/2004 to 12/31/2010, containing the keywords - "hypoxia", "hypoxic", "anoxia" and "anoxic". A board certified neuroradiologist visually inspected the corresponding MR images for the presence, location and extent (focal versus diffuse) of ischemic findings. Clinical data for these patients was collected from the electronic medical records, including mechanism of the hypoxic-ischemic injury, and clinical outcome was measured using modified Rankin Scale (mRS). Review of radiology reports identified 151 cases, of which 64 patients remained after exclusion of normal studies ("no hypoxia" in the report), pediatric patients and patients with remote perinatal hypoxia. Five patients had relatively favorable clinical outcome (mRS of 1 to 3) and 59 had poor outcome (mRS of 4 to 6). Patterns associated with relatively favorable clinical outcome were: a) watershed pattern and b) basal ganglia without cortical involvement. Patterns associated with poor clinical outcome were: a) diffuse cortical and deep grey matter pattern, with and without perirolandic sparing; (b) medial occipital with perirolandic involvement; c) precentral gyrus involvement; d) diffuse white matter involvement; e) brainstem involvement; f) cerebellar involvement and g) hippocampal involvement. The vast majority of patients with MRI patterns of hypoxic-anoxic injury have a poor clinical outcome, independently of the observed pattern, with the only relative exception being the watershed pattern and the basal ganglia pattern without cortical involvement. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  1. 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.

  2. Serum Iron Protects from Renal Postischemic Injury.

    PubMed

    Vaugier, Céline; Amano, Mariane T; Chemouny, Jonathan M; Dussiot, Michael; Berrou, Claire; Matignon, Marie; Ben Mkaddem, Sanae; Wang, Pamella H M; Fricot, Aurélie; Maciel, Thiago T; Grapton, Damien; Mathieu, Jacques R R; Beaumont, Carole; Peraldi, Marie-Noëlle; Peyssonnaux, Carole; Mesnard, Laurent; Daugas, Eric; Vrtovsnik, François; Monteiro, Renato C; Hermine, Olivier; Ginzburg, Yelena Z; Benhamou, Marc; Camara, Niels O S; Flamant, Martin; Moura, Ivan C

    2017-08-07

    Renal transplants remain a medical challenge, because the parameters governing allograft outcome are incompletely identified. Here, we investigated the role of serum iron in the sterile inflammation that follows kidney ischemia-reperfusion injury. In a retrospective cohort study of renal allograft recipients (n=169), increased baseline levels of serum ferritin reliably predicted a positive outcome for allografts, particularly in elderly patients. In mice, systemic iron overload protected against renal ischemia-reperfusion injury-associated sterile inflammation. Furthermore, chronic iron injection in mice prevented macrophage recruitment after inflammatory stimuli. Macrophages cultured in high-iron conditions had reduced responses to Toll-like receptor-2, -3, and -4 agonists, which associated with decreased reactive oxygen species production, increased nuclear localization of the NRF2 transcription factor, increased expression of the NRF2-related antioxidant response genes, and limited NF-κB and proinflammatory signaling. In macrophage-depleted animals, the infusion of macrophages cultured in high-iron conditions did not reconstitute AKI after ischemia-reperfusion, whereas macrophages cultured in physiologic iron conditions did. These findings identify serum iron as a critical protective factor in renal allograft outcome. Increasing serum iron levels in patients may thus improve prognosis of renal transplants. Copyright © 2017 by the American Society of Nephrology.

  3. Contrast-Enhanced Ultrasound for Assessing Renal Perfusion Impairment and Predicting Acute Kidney Injury to Chronic Kidney Disease Progression.

    PubMed

    Cao, Wei; Cui, Shuang; Yang, Li; Wu, Chunyi; Liu, Jian; Yang, Fang; Liu, Youhua; Bin, Jianping; Hou, Fan Fan

    2017-08-22

    Acute kidney injury (AKI) is increasingly recognized as a major risk factor leading to progression to chronic kidney disease (CKD). However, the diagnostic tools for predicting AKI to CKD progression are particularly lacking. Here, we tested the utility of contrast-enhanced ultrasound (CEUS) for predicting progression to CKD after AKI by using both mild (20-min) and severe (45-min) bilateral renal ischemia-reperfusion injury mice. Renal perfusion measured by CEUS reduced to 25% ± 7% and 14% ± 6% of the pre-ischemic levels in mild and severe AKI 1 h after ischemia (p < 0.05). Renal perfusion returned to pre-ischemic levels 1 day after mild AKI followed by restoration of kidney function. However, severe AKI caused persistent renal perfusion impairment (60% ± 9% of baseline levels) accompanied by progressive renal fibrosis and sustained decrease in renal function. Renal perfusion at days 1-21 significantly correlated with tubulointerstitial fibrosis 42 days after AKI. For predicting renal fibrosis at day 42, the area under the receiver operating characteristics curve of renal perfusion impairment at day 1 was 0.84. Similar changes in the renal image of CEUS were observed in patients with AKI-CKD progression. This study demonstrates that CEUS enables dynamic and noninvasive detection of renal perfusion impairment after ischemic AKI and the perfusion abnormalities shown by CEUS can early predict the progression to CKD after AKI. These results indicate that CEUS enables the evaluation of renal perfusion impairment associated with CKD after ischemic AKI and may serve as a noninvasive technique for assessing AKI-CKD progression. Antioxid. Redox Signal. 00, 000-000.

  4. Macrophage and myofibroblast involvement in ischemic acute renal failure is attenuated by endothelin receptor antagonists.

    PubMed

    Forbes, J M; Leaker, B; Hewitson, T D; Becker, G J; Jones, C L

    1999-01-01

    Endothelin (ET) may be a mediator of injury following ischemia-induced acute renal failure (ARF). ET receptor (ETR) antagonists have been reported to increase survival rates and lower serum creatinines when administered postrenal ischemia-reperfusion injury in the rat. Renal cellular and extracellular matrix responses to this therapy have not been addressed. We investigated the use of ETR antagonists, PD 156707 (ETA) and SB 209670 (ETA and ETB) in the treatment of sublethal postischemic ARF. The right kidney of female Sprague-Dawley rats weighing approximately 200 g was removed. After five days, the left renal pedicle was occluded for 45 minutes. Twenty-four hours after renal ischemia, one of two ETR antagonists, PD 156707 (N = 7) or SB 209670 (N = 8), was administered. Experimental animals were compared with an ischemic group receiving only saline (N = 9). Three nephrectomized groups that did not undergo ischemia but that received infusions of saline (N = 6), PD 156707 (N = 6), and SB 209670 (N = 6), respectively, were also studied. Animals were sacrificed one week postischemia. Quantitation of monocytes and macrophages (Mo/Mphi), alpha-smooth muscle actin-positive myofibroblasts, and collagens type III and IV was performed by immunohistochemical staining. Cell kinetics were examined by staining for apoptosis with terminal deoxyuridine triphosphate (dUTP) nick end labeling and for proliferation with proliferating cell nuclear antigen. All ischemic groups of rats initially developed raised serum creatinine levels; however, no significant difference was observed between the groups (Kruskal-Wallis). Creatinines returned to preischemic values in all groups by the time of sacrifice. No significant difference in kidney weights or body weights was found between groups. Histologically, infiltration of Mo/Mphi was significantly reduced in groups treated with ETR antagonists (P < 0.001). The presence of myofibroblasts was also significantly reduced in the antagonist

  5. Renoprotective Effect of Humic Acid on Renal Ischemia-Reperfusion Injury: An Experimental Study in Rats.

    PubMed

    Akbas, Alpaslan; Silan, Coskun; Gulpinar, Murat Tolga; Sancak, Eyup Burak; Ozkanli, Sidika Seyma; Cakir, Dilek Ulker

    2015-12-01

    Humic acid is an antioxidant molecule used in agriculture and livestock breeding, as well as in medicine. Our aim was to investigate the potential renoprotective effects of humic acid in a renal ischemia reperfusion model. Twenty-one rats were randomly divided into three equal groups. Intraperitoneal serum or humic acid was injected at 1, 12, and 24 h. Non-ischemic group I was evaluated as sham. The left renal artery was clamped in serum (group II) and intraperitoneal humic acid (group III) to subject to left renal ischemic reperfusion procedure. Ischemia and reperfusion time was 60 min for each. Total antioxidant status, total oxidative status, oxidative stress index, and ischemia-modified albumin levels were analyzed biochemically from the serum samples. Kidneys were evaluated histopatologically and immunohistochemically. Biochemical results showed that total oxidative status, ischemia-modified albumin, and oxidative stress index levels were significantly decreased, but total antioxidant status was increased in the humic acid group (III) compared with the ischemia group (II) On histopathological examination, renal tubular dilatation, tubular cell damage and necrosis, dilatation of Bowman's capsule, hyaline casts, and tubular cell spillage were decreased in the humic acid group (III) compared with the ischemia group (II). Immunohistochemical results showed that apoptosis was deteriorated in group III. Renal ischemia reperfusion injury was attenuated by humic acid administration. These observations indicate that humic acid may have a potential therapeutic effect on renal ischemia reperfusion injury by preventing oxidative stress.

  6. ISCHEMIC MODEL OF OPTIC NERVE INJURY

    PubMed Central

    Cioffi, George A

    2005-01-01

    Purpose It is proposed that the anterior optic nerve is specifically susceptible to microcirculatory compromise contributing to the development of glaucomatous optic neuropathy. Methods Ischemic optic neuropathy was induced by delivering endothelin-1 (ET-1) to the retrobulbar space in one eye of 12 primates for 6 to 12 months. Regional ganglion cell axonal sizes and densities were compared with the normal, contralateral eyes. Results Without changes of intraocular pressure, mean axonal density was significantly decreased in ET-1 eyes compared to controls (P = .03, paired t test). Two-way matched-pair analysis of variance showed a significant effect of ET-1 on overall axonal density (P < .0001). Among the animals with significant axonal loss, the mean axonal loss was 11.6%, and loss varied from 4% to 21%. Axonal loss was commonly localized within specific quadrants. Five animals were examined for preferential axonal size loss. As a group, there appears to be a tendency toward preferential large axonal loss, but the mean axonal loss of large and small axons did not meet significant differences (P = .1) However, examination of individual animals with significant loss shows significantly greater loss of large axons as compared to the small axons in three of the animals. Conclusions Chronic optic nerve ischemia causes demonstrable and localized damage of the optic nerve, without intraocular pressure elevation. There is preferential loss of large retinal ganglion cell axons in animals with significant axonal loss. Ischemia-induced focal axonal loss is similar to human glaucoma and may represent a differential regional vulnerability. PMID:17057819

  7. Nicotinamide restores the reduction of parvalbumin in cerebral ischemic injury.

    PubMed

    Koh, Phil-Ok

    2013-02-01

    The aim of this study investigated whether nicotinamide affects parvalbumin expression in focal cerebral ischemic injury. Rats were treated with vehicle or nicotinamide (500 mg/kg) 2 hr after middle cerebral artery occlusion (MCAO), and cerebral cortex tissues were collected 24 hr after MCAO. Nicotinamide significantly decreases the volume of infarct areas in the cerebral cortex. A proteomic approach revealed that MCAO induces decreases of parvalbumin levels, while nicotinamide treatment prevents injury-induced decreases in parvalbumin. RT-PCR and Western blot analyses demonstrated that nicotinamide restores injury-induced decreases in parvalbumin. Moreover, immunohistochemical staining confirmed that the numbers of parvalbumin-positive cells were decreased in vehicle-treated animals with MCAO, and that nicotinamide averted this decrease. In cultured hippocampal cells, nicotinamide treatment prevents the glutamate exposure-induced increase in intracellular Ca(2+) concentration and decrease in parvalbumin expression. These results suggest the fact that the maintenance of parvalbumin expression is mediated to the neuroprotective function of nicotinamide against ischemic brain injury.

  8. Computational Biology: Modeling Chronic Renal Allograft Injury

    PubMed Central

    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. PMID:26284070

  9. NLRP3 inflammasome knockout mice are protected against ischemic but not cisplatin-induced acute kidney injury.

    PubMed

    Kim, Hyun-Jung; Lee, Dong Won; Ravichandran, Kameswaran; O Keys, Daniel; Akcay, Ali; Nguyen, Quocan; He, Zhibin; Jani, Alkesh; Ljubanovic, Danica; Edelstein, Charles L

    2013-09-01

    We have demonstrated that caspase-1 is a mediator of both cisplatin-induced acute kidney injury (AKI) and ischemic AKI. As caspase-1 is activated in the inflammasome, we investigated the inflammasome in cisplatin-induced and ischemic AKI. Mice were injected with cisplatin or subjected to bilateral renal pedicle clamping. Immunoblot analysis of whole kidney after cisplatin-induced AKI revealed: 1) an increase in apoptosis-associated Speck-like protein containing a caspase recruitment domain (ASC), the major protein that complexes with nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing proteins (NLRP) 1 or 3 to form the inflammasome; 2) an increase in caspase-1 activity, caspase-5, and NLRP1, components of the NLRP1 inflammasome; and 3) a trend toward increased NLRP3. To determine whether the NLRP3 inflammasome plays an injurious role in cisplatin-induced AKI, we studied NLRP knockout (NLRP3(-/-)) mice. In cisplatin-induced AKI, the blood urea nitrogen, serum creatinine, acute tubular necrosis score, and tubular apoptosis score were not significantly decreased in NALP3(-/-) mice compared with wild-type mice. We have previously demonstrated the injurious role of caspase-1 in ischemic AKI. NLRP3, but not ASC or NLRP1, is increased in ischemic AKI. NLRP3(-/-) mice with ischemic AKI had significantly lower blood urea nitrogen, serum creatinine, and acute tubular necrosis and apoptosis scores than the wild-type controls. The difference in protection against cisplatin-induced AKI compared with ischemic AKI in NLRP3(-/-) mice was not explained by the differences in proinflammatory cytokines interleukin (IL)-1β, IL-6, chemokine (C-X-C motif) ligand 1, or tumor necrosis factor α. NLRP3 inflammasome is a mediator of ischemic AKI but not cisplatin-induced AKI, and further investigation of the NLRP1 inflammasome in cisplatin-induced AKI should prove interesting.

  10. Remote ischemic conditioning and renal function after contrast-enhanced CT scan: A randomized trial.

    PubMed

    Healy, Donagh A; Feeley, Iain; Keogh, Cillian J; Scanlon, Timothy G; Hodnett, Philip A; Stack, Austin G; Clarke Moloney, Mary; Whittaker, Peter; Walsh, Stewart R

    2015-05-31

    Remote ischemic conditioning has been shown to protect against kidney injury in animal and human studies of ischemia-reperfusion. Recent evidence suggests that conditioning may also provide protection against kidney injury caused by contrast medium. The purpose of this study was to determine if conditioning protected against increases in serum creatinine (SCr) after contrast-enhanced computed tomography (CECT). A randomised controlled trial (NCT 01741896) was performed with institutional review board approval and informed patient consent. Adult in-patients undergoing abdomino-pelvic CECT were allocated to conditioned or control groups. Conditioning consisted of four cycles of five minutes of cuff-induced arm ischemia with three minutes of reperfusion applied ~40 minutes before CECT. The primary outcome was SCr change after CECT. Baseline characteristics were similar in both groups. For all patients, conditioning reduced the risk ratio (RR) of increased SCr; RR 0.65 (95% confidence intervals 0.41 to 1.04). The protective effect was greater and the evidence for protection stronger when analysis was restricted to patients with pre-scan reduced renal function (eGFR.

  11. Influence of ascorbic acid on BUN, creatinine, resistive index in canine renal ischemia-reperfusion injury

    PubMed Central

    Lee, Jae-il; Kim, Myung-jin; Park, Chang-sik

    2006-01-01

    Renal ischemia as a course of renal transplantation is a common cause of renal dysfunction as renal failure. The purpose of this study was to investigate the influence of ascorbic acid on blood urea nitrogen (BUN), creatinine (Cr) and resistive index (RI) for dog models with renal ischemia-reperfusion (I/R) injury. Renal ischemia was induced on 6 Beagle dogs. The left kidney was exposed to normothermic ischemia for a short period at 30 min followed by reperfusion. On the blood Cr level and RI, there was no significant difference comparing both groups. 14 days after I/R injury a significant reduction on the blood BUN level was observed in the vehicle group (34.06 mg/dl) compared to that of ischemia induced treated group (10.3mg/dl) (p < 0.05). In conclusion, administration of ascorbic acid for renal ischemic-reperfusion injury had influence on blood BUN level, but it was not revealed the influence on blood Cr and RI. PMID:16434855

  12. Influence of ascorbic acid on BUN, creatinine, resistive index in canine renal ischemia-reperfusion injury.

    PubMed

    Lee, Jae-il; Kim, Myung-jin; Park, Chang-sik; Kim, Myung-cheol

    2006-03-01

    Renal ischemia as a course of renal transplantation is a common cause of renal dysfunction as renal failure. The purpose of this study was to investigate the influence of ascorbic acid on blood urea nitrogen (BUN), creatinine (Cr) and resistive index (RI) for dog models with renal ischemia-reperfusion (I/R) injury. Renal ischemia was induced on 6 Beagle dogs. The left kidney was exposed to normothermic ischemia for a short period at 30 min followed by reperfusion. On the blood Cr level and RI, there was no significant difference comparing both groups. 14 days after I/R injury a significant reduction on the blood BUN level was observed in the vehicle group (34.06 mg/dl) compared to that of ischemia induced treated group (10.3 mg/dl) (p < 0.05). In conclusion, administration of ascorbic acid for renal ischemic-reperfusion injury had influence on blood BUN level, but it was not revealed the influence on blood Cr and RI.

  13. Remote ischemic preconditioning as treatment for non-ischemic gastrointestinal disorders: Beyond ischemia-reperfusion injury

    PubMed Central

    Camara-Lemarroy, Carlos Rodrigo

    2014-01-01

    Common gastrointestinal diseases such as radiation enteritis (RE), acute pancreatitis, inflammatory bowel diseases (IBD) and drug-induced hepatotoxicity share pathophysiological mechanisms at the molecular level, mostly involving the activation of many pathways of the immune response, ultimately leading to tissue injury. Increased oxidative stress, inflammatory cytokine release, inflammatory cell infiltration and activation and the up-regulation of inflammatory transcription factors participate in the pathophysiology of these complex entities. Treatment varies in each specific disease, but at least in the cases of RE and IBD immunosuppressors are effective. However, full therapeutic responses are not always achieved. The pathophysiology of ischemia-reperfusion (IR) injury shares many of these mechanisms. Brief and repetitive periods of ischemia in an organ or limb have been shown to protect against subsequent major IR injury in distant organs, a phenomenon called remote ischemic preconditioning (RIP). This procedure has been shown to protect the gut, pancreas and liver by modulating many of the same inflammatory mechanisms. Since RIP is safe and tolerable, and has shown to be effective in some recent clinical trials, I suggest that RIP could be used as a physiologically relevant adjunct treatment for non-ischemic gastrointestinal inflammatory conditions. PMID:24707140

  14. The hormone melatonin stimulates renoprotective effects of "early outgrowth" endothelial progenitor cells in acute ischemic kidney injury.

    PubMed

    Patschan, D; Hildebrandt, A; Rinneburger, J; Wessels, J T; Patschan, S; Becker, J U; Henze, E; Krüger, A; Müller, G A

    2012-05-15

    Endothelial progenitor cells (EPCs) protect the kidney from acute ischemic injury. The aim of this study was to analyze whether pretreatment of murine "early outgrowth" EPCs (eEPCs) with the hormone melatonin increases the cells' renoprotective effects in the setting of murine acute ischemic renal failure. Male (8-12 wk old) C57Bl/6N mice were subjected to unilateral ischemia-reperfusion injury postuninephrectomy (40 min). Postischemic animals were injected with either 0.5×10(6) untreated syngeneic murine eEPCs or with cells, pretreated with melatonin for 1 h. Injections were performed shortly after reperfusion of the kidney. While animals injected with untreated cells developed acute renal failure, eEPC pretreatment with melatonin dramatically improved renoprotective actions of the cells. These effects were completely reversed after cell pretreatment with melatonin and the MT-1/-2 antagonist luzindole. In vitro analysis revealed that melatonin reduced the amount of tumor growth factor-β-induced eEPC apoptosis/necrosis. Secretion of vascular endothelial growth factor by the cells was markedly stimulated by the hormone. In addition, migratory activity of eEPCs was enhanced by melatonin and supernatant from melatonin-treated eEPCs stimulated migration of cultured mature endothelial cells. In summary, melatonin was identified as a new agonist of eEPCs in acute ischemic kidney injury.

  15. Heat shock proteins and protection against ischemic injury.

    PubMed Central

    Dillmann, W H

    1999-01-01

    Heat shock proteins present a complex family of proteins exerting chaperone-like activities that are classified according to their molecular weight. We especially explored protective functions of inducible heat shock protein 70, the mitochondrial heat shock protein 60 and 10, and the small heat shock proteins HSP27 and alphaB-crystallin against ischemic, reoxygenation-mediated injury using transgenic animals and hearts under in vivo conditions and in isolated cardiac myocyte-derived cells using adenoviral vectors. We noted with great interest that differential protective effects are exerted by specific hsps. For example, alpha-B-crystallin and constitutive hsp70 markedly protect microtubular structure in cardiac myocytes from ischemia-induced injury. Inducible hsp70, hsp60 and hsp10 when coexpressed, and hsp27 and alphaB-crystallin have an overall protective effect against ischemic injury as determined by the release of enzymes like creatine kinase and LDH. We did not note inflammatory or immune responses elicited by the expression of hsps in transgenic animals and cardiac myocytes. The specific cell types in which hsps are expressed may contribute to the protective effect of hsps versus their inflammatory and immunogenic effects when expressed in other cell types. PMID:10231010

  16. Stem Cells for Ischemic Brain Injury: A Critical Review

    PubMed Central

    Burns, Terry C.; Verfaillie, Catherine M.; Low, Walter C.

    2014-01-01

    No effective therapy is currently available to promote recovery following ischemic stroke. Stem cells have been proposed as a potential source of new cells to replace those lost due to central nervous system injury, as well as a source of trophic molecules to minimize damage and promote recovery. We undertook a detailed review of data from recent basic science and preclinical studies to investigate the potential application of endogenous and exogenous stem cell therapies for treatment of cerebral ischemia. To date, spontaneous endogenous neurogenesis has been observed in response to ischemic injury, and can be enhanced via infusion of appropriate cytokines. Exogenous stem cells from multiple sources can generate neural cells that survive and form synaptic connections after transplantation in the stroke-injured brain. Stem cells from multiple sources cells also exhibit neuroprotective properties that may ameliorate stroke deficits. In many cases, functional benefits observed are likely independent of neural differentiation, though exact mechanisms remain poorly understood. Future studies of neuroregeneration will require the demonstration of function in endogenously born neurons following focal ischemia. Further, methods are currently lacking to definitively demonstrate the therapeutic effect of newly introduced neural cells. Increased plasticity following stroke may facilitate the functional integration of new neurons, but the loss of appropriate guidance cues and supporting architecture in the infarct cavity will likely impede the restoration of lost circuitry. As such careful investigation of the mechanisms underlying trophic benefits will be essential. Evidence to date suggest that continued development of stem cell therapies may ultimately lead to viable treatment options for ischemic brain injury. PMID:19399885

  17. 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

  18. The Role of Ghrelin in Neuroprotection after Ischemic Brain Injury

    PubMed Central

    Spencer, Sarah J.; Miller, Alyson A.; Andrews, Zane B.

    2013-01-01

    Ghrelin, a gastrointestinal peptide with a major role in regulating feeding and metabolism, has recently been investigated for its neuroprotective effects. In this review we discuss pre-clinical evidence suggesting ghrelin may be a useful therapeutic in protecting the brain against injury after ischemic stroke. Specifically, we will discuss evidence showing ghrelin administration can improve neuronal cell survival in animal models of focal cerebral ischemia, as well as rescue memory deficits. We will also discuss its proposed mechanisms of action, including anti-apoptotic and anti-inflammatory effects, and suggest ghrelin treatment may be a useful intervention after stroke in the clinic. PMID:24961317

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

    USDA-ARS?s Scientific Manuscript database

    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...

  20. RAGE does not contribute to renal injury and damage upon ischemia/reperfusion-induced injury.

    PubMed

    Dessing, Mark C; Pulskens, Wilco P; Teske, Gwendoline J; Butter, Loes M; van der Poll, Tom; Yang, Huan; Tracey, Kevin J; Nawroth, Peter P; Bierhaus, Angelika; Florquin, Sandrine; Leemans, Jaklien C

    2012-01-01

    The receptor for advanced glycation end products (RAGE) mediates a variety of inflammatory responses in renal diseases, but its role in renal ischemia/reperfusion (I/R) injury is unknown. We showed that during renal I/R, RAGE ligands HMGB1 and S100B are expressed. However, RAGE deficiency does not affect renal injury and function upon I/R-induced injury. Copyright © 2011 S. Karger AG, Basel.

  1. Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke.

    PubMed

    Hu, Xiaoming; De Silva, T Michael; Chen, Jun; Faraci, Frank M

    2017-02-03

    The consequences of cerebrovascular disease are among the leading health issues worldwide. Large and small cerebral vessel disease can trigger stroke and contribute to the vascular component of other forms of neurological dysfunction and degeneration. Both forms of vascular disease are driven by diverse risk factors, with hypertension as the leading contributor. Despite the importance of neurovascular disease and subsequent injury after ischemic events, fundamental knowledge in these areas lag behind our current understanding of neuroprotection and vascular biology in general. The goal of this review is to address select key structural and functional changes in the vasculature that promote hypoperfusion and ischemia, while also affecting the extent of injury and effectiveness of therapy. In addition, as damage to the blood-brain barrier is one of the major consequences of ischemia, we discuss cellular and molecular mechanisms underlying ischemia-induced changes in blood-brain barrier integrity and function, including alterations in endothelial cells and the contribution of pericytes, immune cells, and matrix metalloproteinases. Identification of cell types, pathways, and molecules that control vascular changes before and after ischemia may result in novel approaches to slow the progression of cerebrovascular disease and lessen both the frequency and impact of ischemic events.

  2. Rosiglitazone attenuates renal injury caused by hyperlipidemic pancreatitis

    PubMed Central

    Wang, Rui; Yan, Zhaopeng; Wu, Xingmao; Ji, Kaiqiang; Wang, Haiyuan; Zang, Bin

    2015-01-01

    Hyperlipidemic pancreatitis (HP) is a serious inflammatory disease with very high mortality and multiple organ injuries including renal injury. Rosiglitazone (Ros), an agonist of peroxisome proliferator activated receptor-γ (PPAR-γ), was reported to show a protective role against pancreatitis. However, whether Ros has an effect on renal injury caused by HP is not yet clear. In the present study, the function of Ros was explored using ELISA, RT-PCR, western blot, PAS staining and immunohistochemistry. Results of this study showed that Ros could inhibit the activation of NF-κB and MAPK P38 signaling pathways, relieve inflammatory response and inhibit cell apoptosis, thus attenuating renal injury caused by HP. This study suggested that Ros might be a promising drug for the treatment of renal injury caused by HP and also laid theoretical foundation for the development of renal injury treatment. PMID:26191125

  3. Role of renal oxygenation and mitochondrial function in the pathophysiology of acute kidney injury.

    PubMed

    Nourbakhsh, Noureddin; Singh, Prabhleen

    2014-01-01

    There are unique features of renal oxygenation that render the kidney susceptible to oxygen demand-supply mismatch and hypoxia. Renal oxygen consumption by oxidative metabolism is closely coupled to and driven by tubular transport, which is linked to the filtered solute load and glomerular filtration rate (GFR). In turn, filtered solute load and GFR are dependent on the renal blood flow. Hence, changes in renal blood flow increase oxygen delivery but also increase oxygen demand (consumption) simultaneously by increasing the tubular workload of solute transport. The renal blood flow to different regions of kidney is also inhomogeneous, increasing the oxygen demand-supply mismatch in particular areas such as the outer medulla which become more susceptible to injury. Thus, tubular transport and oxidative metabolism by miochondria are closely coupled in the kidney and are the principal determinants of intrarenal oxygenation. Here we review the published literature characterizing renal oxygenation and mitochondrial function in ischemic and sepsis-associated acute kidney injury (AKI). However, the coupling of transport and metabolism in AKI has not been examined. This is a potentially fruitful area of research that should become increasingly active given the emerging data linking renal oxygenation and hypoxia to acute and chronic dysfunction in the kidney. 2014 S. Karger AG, Basel.

  4. 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

  5. A practical approach to remote ischemic preconditioning and ischemic preconditioning against myocardial ischemia/reperfusion injury

    PubMed Central

    Totzeck, Matthias; Hendgen-Cotta, Ulrike B.; French, Brent A.; Rassaf, Tienush

    2016-01-01

    Although urgently needed in clinical practice, a cardioprotective therapeutic approach against myocardial ischemia/ reperfusion injury remains to be established. Remote ischemic preconditioning (rIPC) and ischemic preconditioning (IPC) represent promising tools comprising three entities: the generation of a protective signal, the transfer of the signal to the target organ, and the response to the transferred signal resulting in cardioprotection. However, in light of recent scientific advances, many controversies arise regarding the efficacy of the underlying signaling. We here show methods for the generation of the signaling cascade by rIPC as well as IPC in a mouse model for in vivo myocardial ischemia/ reperfusion injury using highly reproducible approaches. This is accomplished by taking advantage of easily applicable preconditioning strategies compatible with the clinical setting. We describe methods for using laser Doppler perfusion imaging to monitor the cessation and recovery of perfusion in real time. The effects of preconditioning on cardiac function can also be assessed using ultrasound or magnetic resonance imaging approaches. On a cellular level, we confirm how tissue injury can be monitored using histological assessment of infarct size in conjunction with immunohistochemistry to assess both aspects in a single specimen. Finally, we outline, how the rIPC-associated signaling can be transferred to the target cell via conservation of the signal in the humoral (blood) compartment. This compilation of experimental protocols including a conditioning regimen comparable to the clinical setting should proof useful to both beginners and experts in the field of myocardial infarction, supplying information for the detailed procedures as well as troubleshooting guides. PMID:28066791

  6. The Role of Cell Swelling in Ischemic Renal Damage and the Protective Effect of Hypertonic Solute

    PubMed Central

    Flores, Jorge; DiBona, Donald R.; Beck, Clyde H.; Leaf, Alexander

    1972-01-01

    The failure of blood flow to return to the kidney following a transient period of ischemia has long been recognized. The cause of this “no-reflow” has been investigated in the rat after a transient period of total obstruction of the renal arteries. The vascular pattern of the kidneys as visualized with silicone rubber injection shows a diffuse patchy ischemia throughout the kidney, which persists after release of the obstructed renal artery. Electron microscopic studies of ischemic kidneys showed that all cellular elements were swollen and limiting the available vascular space. Functional studies revealed an increase in plasma urea nitrogen and creatinine after 1 hr or longer ischemic periods. The ischemia, cell swelling, “no-reflow,” and subsequent renal dysfunction occurring after obstruction to the renal arteries were corrected by the administration of hypertonic mannitol, but were unaffected by an equivalent expansion of the extracellular fluid volume either with isotonic saline or isotonic mannitol, showing that the osmotic effect was primary. The hypothesis is presented that ischemic swelling of cells may occlude small blood vessels so that recirculation does not resume even after the initial cause of the ischemia is no longer present; solutes which do not penetrate cell membranes are able to shrink swollen cells, increase the available vascular space and thus permit reflow of blood to the ischemic organ. Images PMID:5007042

  7. The role of cell swelling in ischemic renal damage and the protective effect of hypertonic solute.

    PubMed

    Flores, J; DiBona, D R; Beck, C H; Leaf, A

    1972-01-01

    The failure of blood flow to return to the kidney following a transient period of ischemia has long been recognized. The cause of this "no-reflow" has been investigated in the rat after a transient period of total obstruction of the renal arteries. The vascular pattern of the kidneys as visualized with silicone rubber injection shows a diffuse patchy ischemia throughout the kidney, which persists after release of the obstructed renal artery. Electron microscopic studies of ischemic kidneys showed that all cellular elements were swollen and limiting the available vascular space. Functional studies revealed an increase in plasma urea nitrogen and creatinine after 1 hr or longer ischemic periods. The ischemia, cell swelling, "no-reflow," and subsequent renal dysfunction occurring after obstruction to the renal arteries were corrected by the administration of hypertonic mannitol, but were unaffected by an equivalent expansion of the extracellular fluid volume either with isotonic saline or isotonic mannitol, showing that the osmotic effect was primary. The hypothesis is presented that ischemic swelling of cells may occlude small blood vessels so that recirculation does not resume even after the initial cause of the ischemia is no longer present; solutes which do not penetrate cell membranes are able to shrink swollen cells, increase the available vascular space and thus permit reflow of blood to the ischemic organ.

  8. Neuroprotective Therapies after Perinatal Hypoxic-Ischemic Brain Injury

    PubMed Central

    de Cerio, Felipe Goñi; Lara-Celador, Idoia; Alvarez, Antonia; Hilario, Enrique

    2013-01-01

    Hypoxic-ischemic (HI) brain injury is one of the main causes of disabilities in term-born infants. It is the result of a deprivation of oxygen and glucose in the neural tissue. As one of the most important causes of brain damage in the newborn period, the neonatal HI event is a devastating condition that can lead to long-term neurological deficits or even death. The pattern of this injury occurs in two phases, the first one is a primary energy failure related to the HI event and the second phase is an energy failure that takes place some hours later. Injuries that occur in response to these events are often manifested as severe cognitive and motor disturbances over time. Due to difficulties regarding the early diagnosis and treatment of HI injury, there is an increasing need to find effective therapies as new opportunities for the reduction of brain damage and its long term effects. Some of these therapies are focused on prevention of the production of reactive oxygen species, anti-inflammatory effects, anti-apoptotic interventions and in a later stage, the stimulation of neurotrophic properties in the neonatal brain which could be targeted to promote neuronal and oligodendrocyte regeneration. PMID:24961314

  9. Neuroprotective therapies after perinatal hypoxic-ischemic brain injury.

    PubMed

    Cerio, Felipe Goñi de; Lara-Celador, Idoia; Alvarez, Antonia; Hilario, Enrique

    2013-03-05

    Hypoxic-ischemic (HI) brain injury is one of the main causes of disabilities in term-born infants. It is the result of a deprivation of oxygen and glucose in the neural tissue. As one of the most important causes of brain damage in the newborn period, the neonatal HI event is a devastating condition that can lead to long-term neurological deficits or even death. The pattern of this injury occurs in two phases, the first one is a primary energy failure related to the HI event and the second phase is an energy failure that takes place some hours later. Injuries that occur in response to these events are often manifested as severe cognitive and motor disturbances over time. Due to difficulties regarding the early diagnosis and treatment of HI injury, there is an increasing need to find effective therapies as new opportunities for the reduction of brain damage and its long term effects. Some of these therapies are focused on prevention of the production of reactive oxygen species, anti-inflammatory effects, anti-apoptotic interventions and in a later stage, the stimulation of neurotrophic properties in the neonatal brain which could be targeted to promote neuronal and oligodendrocyte regeneration.

  10. Nitroxyl exacerbates ischemic cerebral injury and oxidative neurotoxicity.

    PubMed

    Choe, Chi-un; Lewerenz, Jan; Fischer, Gerry; Uliasz, Tracy F; Espey, Michael Graham; Hummel, Friedhelm C; King, Stephen Bruce; Schwedhelm, Edzard; Böger, Rainer H; Gerloff, Christian; Hewett, Sandra J; Magnus, Tim; Donzelli, Sonia

    2009-09-01

    Nitroxyl (HNO) donor compounds function as potent vasorelaxants, improve myocardial contractility and reduce ischemia-reperfusion injury in the cardiovascular system. With respect to the nervous system, HNO donors have been shown to attenuate NMDA receptor activity and neuronal injury, suggesting that its production may be protective against cerebral ischemic damage. Hence, we studied the effect of the classical HNO-donor, Angeli's salt (AS), on a cerebral ischemia/reperfusion injury in a mouse model of experimental stroke and on related in vitro paradigms of neurotoxicity. I.p. injection of AS (40 mumol/kg) in mice prior to middle cerebral artery occlusion exacerbated cortical infarct size and worsened the persistent neurological deficit. AS not only decreased systolic blood pressure, but also induced systemic oxidative stress in vivo indicated by increased isoprostane levels in urine and serum. In vitro, neuronal damage induced by oxygen-glucose-deprivation of mature neuronal cultures was exacerbated by AS, although there was no direct effect on glutamate excitotoxicity. Finally, AS exacerbated oxidative glutamate toxicity - that is, cell death propagated via oxidative stress in immature neurons devoid of ionotropic glutamate receptors. Taken together, our data indicate that HNO might worsen cerebral ischemia-reperfusion injury by increasing oxidative stress and decreasing brain perfusion at concentrations shown to be cardioprotective in vivo.

  11. Macrophages mediate lung inflammation in a mouse model of ischemic acute kidney injury

    PubMed Central

    Altmann, Christopher; Andres-Hernando, Ana; McMahan, Rachel H.; Ahuja, Nilesh; He, Zhibin; Rivard, Chris J.; Edelstein, Charles Louis; Barthel, Lea; Janssen, William J.

    2012-01-01

    Serum IL-6 is increased in acute kidney injury (AKI) and inhibition of IL-6 reduces AKI-mediated lung inflammation. We hypothesized that circulating monocytes produce IL-6 and that alveolar macrophages mediate lung inflammation after AKI via chemokine (CXCL1) production. To investigate systemic and alveolar macrophages in lung injury after AKI, sham operation or 22 min of renal pedicle clamping (AKI) was performed in three experimental settings: 1) systemic macrophage depletion via diphtheria toxin (DT) injection to CD11b-DTR transgenic mice, 2) DT injection to wild-type mice, and 3) alveolar macrophage depletion via intratracheal (IT) liposome-encapsulated clodronate (LEC) administration to wild-type mice. In mice with AKI and systemic macrophage depletion (CD11b-DTR transgenic administered DT) vs. vehicle-treated AKI, blood monocytes and lung interstitial macrophages were reduced, renal function was similar, serum IL-6 was increased, lung inflammation was improved, lung CXCL1 was reduced, and lung capillary leak was increased. In wild-type mice with AKI administered DT vs. vehicle, serum IL-6 was increased. In mice with AKI and alveolar macrophage depletion (IT-LEC) vs. AKI with normal alveolar macrophage content, blood monocytes and lung interstitial macrophages were similar, alveolar macrophages were reduced, renal function was similar, lung inflammation was improved, lung CXCL1 was reduced, and lung capillary leak was increased. In conclusion, administration of DT in AKI is proinflammatory, limiting the use of the DTR-transgenic model to study systemic effects of AKI. Mice with AKI and either systemic mononuclear phagocyte depletion or alveolar macrophage depletion had reduced lung inflammation and lung CXCL1, but increased lung capillary leak; thus, mononuclear phagocytes mediate lung inflammation, but they protect against lung capillary leak after ischemic AKI. Since macrophage activation and chemokine production are key events in the development of acute

  12. Elevated Plasma Homocysteine Level Increased the Risk of Early Renal Impairment in Acute Ischemic Stroke Patients.

    PubMed

    Chen, Jingjuan; Li, Guode; Xu, Zuohang; Zhang, Chengguo; Wang, Yukai; Xie, Haiqun; Shao, Yan; Peng, Lingmei; Lu, Jiancong; Yuan, Dahua

    2017-03-08

    Renal insufficiency is associated with the prognosis of acute ischemic stroke (AIS) and homocysteine (Hcy) levels. This study investigated the association between plasma Hcy levels and renal insufficiency in patients with AIS. A total of 987 patients with AIS who had been treated at the First People's Hospital of Foshan between 2011 and 2014 were retrospectively studied. Based on their cystatin C (Cys C) levels, the patients were divided into the normal renal function group (Cys C ≤ 1.25 mg/L) or the renal impairment group (Cys C > 1.25 mg/L). Multivariate regression analysis was applied to reveal the association between hyperhomocysteinemia (HHcy) and renal impairment. The renal impairment group showed more advanced age of onset, higher percentage of prior stroke and hypertension, higher baseline National Institute of Health Stroke Scale score, lower high-density lipoprotein cholesterol levels, and higher Hcy levels compared with the normal renal function group. A multivariate analysis revealed a relationship between early renal impairment and Hcy levels: an increase of Hcy by 1 μmol/L was associated with an increase of 12-18% of the risk of renal impairment among patients with AIS and HHcy. Patients with AIS and HHcy had a 2.42-3.51 fold increase of the risk of renal impairment compared with patients with normal Hcy level (P < 0.001). In conclusion, patients with stroke and HHcy could be more prone to renal impairment.

  13. Remote ischemic preconditioning does not affect the incidence of acute kidney injury after elective abdominal aortic aneurysm repair.

    PubMed

    Murphy, Noelle; Vijayan, Ajith; Frohlich, Stephen; O'Farrell, Frank; Barry, Mary; Sheehan, Stephen; Boylan, John; Conlon, Niamh

    2014-10-01

    Open abdominal aortic aneurysm (AAA) repair is associated with a high risk of renal injury with few known strategies demonstrating a reduction in this risk. Remote ischemic preconditioning (RIPC) has been identified as having the potential to minimize organ injury following major vascular surgery. This trial investigated the potential for RIPC to attenuate renal and myocardial injury in patients undergoing elective open AAA repair. Prospective, randomized double-blinded control trial. Tertiary referral hospital. Sixty-two patients undergoing elective open AAA repair. RIPC was achieved via three 5-minute cycles of upper limb ischemia using a blood pressure cuff or control (sham cuff). Primary outcome was the occurrence of renal injury, as measured by an increase in creatinine during the first 4 postoperative days. Secondary outcomes included urinary neutrophil-gelatinase-associated lipocalin (NGAL), occurrence of acute kidney injury (AKI), occurrence of myocardial injury as defined by troponin rise, incidence of postoperative complications, and mortality. There was no difference in postoperative creatinine levels, NGAL levels, or the occurrence of AKI between the groups at any postoperative time point. Similarly, there was no difference in the occurrence of myocardial injury or mortality. Of note, 6 patients in the RIPC group, while no patient in the control group, experienced postoperative complications that required repeat surgical laparotomy, potentially masking any renoprotective effects of RIPC. RIPC did not reduce the risk of postoperative renal failure or myocardial injury in patients undergoing open AAA repair. The authors' results do not support the introduction of this technique to routine clinical practice. Copyright © 2014 Elsevier Inc. All rights reserved.

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

    PubMed

    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

    2016-10-14

    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.

  15. [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.

  16. 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.

  17. Automatic quantification of ischemic injury on diffusion-weighted MRI of neonatal hypoxic ischemic encephalopathy.

    PubMed

    Murphy, Keelin; van der Aa, Niek E; Negro, Simona; Groenendaal, Floris; de Vries, Linda S; Viergever, Max A; Boylan, Geraldine B; Benders, Manon J N L; Išgum, Ivana

    2017-01-01

    A fully automatic method for detection and quantification of ischemic lesions in diffusion-weighted MR images of neonatal hypoxic ischemic encephalopathy (HIE) is presented. Ischemic lesions are manually segmented by two independent observers in 1.5 T data from 20 subjects and an automatic algorithm using a random forest classifier is developed and trained on the annotations of observer 1. The algorithm obtains a median sensitivity and specificity of 0.72 and 0.99 respectively. F1-scores are calculated per subject for algorithm performance (median = 0.52) and observer 2 performance (median = 0.56). A paired t-test on the F1-scores shows no statistical difference between the algorithm and observer 2 performances. The method is applied to a larger dataset including 54 additional subjects scanned at both 1.5 T and 3.0 T. The algorithm findings are shown to correspond well with the injury pattern noted by clinicians in both 1.5 T and 3.0 T data and to have a strong relationship with outcome. The results of the automatic method are condensed to a single score for each subject which has significant correlation with an MR score assigned by experienced clinicians (p < 0.0001). This work represents a quantitative method of evaluating diffusion-weighted MR images in neonatal HIE and a first step in the development of an automatic system for more in-depth analysis and prognostication.

  18. Management of high-grade renal injury in children.

    PubMed

    Okur, M H; Arslan, S; Aydogdu, B; Arslan, M S; Goya, C; Zeytun, H; Basuguy, E; Uygun, I; Çigdem, M K; Önen, A; Otcu, S

    2017-02-01

    The management of severe renal trauma is disputable. Herein, we present diagnosis and treatment of patients with high-grade renal injury (grades IV and V). The records of 31 patients with severe renal trauma who were treated between 2009 and 2014 were analyzed retrospectively. All patients' CT results were evaluated by two radiologists and assigned grades of IV or V in accordance with the American Association for the Surgery of Trauma Organ Injury Severity Scale. All hemodynamically stable renal trauma patients were treated conservatively. Patients with renal traumas of grade IV and V were evaluated statistically via the SPSS 15.0 software program. Chi-square and Mann-Whitney U tests were used to evaluate the categorical data. Thirteen (42 %) of 31 patients had grade IV, and 18 (58 %) had grade V renal traumas. Twenty-seven (87 %) of the patients had suffered blunt trauma, and four (13 %) had sustained penetrating injuries. Additional organ injuries were seen in 16 patients (52 %), and 15 (48 %) had no concurrent injuries. Twenty-five patients (89 %) were monitored conservatively, three (10 %) underwent surgery, and three patients with grade V renal trauma and additional organ injuries died. There was no statistically significant difference between the grade IV and grade V groups, except in hemoglobin values and the affected kidney (P = 0.07 and P = 0.02, respectively). Computerized tomography can help to grade renal injury and assess additional organ injuries quickly. Most children with high-grade renal injury can be managed conservatively. However, conservative management of renal traumas relies on a multidisciplinary approach. Additionally, surgical intervention is generally required in the face of hemodynamic instability or other concurrent organ injuries.

  19. 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

  20. Toll-Like Receptor-4 Coordinates the Innate Immune Response of the Kidney to Renal Ischemia/Reperfusion Injury

    PubMed Central

    Pulskens, Wilco P.; Teske, Gwendoline J.; Butter, Loes M.; Roelofs, Joris J.; van der Poll, Tom; Florquin, Sandrine; Leemans, Jaklien C.

    2008-01-01

    Toll-like receptors (TLRs) can detect endogenous danger molecules released upon tissue injury resulting in the induction of a proinflammatory response. One of the TLR family members, TLR4, is constitutively expressed at RNA level on renal epithelium and this expression is enhanced upon renal ischemia/reperfusion (I/R) injury. The functional relevance of this organ-specific upregulation remains however unknown. We therefore investigated the specific role of TLR4 and the relative contribution of its two downstream signaling cascades, the MyD88-dependent and TRIF-dependent cascades in renal damage by using TLR4−/−, MyD88−/− and TRIF-mutant mice that were subjected to renal ischemia/reperfusion injury. Our results show that TLR4 initiates an exaggerated proinflammatory response upon I/R injury, as reflected by lower levels of chemokines and infiltrating granulocytes, less renal damage and a more preserved renal function in TLR4−/− mice as compared to wild type mice. In vitro studies demonstrate that renal tubular epithelial cells can coordinate an immune response to ischemic injury in a TLR4-dependent manner. In vivo we found that epithelial- and leukocyte-associated functional TLR4 contribute in a similar proportion to renal dysfunction and injury as assessed by bone marrow chimeric mice. Surprisingly, no significant differences were found in renal function and inflammation in MyD88−/− and TRIF-mutant mice compared with their wild types, suggesting that selective targeting of TLR4 directly may be more effective for the development of therapeutic tools to prevent I/R injury than targeting the intracellular pathways used by TLR4. In conclusion, we identified TLR4 as a cellular sentinel for acute renal damage that subsequently controls the induction of an innate immune response. PMID:18974879

  1. Fructokinase activity mediates dehydration-induced renal injury.

    PubMed

    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

    2014-08-01

    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.

  2. Forebrain neurogenesis after focal Ischemic and traumatic brain injury.

    PubMed

    Kernie, Steven G; Parent, Jack M

    2010-02-01

    Neural stem cells persist in the adult mammalian forebrain and are a potential source of neurons for repair after brain injury. The two main areas of persistent neurogenesis, the subventricular zone (SVZ)-olfactory bulb pathway and hippocampal dentate gyrus, are stimulated by brain insults such as stroke or trauma. Here we focus on the effects of focal cerebral ischemia on SVZ neural progenitor cells in experimental stroke, and the influence of mechanical injury on adult hippocampal neurogenesis in models of traumatic brain injury (TBI). Stroke potently stimulates forebrain SVZ cell proliferation and neurogenesis. SVZ neuroblasts are induced to migrate to the injured striatum, and to a lesser extent to the peri-infarct cortex. Controversy exists as to the types of neurons that are generated in the injured striatum, and whether adult-born neurons contribute to functional restoration remains uncertain. Advances in understanding the regulation of SVZ neurogenesis in general, and stroke-induced neurogenesis in particular, may lead to improved integration and survival of adult-born neurons at sites of injury. Dentate gyrus cell proliferation and neurogenesis similarly increase after experimental TBI. However, pre-existing neuroblasts in the dentate gyrus are vulnerable to traumatic insults, which appear to stimulate neural stem cells in the SGZ to proliferate and replace them, leading to increased numbers of new granule cells. Interventions that stimulate hippocampal neurogenesis appear to improve cognitive recovery after experimental TBI. Transgenic methods to conditionally label or ablate neural stem cells are beginning to further address critical questions regarding underlying mechanisms and functional significance of neurogenesis after stroke or TBI. Future therapies should be aimed at directing appropriate neuronal replacement after ischemic or traumatic injury while suppressing aberrant integration that may contribute to co-morbidities such as epilepsy or

  3. Ceftriaxone attenuates hypoxic-ischemic brain injury in neonatal rats

    PubMed Central

    2011-01-01

    Background Perinatal brain injury is the leading cause of subsequent neurological disability in both term and preterm baby. Glutamate excitotoxicity is one of the major factors involved in perinatal hypoxic-ischemic encephalopathy (HIE). Glutamate transporter GLT1, expressed mainly in mature astrocytes, is the major glutamate transporter in the brain. HIE induced excessive glutamate release which is not reuptaked by immature astrocytes may induce neuronal damage. Compounds, such as ceftriaxone, that enhance the expression of GLT1 may exert neuroprotective effect in HIE. Methods We used a neonatal rat model of HIE by unilateral ligation of carotid artery and subsequent exposure to 8% oxygen for 2 hrs on postnatal day 7 (P7) rats. Neonatal rats were administered three dosages of an antibiotic, ceftriaxone, 48 hrs prior to experimental HIE. Neurobehavioral tests of treated rats were assessed. Brain sections from P14 rats were examined with Nissl and immunohistochemical stain, and TUNEL assay. GLT1 protein expression was evaluated by Western blot and immunohistochemistry. Results Pre-treatment with 200 mg/kg ceftriaxone significantly reduced the brain injury scores and apoptotic cells in the hippocampus, restored myelination in the external capsule of P14 rats, and improved the hypoxia-ischemia induced learning and memory deficit of P23-24 rats. GLT1 expression was observed in the cortical neurons of ceftriaxone treated rats. Conclusion These results suggest that pre-treatment of infants at risk for HIE with ceftriaxone may reduce subsequent brain injury. PMID:21933448

  4. Ischemic Stroke Injury Is Mediated by Aberrant Cdk5

    PubMed Central

    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.

    2014-01-01

    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. PMID:24920629

  5. Renal Dysfunction and Thrombolytic Therapy in Patients With Acute Ischemic Stroke

    PubMed Central

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

    2014-01-01

    Abstract 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; I2 = 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; I2 = 70.3). No association was observed between symptomatic ICH (OR = 1.02; 95% CI: 0.94–1.10; I2 = 0) and any ICH (OR = 1.07; 95% CI: 0.96–1.18; I2 = 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

  6. Should blunt segmental vascular renal injuries be considered an American Association for the Surgery of Trauma Grade 4 renal injury?

    PubMed

    Malaeb, Bahaa; Figler, Brad; Wessells, Hunter; Voelzke, Bryan B

    2014-02-01

    Renal segmental vascular injury (SVI) following blunt abdominal trauma is not part of the original American Association for the Surgery of Trauma (AAST) renal injury grading system. Recent recommendations support classifying SVI as an AAST Grade 4 (G4) injury. Our primary aim was to compare outcomes following blunt renal SVI and blunt renal collecting system lacerations (CSLs). We hypothesize that renal SVI fare well with conservative management alone and should be relegated a less severe renal AAST grade. We retrospectively identified patients with SVI and G4 CSL admitted to a Level 1 trauma center between 2003 and 2010. Penetrating trauma was excluded. Need for surgical intervention, length of stay, kidney salvage (>25% renal preservation on renography 6-12 weeks after injury), and delayed complication rates were compared between the SVI and CSL injuries. Statistical analysis used χ, Fisher's exact, and t tests. A total of 56 patients with SVI and 88 patients with G4 CSL sustained blunt trauma. Age, Injury Severity Score (ISS), and length of stay were similar for the two groups. Five patients in each group died of concomitant, nonrenal injuries. In the G4 CSL group, 15 patients underwent major interventions, and 32 patients underwent minor interventions. Only one patient in the SVI group underwent a major intervention. The renal salvage rate was 85.7% following SVI versus 62.5% following CSL (p = 0.107). Overall, surgical interventions are significantly lower among the SVI cohort than the G4 CSL cohort. Further analysis using a larger cohort of patients is recommended before revising the current renal grading system. Adding SVI as a G4 injury could potentially increase the heterogeneity of G4 injuries and decrease the ability of the AAST renal injury grading system to predict outcomes, such as nephrectomy rate. Epidemiologic study, level IV.

  7. Proteome analysis of acute kidney injury - Discovery of new predominantly renal candidates for biomarker of kidney disease.

    PubMed

    Malagrino, Pamella Araujo; Venturini, Gabriela; Yogi, Patrícia Schneider; Dariolli, Rafael; Padilha, Kallyandra; Kiers, Bianca; Gois, Tamiris Carneiro; Cardozo, Karina Helena Morais; Carvalho, Valdemir Melechco; Salgueiro, Jéssica Silva; Girardi, Adriana Castello Costa; Titan, Silvia Maria de Oliveira; Krieger, José Eduardo; Pereira, Alexandre Costa

    2017-01-16

    The main bottleneck in studies aiming to identify novel biomarkers in acute kidney injury (AKI) has been the identification of markers that are organ and process specific. Here, we have used different tissues from a controlled porcine renal ischemia/reperfusion (I/R) model to identify new, predominantly renal biomarker candidates for kidney disease. Urine and serum samples were analyzed in pre-ischemia, ischemia (60min) and 4, 11 and 16h post-reperfusion, and renal cortex samples after 24h of reperfusion. Peptides were analyzed on the Q-Exactive™. In renal cortex proteome, we observed an increase in the synthesis of proteins in the ischemic kidney compared to the contralateral, highlighted by transcription factors and epithelial adherens junction proteins. Intersecting the set of proteins up- or down-regulated in the ischemic tissue with both serum and urine proteomes, we identified 6 proteins in the serum that may provide a set of targets for kidney injury. Additionally, we identified 49, being 4 predominantly renal, proteins in urine. As prove of concept, we validated one of the identified biomarkers, dipeptidyl peptidase IV, in a set of patients with diabetic nephropathy. In conclusion, we identified 55 systemic proteins, some of them predominantly renal, candidates for biomarkers of renal disease.

  8. 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

  9. The multifaceted role of the renal microvasculature during acute kidney injury

    PubMed Central

    Maringer, Katherine

    2016-01-01

    Pediatric acute kidney injury (AKI) represents a complex disease process for clinicians as it is multifactorial in cause and only limited treatment or preventatives are available. The renal microvasculature has recently been implicated in AKI as a strong therapeutic candidate involved in both injury and recovery. Significant progress has been made in the ability to study the renal microvasculature following ischemic AKI and its role in repair. Advances have also been made in elucidating cell–cell interactions and the molecular mechanisms involved in these interactions. The ability of the kidney to repair post AKI is closely linked to alterations in hypoxia, and these studies are elucidated in this review. Injury to the microvasculature following AKI plays an integral role in mediating the inflammatory response, thereby complicating potential therapeutics. However, recent work with experimental animal models suggests that the endothelium and its cellular and molecular interactions are attractive targets to prevent injury or hasten repair following AKI. Here, we review the cellular and molecular mechanisms of the renal endothelium in AKI, as well as repair and recovery, and potential therapeutics to prevent or ameliorate injury and hasten repair. PMID:26493067

  10. Rapid renal alpha-1 antitrypsin gene induction in experimental and clinical acute kidney injury.

    PubMed

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

    2014-01-01

    Alpha-1-antitrypsin (AAT) is a hepatic stress protein with protease inhibitor activity. Recent evidence indicates that ischemic or toxic injury can evoke selective changes within kidney that resemble a hepatic phenotype. Hence, we tested the following: i) Does acute kidney injury (AKI) up-regulate the normally renal silent AAT gene? ii) Does rapid urinary AAT excretion result? And iii) Can AAT's anti-protease/anti-neutrophil elastase (NE) activity protect injured proximal tubule cells? CD-1 mice were subjected to ischemic or nephrotoxic (glycerol, maleate, cisplatin) AKI. Renal functional and biochemical assessments were made 4-72 hrs later. Rapidly following injury, 5-10 fold renal cortical and isolated proximal tubule AAT mRNA and protein increases occurred. These were paralleled by rapid (>100 fold) increases in urinary AAT excretion. AKI also induced marked increases in renal cortical/isolated proximal tubule NE mRNA. However, sharp NE protein levels declines resulted, which strikingly correlated (r, -0.94) with rising AAT protein levels (reflecting NE complexing by AAT/destruction). NE addition to HK-2 cells evoked ∼95% cell death. AAT completely blocked this NE toxicity, as well as Fe induced oxidant HK-2 cell attack. Translational relevance of experimental AAT gene induction was indicated by ∼100-1000 fold urinary AAT increases in 22 AKI patients (matching urine NGAL increases). We conclude: i) AKI rapidly up-regulates the renal cortical/proximal tubule AAT gene; ii) NE gene induction also results; iii) AAT can confer cytoprotection, potentially by blocking/reducing cytotoxic NE accumulation; and iv) marked increases in urinary AAT excretion in AKI patients implies clinical relevance of the AKI- AAT induction pathway.

  11. Contribution of apoptotic cell death to renal injury.

    PubMed

    Ortiz, A; Lorz, C; Justo, P; Catalán, M P; Egido, J

    2001-01-01

    Cell number abnormalities are frequent in renal diseases, and range from the hypercellularity of postinfectious glomerulonephritis to the cell depletion of chronic renal atrophy. Recent research has shown that apoptosis and its regulatory mechanisms contribute to cell number regulation in the kidney. The role of apoptosis ranges from induction to repair and progression of renal injury. Death ligands and receptors, such as TNF and FasL, proapoptotic and antiapoptotic Bcl-2 family members and caspases have all been shown to participate in apoptosis regulation in the course of renal injury. These proteins represent potential therapeutic targets, which should be further explored.

  12. Heat shock (stress response) proteins and renal ischemia/reperfusion injury.

    PubMed

    Kelly, Katherine J

    2005-01-01

    Acute renal failure occurs frequently, may be increasing, carries an unacceptably high mortality, yet there is no specific treatment. The induction of stress response (heat shock) proteins (HSPs) is a highly conserved response that protects many cell types from diverse physiological and environmental stressors. HSP families of different sizes function as molecular chaperones that facilitate the folding of enzymes and other proteins into functional conformations. After injury, HSPs are believed to facilitate the restoration of normal function by assisting in the refolding of denatured proteins and degradation of irreparably damaged proteins and toxic metabolites, limitation of aggregation of damaged peptides and aiding appropriate folding of newly synthesized essential polypeptides. HSPs may also regulate apoptosis and immune functions. We have demonstrated protection from the functional deficits and histological evidence of experimental ischemic renal injury with heat stress 6 but not 48 h prior to ischemia. Limitation of the induction of HSPs (either with a short period of hyperthermia or pharmacologically) attenuated the protection observed. Other investigators have demonstrated a correlation between the levels of HSP25 and renal ischemic preconditioning in the mouse. Several pharmacological agents have been shown to increase HSP expression. Enhancement of these endogenous protective mechanisms has potential benefit in human disease.

  13. Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat

    PubMed Central

    Feng, Yangzheng; Paul, Ian A.; LeBlanc, Michael H.

    2011-01-01

    Nicotinamide reduces ischemic brain injury in adult rats. Can similar brain protection be seen in newborn animals? Seven-day-old rat pups had the right carotid artery permanently ligated followed by 2.5 h of 8% oxygen. Nicotinamide 250 or 500 mg/kg was administered i.p. 5 min after reoxygenation, with a second dose given at 6 h after the first. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Nicotinamide 500 mg/kg reduced brain weight loss from 24.6 ± 3.6% in vehicle pups (n = 28) to 11.9 ± 2.6% in the treated pups (n = 29, P < 0.01), but treatment with 250 mg/kg did not affect brain weight. Nicotinamide 500 mg/kg also improved behavior in rotarod performance. Levels of 8-isoprostaglandin F2α measured in the cortex by enzyme immune assay 16 h after reoxygenation was 115 ± 7 pg/g in the shams (n = 6), 175 ± 17 pg/g in the 500 mg/kg nicotinamide treated (n = 7), and 320 ± 79 pg/g in the vehicle treated pups (n = 7, P < 0.05 versus sham, P < 0.05 versus nicotinamide). Nicotinamide reduced the increase in caspase-3 activity caused by hypoxic ischemia (P < 0.01). Nicotinamide reduces brain injury in the neonatal rat, possibly by reducing oxidative stress and caspase-3 activity. PMID:16533659

  14. 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

  15. Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat.

    PubMed

    Feng, Yangzheng; Paul, Ian A; LeBlanc, Michael H

    2006-03-31

    Nicotinamide reduces ischemic brain injury in adult rats. Can similar brain protection be seen in newborn animals? Seven-day-old rat pups had the right carotid artery permanently ligated followed by 2.5 h of 8% oxygen. Nicotinamide 250 or 500 mg/kg was administered i.p. 5 min after reoxygenation, with a second dose given at 6 h after the first. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Nicotinamide 500 mg/kg reduced brain weight loss from 24.6 +/- 3.6% in vehicle pups (n = 28) to 11.9 +/- 2.6% in the treated pups (n = 29, P < 0.01), but treatment with 250 mg/kg did not affect brain weight. Nicotinamide 500 mg/kg also improved behavior in rotarod performance. Levels of 8-isoprostaglandin F2alpha measured in the cortex by enzyme immune assay 16 h after reoxygenation was 115 +/- 7 pg/g in the shams (n = 6), 175 +/- 17 pg/g in the 500 mg/kg nicotinamide treated (n = 7), and 320 +/- 79 pg/g in the vehicle treated pups (n = 7, P < 0.05 versus sham, P < 0.05 versus nicotinamide). Nicotinamide reduced the increase in caspase-3 activity caused by hypoxic ischemia (P < 0.01). Nicotinamide reduces brain injury in the neonatal rat, possibly by reducing oxidative stress and caspase-3 activity.

  16. Preconditioning strategies for kidney ischemia reperfusion injury: implications of the "time-window" in remote ischemic preconditioning.

    PubMed

    Yoon, Young Eun; Lee, Kwang Suk; Choi, Kyung Hwa; Kim, Kwang Hyun; Yang, Seung Choul; Han, Woong Kyu

    2015-01-01

    Remote ischemic preconditioning (IP) is a potential renoprotective strategy. However, there has been no demonstrated result in large animals and the role of time window in remote IP remains to be defined. Using a single-kidney porcine model, we evaluated organ protective function of remote IP in renal ischemia reperfusion injury. Fifteen Yorkshire pigs, 20 weeks old and weighing 35-38 kg were used. One week after left nephrectomy, we performed remote IP (clamping right external iliac artery, 2 cycles of 10 minutes) and right renal artery clamping (warm ischemia; 90 minutes). The animals were randomly divided into three groups: control group, warm ischemia without IP; group 1 (remote IP with early window [IP-E]), IP followed by warm ischemia with a 10-minute time window; and group 2 (remote IP with late window [IP-L]), IP followed by warm ischemia after a 24-hour time window. There were no differences in serum creatinine changes between groups. The IP-L group had lower urinary neutrophil gelatinase-associated lipocalin than control and IP-E at 72 hours post-ischemia. At 72 hours post-ischemia, the urinary kidney injury molecule-1 (KIM-1) was lower in the IP-L group than in the control and IP-E groups, and the IP-L group KIM-1 was near pre-ischemic levels, whereas the control and IP-E group KIM-1 levels were rising. Microalbumin also tended to be lower in the IP-L group. Taken together, remote IP showed a significant reduction in renal injury biomarkers from ischemia reperfusion injury. To effectively provide kidney protection, remote IP might require a considerable, rather than short, time window of ischemia.

  17. 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

  18. NADPH oxidase 4 deficiency increases tubular cell death during acute ischemic reperfusion injury

    PubMed Central

    Nlandu-Khodo, Stellor; Dissard, Romain; Hasler, Udo; Schäfer, Matthias; Pircher, Haymo; Jansen-Durr, Pidder; Krause, Karl Heinz; Martin, Pierre-Yves; de Seigneux, Sophie

    2016-01-01

    NADPH oxidase 4 (NOX4) is highly expressed in kidney proximal tubular cells. NOX4 constitutively produces hydrogen peroxide, which may regulate important pro-survival pathways. Renal ischemia reperfusion injury (IRI) is a classical model mimicking human ischemic acute tubular necrosis. We hypothesized that NOX4 plays a protective role in kidney IRI. In wild type (WT) animals subjected to IRI, NOX4 protein expression increased after 24 hours. NOX4 KO (knock-out) and WT littermates mice were subjected to IRI. NOX4 KO mice displayed decreased renal function and more severe tubular apoptosis, decreased Bcl-2 expression and higher histologic damage scores compared to WT. Activation of NRF2 was decreased in NOX4 KO mice in response to IRI. This was related to decreased KEAP1 oxidation leading to decreased NRF2 stabilization. This resulted in decreased glutathione levels. In vitro silencing of NOX4 in cells showed an enhanced propensity to apoptosis, with reduced expression of NRF2, glutathione content and Bcl-2 expression, similar to cells derived from NOX4 KO mice. Overexpression of a constitutively active form of NRF2 (caNRF2) in NOX4 depleted cells rescued most of this phenotype in cultured cells, implying that NRF2 regulation by ROS issued from NOX4 may play an important role in its anti-apoptotic property. PMID:27924932

  19. Bβ15–42 Attenuates the Effect of Ischemia-Reperfusion Injury in Renal Transplantation

    PubMed Central

    Sörensen, Inga; Rong, Song; Susnik, Nathan; Gueler, Faikah; Shushakova, Nelli; Albrecht, Melanie; Dittrich, Anna-Maria; von Vietinghoff, Sibylle; Becker, Jan Ulrich; Melk, Anette; Bohlmann, Andrea; Reingruber, Sonja; Petzelbauer, Peter; Haller, Hermann

    2011-01-01

    Renal ischemia-reperfusion contributes to reduced renal allograft survival. The peptide Bβ15–42, a breakdown product of fibrin, attenuates inflammation induced by ischemia-reperfusion in the heart by competitively blocking the binding of leukocytes to endothelial VE-cadherin, but whether it could improve outcomes in renal transplantation is unknown. Here, we tested the ability of Bβ15–42 to ameliorate the effects of renal ischemic injury during allogenic kidney transplantation in mice. In our renal transplantation model (C57BL/6 into BALB/c mice), treatment with Bβ15–42 at the time of allograft reperfusion resulted in significantly improved survival of recipients during the 28-day follow-up (60% versus 10%). Bβ15–42 treatment decreased leukocyte infiltration, expression of endothelial adhesion molecules, and proinflammatory cytokines. Treatment significantly attenuated allogenic T cell activation and reduced cellular rejection. Moreover, Bβ15–42 significantly reduced tubular epithelial damage and apoptosis, which we reproduced in vitro. These data suggest that Bβ15–42 may have therapeutic potential in transplant surgery by protecting grafts from ischemia-reperfusion injury. PMID:21841063

  20. Magnetic resonance imaging spectrum of perinatal hypoxic-ischemic brain injury.

    PubMed

    Varghese, Binoj; Xavier, Rose; Manoj, V C; Aneesh, M K; Priya, P S; Kumar, Ashok; Sreenivasan, V K

    2016-01-01

    Perinatal hypoxic-ischemic brain injury results in neonatal hypoxic-ischemic encephalopathy and serious long-term neurodevelopmental sequelae. Magnetic resonance imaging (MRI) of the brain is an ideal and safe imaging modality for suspected hypoxic-ischemic injury. The pattern of injury depends on brain maturity at the time of insult, severity of hypotension, and duration of insult. Time of imaging after the insult influences the imaging findings. Mild to moderate hypoperfusion results in germinal matrix hemorrhages and periventricular leukomalacia in preterm neonates and parasagittal watershed territory infarcts in full-term neonates. Severe insult preferentially damages the deep gray matter in both term and preterm infants. However, associated frequent perirolandic injury is seen in term neonates. MRI is useful in establishing the clinical diagnosis, assessing the severity of injury, and thereby prognosticating the outcome. Familiarity with imaging spectrum and insight into factors affecting the injury will enlighten the radiologist to provide an appropriate diagnosis.

  1. Magnetic resonance imaging spectrum of perinatal hypoxic-ischemic brain injury

    PubMed Central

    Varghese, Binoj; Xavier, Rose; Manoj, V C; Aneesh, M K; Priya, P S; Kumar, Ashok; Sreenivasan, V K

    2016-01-01

    Perinatal hypoxic–ischemic brain injury results in neonatal hypoxic–ischemic encephalopathy and serious long-term neurodevelopmental sequelae. Magnetic resonance imaging (MRI) of the brain is an ideal and safe imaging modality for suspected hypoxic–ischemic injury. The pattern of injury depends on brain maturity at the time of insult, severity of hypotension, and duration of insult. Time of imaging after the insult influences the imaging findings. Mild to moderate hypoperfusion results in germinal matrix hemorrhages and periventricular leukomalacia in preterm neonates and parasagittal watershed territory infarcts in full-term neonates. Severe insult preferentially damages the deep gray matter in both term and preterm infants. However, associated frequent perirolandic injury is seen in term neonates. MRI is useful in establishing the clinical diagnosis, assessing the severity of injury, and thereby prognosticating the outcome. Familiarity with imaging spectrum and insight into factors affecting the injury will enlighten the radiologist to provide an appropriate diagnosis. PMID:27857456

  2. Mesenchymal stem cells in renal function recovery after acute kidney injury: use of a differentiating agent in a rat model.

    PubMed

    La Manna, Gaetano; Bianchi, Francesca; Cappuccilli, Maria; Cenacchi, Giovanna; Tarantino, Lucia; Pasquinelli, Gianandrea; Valente, Sabrina; Della Bella, Elena; Cantoni, Silvia; Claudia, Cavallini; Neri, Flavia; Tsivian, Matvey; Nardo, Bruno; Ventura, Carlo; Stefoni, Sergio

    2011-01-01

    Acute kidney injury (AKI) is a major health care condition with limited current treatment options. Within this context, stem cells may provide a clinical approach for AKI. Moreover, a synthetic compound previously developed, hyaluronan monoesters with butyric acid (HB), able to induce metanephric differentiation, formation of capillary-like structures, and secretion of angiogenic cytokines, was tested in vitro. Thereafter, we investigated the effects of human mesenchymal stem cells from fetal membranes (FMhMSCs), both treated and untreated with HB, after induction of ischemic AKI in a rat model. At reperfusion following 45-min clamping of renal pedicles, each rat was randomly assigned to one of four groups: CTR, PBS, MSC, and MSC-HB. Renal function at 1, 3, 5, and 7 days was assessed. Histological samples were analyzed by light and electron microscopy and renal injury was graded. Cytokine analysis on serum samples was performed. FMhMSCs induced an accelerated renal functional recovery, demonstrated by biochemical parameters and confirmed by histology showing that histopathological alterations associated with ischemic injury were less severe in cell-treated kidneys. HB-treated rats showed a minor degree of inflammation, both at cytokine and TEM analyses. Better functional and morphological recovery were not associated to stem cells' regenerative processes, but possibly suggest paracrine effects on microenvironment that induce retrieval of renal damaged tissues. These results suggest that FMhMSCs could be useful in the treatment of AKI and the utilization of synthetic compounds could enhance the recovery induction ability of cells.

  3. 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

  4. DNA damage response in renal ischemia-reperfusion and ATP-depletion injury of renal tubular cells.

    PubMed

    Ma, Zhengwei; Wei, Qingqing; Dong, Guie; Huo, Yuqing; Dong, Zheng

    2014-07-01

    Renal ischemia-reperfusion leads to acute kidney injury (AKI) that is characterized pathologically by tubular damage and cell death, followed by tubular repair, atrophy and interstitial fibrosis. Recent work suggested the possible presence of DNA damage response (DDR) in AKI. However, the evidence is sketchy and the role and regulation of DDR in ischemic AKI remain elusive. In this study, we demonstrated the induction of phosphorylation of ATM, H2AX, Chk2 and p53 during renal ischemia-reperfusion in mice, suggesting DDR in kidney tissues. DDR was also induced in vitro during the recovery or "reperfusion" of renal proximal tubular cells (RPTCs) after ATP depletion. DDR in RPTCs was abrogated by supplying glucose to maintain ATP via glycolysis, indicating that the DDR depends on ATP depletion. The DDR was also suppressed by the general caspase inhibitor z-VAD and the overexpression of Bcl-2, supporting a role of apoptosis-associated DNA damage in the DDR. N-acetylcysteine (NAC), an antioxidant, suppressed the phosphorylation of ATM and p53 and, to a less extent, Chk2, but NAC increased the phosphorylation and nuclear foci formation of H2AX. Interestingly, NAC increased apoptosis, which may account for the observed H2AX activation. Ku55933, an ATM inhibitor, blocked ATM phosphorylation and ameliorated the phosphorylation of Chk2 and p53, but it increased H2AX phosphorylation and nuclear foci formation. Ku55933 also increased apoptosis in RPTCs following ATP depletion. The results suggest that DDR occurs during renal ischemia-reperfusion in vivo and ATP-depletion injury in vitro. The DDR is partially induced by apoptosis and oxidative stress-related DNA damage. ATM, as a sensor in the DDR, may play a cytoprotective role against tubular cell injury and death.

  5. Upregulation of Interleukin-33 in obstructive renal injury

    SciTech Connect

    Chen, Wei-Yu; Chang, Ya-Jen; Su, Chia-Hao; Tsai, Tzu-Hsien; Chen, Shang-Der; Hsing, Chung-Hsi; Yang, Jenq-Lin

    2016-05-13

    Interstitial fibrosis and loss of parenchymal tubular cells are the common outcomes of progressive renal diseases. Pro-inflammatory cytokines have been known contributing to the damage of tubular cells and fibrosis responses after renal injury. Interleukin (IL)-33 is a tissue-derived nucleus alarmin that drives inflammatory responses. The regulation and function of IL-33 in renal injury, however, is not well understood. To investigate the involvement of cytokines in the pathogenesis of renal injury and fibrosis, we performed the mouse renal injury model induced by unilateral urinary obstruction (UUO) and analyze the differentially upregulated genes between the obstructed and the contralateral unobstructed kidneys using RNA sequencing (RNAseq). Our RNAseq data identified IL33 and its receptor ST2 were upregulated in the UUO kidney. Quantitative analysis confirmed that transcripts of IL33 and ST2 were upregulated in the obstructed kidneys. Immunofluorescent staining revealed that IL-33 was upregulated in Vimentin- and alpha-SMA-positive interstitial cells. By using genetically knockout mice, deletion of IL33 reduced UUO-induced renal fibrosis. Moreover, in combination with BrdU labeling technique, we observed that the numbers of proliferating tubular epithelial cells were increased in the UUO kidneys from IL33-or ST2-deficient mice compared to wild type mice. Collectively, our study demonstrated the upregulation of IL-33/ST2 signaling in the obstructed kidney may promote tubular cell injury and interstitial fibrosis. IL-33 may serve as a biomarker to detect renal injury and that IL-33/ST2 signaling may represent a novel target for treating renal diseases. -- Highlights: •Interleukin (IL)-33 was upregulated in obstructed kidneys. •Interstitial myofibroblasts expressed IL-33 after UUO-induced renal injury. •Deficiency of IL33 reduced interstitial fibrosis and promoted tubular cell proliferation.

  6. Early peritoneal dialysis reduces lung inflammation in mice with ischemic acute kidney injury.

    PubMed

    Altmann, Chris; Ahuja, Nilesh; Kiekhaefer, Carol M; Andres Hernando, Ana; Okamura, Kayo; Bhargava, Rhea; Duplantis, Jane; Kirkbride-Romeo, Lara A; Huckles, Jill; Fox, Benjamin M; Kahn, Kashfi; Soranno, Danielle; Gil, Hyo-Wook; Teitelbaum, Isaac; Faubel, Sarah

    2017-03-16

    Although dialysis has been used in the care of patients with acute kidney injury (AKI) for over 50 years, very little is known about the potential benefits of uremic control on systemic complications of AKI. Since the mortality of AKI requiring renal replacement therapy (RRT) is greater than half in the intensive care unit, a better understanding of the potential of RRT to improve outcomes is urgently needed. Therefore, we sought to develop a technically feasible and reproducible model of RRT in a mouse model of AKI. Models of low- and high-dose peritoneal dialysis (PD) were developed and their effect on AKI, systemic inflammation, and lung injury after ischemic AKI was examined. High-dose PD had no effect on AKI, but effectively cleared serum IL-6, and dramatically reduced lung inflammation, while low-dose PD had no effect on any of these three outcomes. Both models of RRT using PD in AKI in mice reliably lowered urea in a dose-dependent fashion. Thus, use of these models of PD in mice with AKI has great potential to unravel the mechanisms by which RRT may improve the systemic complications that have led to increased mortality in AKI. In light of recent data demonstrating reduced serum IL-6 and improved outcomes with prophylactic PD in children, we believe that our results are highly clinically relevant.

  7. Vascular adhesion protein-1 enhances neutrophil infiltration by generation of hydrogen peroxide in renal ischemia/reperfusion injury.

    PubMed

    Tanaka, Shinji; Tanaka, Tetsuhiro; Kawakami, Takahisa; Takano, Hideki; Sugahara, Mai; Saito, Hisako; Higashijima, Yoshiki; Yamaguchi, Junna; Inagi, Reiko; Nangaku, Masaomi

    2017-07-01

    Vascular adhesion protein-1 (VAP-1) is a unique molecule since it acts as an adhesion molecule as well as an ectoenzyme catalyzing oxidative deamination of primary amines and generates hydrogen peroxide in the extracellular space. While VAP-1 is implicated in various inflammatory diseases, its role in acute kidney injury is less characterized. Here we studied VAP-1 expression in the kidney and the effect of its inhibition in a rat model of renal ischemia/reperfusion injury. VAP-1 was predominantly expressed in pericytes, which released enzymatically active enzyme. In vivo, a specific VAP-1 inhibitor, RTU-1096, significantly ameliorated rat renal ischemia/reperfusion injury and decreased neutrophil infiltration measured 12 hours after injury without altering macrophage or T lymphocyte populations. The protective effect of VAP-1 inhibition was lost in neutrophil-depleted rats, suggesting its inhibition ameliorated renal ischemia/reperfusion injury by suppressing neutrophil infiltration. To investigate whether hydrogen peroxide generated by VAP-1 enzyme reaction enhances neutrophil infiltration, we conducted an under-agarose migration assay with purified human neutrophils. Recombinant human VAP-1 significantly induced neutrophil migration, which was almost completely inhibited by RTU-1096 or catalase. Thus, VAP-1 plays a critical role in the pathophysiology of renal ischemia/reperfusion injury by enhancement of neutrophil infiltration generating a local hydrogen peroxide gradient. Hence, VAP-1 inhibition may be a novel therapy in ischemic acute kidney injury. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  8. A novel rodent model of severe renal ischemia reperfusion injury.

    PubMed

    Whalen, Henry; Shiels, Paul; Littlejohn, Marc; Clancy, Marc

    2016-11-01

    Renal ischemia reperfusion injury (IRI) is a major problem, currently without treatments in clinical use. This reflects the failure of animal models to mimic the severity of IRI observed in clinical practice. Most described models lack both the ability to inflict a permanent reduction in renal function and the sensitivity to demonstrate the protective efficacy of different therapies in vivo. To test novel cell-based therapies, we have developed a model of renal IRI in Fisher 344 rats. Animals were subjected to 120 min of unilateral warm ischemia, during which they underwent an intra-renal artery infusion of therapeutic agents or vehicle. At either 2 or 6 weeks post-surgery, animals underwent terminal glomerular filtration rate (GFR) studies by inulin clearance to most accurately quantify renal function. Harvested kidneys underwent histological analysis. Compared to sham operations, saline treated animals suffered a long-term reduction in GFR of ≈50%. Histology revealed short- and long-term disruption of renal architecture. Despite the injury severity, post-operative animal losses are <5%. This model produces a severe, consistent renal injury that closely replicates the pathological processes encountered in clinical medicine. Renal artery infusion mimics the route likely employed in clinical transplantation, where the renal artery is accessible. Inulin clearance characterizes GFR, allowing full assessment of therapeutic intervention. This model is useful for screening therapeutic agents prior to testing in a transplant model. This reduces animal numbers needed to test drugs for clinical transplantation and allows for refinement of dosing schedules.

  9. Coenzyme Q10 ameliorates oxidative stress and prevents mitochondrial alteration in ischemic retinal injury.

    PubMed

    Lee, Dongwook; Kim, Keun-Young; Shim, Myoung Sup; Kim, Sang Yeop; Ellisman, Mark H; Weinreb, Robert N; Ju, Won-Kyu

    2014-04-01

    Coenzyme Q10 (CoQ10) acts by scavenging reactive oxygen species for protecting neuronal cells against oxidative stress in neurodegenerative diseases. We tested whether a diet supplemented with CoQ10 ameliorates oxidative stress and mitochondrial alteration, as well as promotes retinal ganglion cell (RGC) survival in ischemic retina induced by intraocular pressure elevation. A CoQ10 significantly promoted RGC survival at 2 weeks after ischemia. Superoxide dismutase 2 (SOD2) and heme oxygenase-1 (HO-1) expression were significantly increased at 12 h after ischemic injury. In contrast, the CoQ10 significantly prevented the upregulation of SOD2 and HO-1 protein expression in ischemic retina. In addition, the CoQ10 significantly blocked activation of astroglial and microglial cells in ischemic retina. Interestingly, the CoQ10 blocked apoptosis by decreasing caspase-3 protein expression in ischemic retina. Bax and phosphorylated Bad (pBad) protein expression were significantly increased in ischemic retina at 12 h. Interestingly, while CoQ10 significantly decreased Bax protein expression in ischemic retina, CoQ10 showed greater increase of pBad protein expression. Of interest, ischemic injury significantly increased mitochondrial transcription factor A (Tfam) protein expression in the retina at 12 h, however, CoQ10 significantly preserved Tfam protein expression in ischemic retina. Interestingly, there were no differences in mitochondrial DNA content among control- or CoQ10-treated groups. Our findings demonstrate that CoQ10 protects RGCs against oxidative stress by modulating the Bax/Bad-mediated mitochondrial apoptotic pathway as well as prevents mitochondrial alteration by preserving Tfam protein expression in ischemic retina. Our results suggest that CoQ10 may provide neuroprotection against oxidative stress-mediated mitochondrial alterations in ischemic retinal injury.

  10. Remote ischemic preconditioning has a neutral effect on the incidence of kidney injury after coronary artery bypass graft surgery.

    PubMed

    Gallagher, Sean M; Jones, Dan A; Kapur, Akhil; Wragg, Andrew; Harwood, Steve M; Mathur, Rohini; Archbold, R Andrew; Uppal, Rakesh; Yaqoob, Muhammad M

    2015-02-01

    Acute kidney injury (AKI) is a frequent complication of cardiac surgery and usually occurs in patients with preexisting chronic kidney disease (CKD). Remote ischemic preconditioning (RIPC) may mitigate the renal ischemia-reperfusion injury associated with cardiac surgery and may be a preventive strategy for postsurgical AKI. We undertook a randomized controlled trial of RIPC to prevent AKI in 86 patients with CKD (estimated glomerular filtration rate under 60 ml/min per 1.73 m(2)) undergoing coronary artery bypass graft (CABG) surgery. Forty-three patients each were randomized to receive standard care with or without RIPC consisting of three 5-minute cycles of forearm ischemia followed by reperfusion. The primary end point was the development of AKI defined as an increase in serum creatinine concentration over 0.3 mg/dl within 48 h of surgery. Secondary end points included a comparison between the study and control groups of several serum biomarkers of renal injury including cystatin-C, neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18), and urinary biomarkers including NGAL, IL-18, and kidney injury molecule-1 measured at 6, 12, and 24 h after CABG, and the 72-h serum troponin T concentration area under the curve as a marker of myocardial injury. Clinical and operative characteristics were similar between the preconditioned and control groups. AKI developed in 12 patients in both groups within 48 h of CABG. There were no significant differences between the two groups in the concentrations of any of the serum or urinary biomarkers of renal or cardiac injury after CABG. Thus, RIPC induced by forearm ischemia-reperfusion had no effect on the frequency of AKI after CABG in patients with CKD.

  11. Vitamin D ameliorates hepatic ischemic/reperfusion injury in rats.

    PubMed

    Seif, Ansam Aly; Abdelwahed, Doaa Mohamed

    2014-09-01

    Vitamin D, most commonly associated with the growth and remodeling of bone, has been shown to ameliorate ischemia/reperfusion injury (IRI) in some tissues, yet its underlying mechanism remains elusive. This study was designed to examine the protective effect of vitamin D, if any, against hepatic IRI in rats and the underlying mechanism involved. Adult female Wistar rats were randomly divided into control, sham-operated (sham), ischemia/reperfusion (I/R), and ischemic-reperfused vitamin D-treated (vit D) groups. Rats in the I/R and vit D groups were subjected to partial (70%) hepatic ischemia for 45 min, followed by 1 h of reperfusion. Vitamin D was given to rats orally in a dose of 500 IU/kg daily for 2 weeks before being subjected to I/R. Markers of liver damage, oxidative stress, inflammation and apoptosis were evaluated. Hepatic morphology was also examined. Vit D-treated rats had significantly lower serum levels of alanine aminotransferase, aspartate aminotransferase, and γ glutamyl transferase compared to rats in the I/R group. Also, vit D-treated rats showed a significant decrease in malondialdehyde, interleukin-1 beta, interleukin-6, tumor necrosis factor-α, nuclear factor κB, B cell leukemia/lymphoma 2-associated X protein, cytochrome c, and caspase-3 levels, with higher levels of glutathione peroxidase and B cell lymphoma 2 protein levels in liver tissues compared to I/R rats. Histological examination showed less damaged liver tissues with amelioration of apoptotic signs in the vit D group compared to the I/R group. In conclusion, vitamin D supplementation ameliorates hepatic IRI mostly by alleviating the inflammatory-apoptotic response mediated by the oxidative reperfusion injury insult.

  12. Cardioprotective effects of grape seed proanthocyanidin against ischemic reperfusion injury.

    PubMed

    Sato, M; Maulik, G; Ray, P S; Bagchi, D; Das, D K

    1999-06-01

    There is increasing evidence to indicate cardioprotective effects of red wine consumption. Such cardioprotective properties of wine have been attributed to certain polyphenolic constituents of grapes. The purpose of this investigation was to examine whether proanthocyanidins derived from grape seeds possess cardioprotective properties. Rats were randomly divided into two groups: grape-seed proanthocyanidin was administered orally to one group of rats (100 mg/kg/day) for 3 weeks while the other group served as control. After 3 weeks, rats were killed, hearts excised, mounted on the perfusion apparatus and perfused with Krebs-Henseleit bicarbonate (KHB) buffer. After stabilization hearts were perfused in the working mode for baseline measurements of contractile functions. Hearts were then subjected to 30 min of global ischemia followed by 2 h of reperfusion. Coronary perfusates were collected to monitor malonaldehyde formation, a presumptive marker for oxidative stress development. At the end of each experiment, the heart was processed for infarct size determination. Peroxyl radical scavenging activity of proanthocyanidin was determined by examining its ability to remove peroxyl radical generated by 2,2'-azobis (2-amidinopropane) dihydrochloride while hydroxyl radical scavenging activity was tested with its ability to reduce 7-OH.-coumarin-3-carboxylic acid. The results of our study demonstrated that proanthocyanidin-fed animals were resistant to myocardial ischemia reperfusion injury as evidenced by improved recovery of post-ischemic contractile functions. The proanthocyanidin-fed group revealed reduced extent of myocardial infarction compared to the control group. Fluorimetric study demonstrated the antioxidant property of proanthocyanidin as judged by its ability to directly scavenge peroxyl radicals. Taken together, the results of this study showed that grape seed-proanthocyanidins possess a cardioprotective effect against ischemia reperfusion injury. Such

  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. T-wave inversion after a severe head injury without ischemic heart disease.

    PubMed

    La Rocca, Roberto; Materia, Valeria; Pasquini, Annalisa; La Rosa, Felice Carmelo; Marte, Filippo; Patanè, Salvatore

    2011-09-01

    Electrocardiographic changes mimicking an acute coronary event with T-wave inversion have been reported in the resting electrocardiogram in patients without ischemic heart disease but with acute ischemic stroke, or subarachnoid hemorrhage, or intracerebral hemorrhage, or a severe head injury. We present a case of T-wave inversion in a 73-year-old Italian woman admitted to the Emergency Department following a severe head injury. Pericarditis, pericardial effusion, and acute coronary event were excluded. Ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage were also excluded. Also this case focuses attention on T-wave inversion after a severe head injury without ischemic heart disease. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

  15. Marine Compound Xyloketal B Reduces Neonatal Hypoxic-Ischemic Brain Injury

    PubMed Central

    Xiao, Ai-Jiao; Chen, Wenliang; Xu, Baofeng; Liu, Rui; Turlova, Ekaterina; Barszczyk, Andrew; Sun, Christopher Lf; Liu, Ling; Deurloo, Marielle; Wang, Guan-Lei; Feng, Zhong-Ping; Sun, Hong-Shuo

    2014-01-01

    Neonatal hypoxic-ischemic encephalopathy causes neurodegeneration and brain injury, leading to sensorimotor dysfunction. Xyloketal B is a novel marine compound isolated from a mangrove fungus Xylaria species (no. 2508) with unique antioxidant effects. In this study, we investigated the effects and mechanism of xyloketal B on oxygen-glucose deprivation-induced neuronal cell death in mouse primary cortical culture and on hypoxic-ischemic brain injury in neonatal mice in vivo. We found that xyloketal B reduced anoxia-induced neuronal cell death in vitro, as well as infarct volume in neonatal hypoxic-ischemic brain injury model in vivo. Furthermore, xyloketal B improved functional behavioral recovery of the animals following hypoxic-ischemic insult. In addition, xyloketal B significantly decreased calcium entry, reduced the number of TUNEL-positive cells, reduced the levels of cleaved caspase-3 and Bax proteins, and increased the level of Bcl-2 protein after the hypoxic-ischemic injury. Our findings indicate that xyloketal B is effective in models of hypoxia-ischemia and thus has potential as a treatment for hypoxic-ischemic brain injury. PMID:25546517

  16. [Effects of combined ischemic postconditioning, remote ischemic postconditioning and naloxone postconditioning on focal cerebral ischemia-reperfusion injury in rats].

    PubMed

    Liu, Yi; Liao, Xu; Xue, Fu-shan; Xu, Ya-chao; Xiong, Jun; Yuan, Yu-jing; Wang, Qiang; Liu, Jian-hua; Zhao, Jia-xun

    2011-06-07

    To assess the effects of ischemic postconditioning, remote ischemic postconditioning and naloxone postconditioning on focal cerebral ischemia-reperfusion injury in rats. A total of 110 adult SD rats were randomly divided into 5 groups (n = 22 each). The focal cerebral ischemia-reperfusion injury was induced by a 90-minute occlusion of right middle cerebral artery (MCA) and a 24-hour reperfusion sequentially. Group 1 was of ischemia-reperfusion control; Group 2 ischemic postconditioning induced by three 30-second cycles of MCA occlusion followed by a 30-second reperfusion; Group 3 remote ischemic postconditioning performed via a transient occlusion of right femoral artery at 5 min before the initiation of reperfusion; Group 4 naloxone postconditioning with naloxone 10 mg/kg intraperitoneally injected at the initiation of reperfusion; Group 5 combined ischemic, remote ischemic & naloxone postconditioning performed simultaneously in accordance with the methods used in Groups 2, 3 & 4. The neurologic deficit scores (NDS) were obtained at 2 h & 24 h post-reperfusion. At 24 h post-reperfusion, the anesthetized rat was sacrificed by decapitation and the brain rapidly extracted to assess the size of cerebral infarct (n = 10), detect the cerebral expression of microtubule-associated protein-2 (MAP2) (n = 6), measure the plasma volume of cerebral tissues and quantify the diameter and segment length of cerebral microvessel (n = 6). There were no significant differences in the heart rate (HR) and mean arterial pressure (MAP) among the above five groups at all observed time points (P > 0.05). At 24 h post-reperfusion, the percentage of ischemic cerebral infarct size was 43% ± 6%, 31% ± 4%, 32% ± 5%, 28% ± 6% & 21% ± 7% in ipsilateral hemisphere area (i.e., cerebral infarct severity) in Groups 1-5 respectively. Compared with Group 1, the levels of NDS and cerebral infarct severity significantly decreased at ischemic side in Groups 2-5 (P < 0.05). And the cerebral expression

  17. 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

  18. Changing picture of renal cortical necrosis in acute kidney injury in developing country.

    PubMed

    Prakash, Jai; Singh, Vijay Pratap

    2015-11-06

    Renal cortical necrosis (RCN) is characterized by patchy or diffuse ischemic destruction of all the elements of renal cortex resulting from significantly diminished renal arterial perfusion due to vascular spasm and microvascular injury. In addition, direct endothelial injury particularly in setting of sepsis, eclampsia, haemolytic uremic syndrome (HUS) and snake bite may lead to endovascular thrombosis with subsequent renal ischemia. Progression to end stage renal disease is a rule in diffuse cortical necrosis. It is a rare cause of acute kidney injury (AKI) in developed countries with frequency of 1.9%-2% of all patients with AKI. In contrast, RCN incidence is higher in developing countries ranging between 6%-7% of all causes of AKI. Obstetric complications (septic abortion, puerperal sepsis, abruptio placentae, postpartum haemorrhage and eclampsia) are the main (60%-70%) causes of RCN in developing countries. The remaining 30%-40% cases of RCN are caused by non-obstetrical causes, mostly due to sepsis and HUS. The incidence of RCN ranges from 10% to 30% of all cases of obstetric AKI compared with only 5% in non-gravid patients. In the developed countries, RCN accounts for 2% of all cases of AKI in adults and more than 20% of AKI during the third trimester of pregnancy. The reported incidence of RCN in obstetrical AKI varies between 18%-42.8% in different Indian studies. However, the overall incidence of RCN in pregnancy related AKI has decreased from 20%-30% to 5% in the past two decades in India. Currently RCN accounts for 3% of all causes of AKI. The incidence of RCN in obstetrical AKI was 1.44% in our recent study. HUS is most common cause of RCN in non-obstetrical group, while puerperal sepsis is leading cause of RCN in obstetric group. Because of the catastrophic sequelae of RCN, its prevention and aggressive management should always be important for the better renal outcome and prognosis of the patients.

  19. Changing picture of renal cortical necrosis in acute kidney injury in developing country

    PubMed Central

    Prakash, Jai; Singh, Vijay Pratap

    2015-01-01

    Renal cortical necrosis (RCN) is characterized by patchy or diffuse ischemic destruction of all the elements of renal cortex resulting from significantly diminished renal arterial perfusion due to vascular spasm and microvascular injury. In addition, direct endothelial injury particularly in setting of sepsis, eclampsia, haemolytic uremic syndrome (HUS) and snake bite may lead to endovascular thrombosis with subsequent renal ischemia. Progression to end stage renal disease is a rule in diffuse cortical necrosis. It is a rare cause of acute kidney injury (AKI) in developed countries with frequency of 1.9%-2% of all patients with AKI. In contrast, RCN incidence is higher in developing countries ranging between 6%-7% of all causes of AKI. Obstetric complications (septic abortion, puerperal sepsis, abruptio placentae, postpartum haemorrhage and eclampsia) are the main (60%-70%) causes of RCN in developing countries. The remaining 30%-40% cases of RCN are caused by non-obstetrical causes, mostly due to sepsis and HUS. The incidence of RCN ranges from 10% to 30% of all cases of obstetric AKI compared with only 5% in non-gravid patients. In the developed countries, RCN accounts for 2% of all cases of AKI in adults and more than 20% of AKI during the third trimester of pregnancy. The reported incidence of RCN in obstetrical AKI varies between 18%-42.8% in different Indian studies. However, the overall incidence of RCN in pregnancy related AKI has decreased from 20%-30% to 5% in the past two decades in India. Currently RCN accounts for 3% of all causes of AKI. The incidence of RCN in obstetrical AKI was 1.44% in our recent study. HUS is most common cause of RCN in non-obstetrical group, while puerperal sepsis is leading cause of RCN in obstetric group. Because of the catastrophic sequelae of RCN, its prevention and aggressive management should always be important for the better renal outcome and prognosis of the patients. PMID:26558184

  20. Acute Trypanosoma cruzi experimental infection induced renal ischemic/reperfusion lesion in mice.

    PubMed

    de Oliveira, Gabriel Melo; da Silva, Tshaca Mahatma; Batista, Wanderson Silva; Franco, Marcello; Schor, Nestor

    2009-12-01

    Experimental acute infection with Trypanosoma cruzi in mice promotes an intense myocarditis and other systemic changes. However, the network of pathophysiological disorders and renal injury caused by the infection has not been elucidated. Our previous results with a murine model observed a discrete acute myocarditis and high mortality with significant inflammatory kidney injury with T. cruzi infection. The aim of this study was to investigate the mechanisms of kidney injury caused by the parasite in mice during the experimental acute phase. Results employing BALB/c mice infected with T. cruzi of Y strain showed renal injury on the 6th day postinfection (dpi) caused by a transitory decrease of renal blood flow. Acute kidney injury (AKI) was also observed similar to the model of ischemia/reperfusion lesion in these infected mice. The injury was not related to the presence (or multiplication) of parasites. Only rare nests were microscopically detected, and the presence of scattered parasites in renal parenchyma was seen on the 15th dpi. Thus, it was observed that during the acute phase of the disease, AKI in infected mice is linked to early cardiovascular effects, including heart failure, caused by striking inflammatory lesions in the myocardium, which lead to the high mortality rate of animals.

  1. Chemokine expression in renal ischemia/reperfusion injury is most profound during the reparative phase.

    PubMed

    Stroo, Ingrid; Stokman, Geurt; Teske, Gwen J D; Raven, Anje; Butter, Loes M; Florquin, Sandrine; Leemans, Jaklien C

    2010-06-01

    Chemokines are important players in the migration of leukocytes to sites of injury and are also involved in angiogenesis, development and wound healing. In this study, we performed microarray analyses to identify chemokines that play a role during the inflammatory and repair phase after renal ischemia/reperfusion (I/R) injury and investigated the temporal relationship between chemokine expression, leukocyte accumulation and renal damage/repair. C57Bl/6 mice were subjected to unilateral ischemia for 45 min and sacrificed 3 h, 1 day and 7 days after reperfusion. From ischemic and contralateral kidney, RNA was isolated and hybridized to a microarray. Microarray results were validated with quantitative real-time reverse transcription-PCR (QRT-PCR) on RNA from an independent experiment. (Immuno)histochemical analyses were performed to determine renal damage/repair and influx of leukocytes. Twenty out of 114 genes were up-regulated at one or more reperfusion periods. All these genes were up-regulated 7 days after I/R. Up-regulated genes included CC chemokines MCP-1 and TARC, CXC chemokines KC and MIP-2alpha, chemokine receptors Ccr1 and Cx3cr1 and related genes like matrix metalloproteinases. Microarray data of 1 and 7 days were confirmed for 17 up-regulated genes by QRT-PCR. (Immuno)histochemical analysis showed that the inflammatory and repair phase after renal I/R injury take place after, respectively, 1 and 7 days. Interestingly, chemokine expression was highest during the repair phase. In addition, expression profiles showed a biphasic expression of all up-regulated CXC chemokines coinciding with the early inflammatory and late repair phase. In conclusion, we propose that temporal expression of chemokines is a crucial factor in the regulation of renal I/R injury and repair.

  2. 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.

  3. Interleukin-19 as a translational indicator of renal injury.

    PubMed

    Jennings, Paul; Crean, Daniel; Aschauer, Lydia; Limonciel, Alice; Moenks, Konrad; Kern, Georg; Hewitt, Philip; Lhotta, Karl; Lukas, Arno; Wilmes, Anja; Leonard, Martin O

    2015-01-01

    Accurate detection and prediction of renal injury are central not only to improving renal disease management but also for the development of new strategies to assess drug safety in pre-clinical and clinical testing. In this study, we utilised the well-characterised and differentiated human renal proximal tubule cell line, RPTEC/TERT1 in an attempt to identify markers of renal injury, independent of the mechanism of toxicity. We chose zoledronate as a representative nephrotoxic agent to examine global transcriptomic alterations using a daily repeat bolus protocol over 14 days, reflective of sub-acute or chronic injury. We identified alterations in targets of the cholesterol and mevalonate biosynthetic pathways reflective of zoledronate specific effects. We also identified interleukin-19 (IL-19) among other inflammatory signals such as SERPINA3 and DEFB4 utilising microarray analysis. Release of IL-19 protein was highly induced by an additional four nephrotoxic agents, at magnitudes greater than the characterised marker of renal injury, lipocalin-2. We also demonstrate a large increase in levels of IL-19 in urine of patients with chronic kidney disease, which significantly correlated with estimated glomerular filtration rate levels. We suggest IL-19 as a potential new translational marker of renal injury.

  4. Ischemia-Reperfusion Injury and Ischemic-Type Biliary Lesions following Liver Transplantation

    PubMed Central

    Cursio, Raffaele; Gugenheim, Jean

    2012-01-01

    Ischemia-reperfusion (I-R) injury after liver transplantation (LT) induces intra- and/or extrahepatic nonanastomotic ischemic-type biliary lesions (ITBLs). Subsequent bile duct stricture is a significant cause of morbidity and even mortality in patients who underwent LT. Although the pathogenesis of ITBLs is multifactorial, there are three main interconnected mechanisms responsible for their formation: cold and warm I-R injury, injury induced by cytotoxic bile salts, and immunological-mediated injury. Cold and warm ischemic insult can induce direct injury to the cholangiocytes and/or damage to the arterioles of the peribiliary vascular plexus, which in turn leads to apoptosis and necrosis of the cholangiocytes. Liver grafts from suboptimal or extended-criteria donors are more susceptible to cold and warm I-R injury and develop more easily ITBLs than normal livers. This paper, focusing on liver I-R injury, reviews the risk factors and mechanisms leading to ITBLs following LT. PMID:22530107

  5. Pathophysiological role of the glyoxalase system in renal hypoxic injury.

    PubMed

    Kumagai, Takanori; Nangaku, Masaomi; Inagi, Reiko

    2008-04-01

    Methylglyoxal (MG), a reactive dicarbonyl compound mainly produced by metabolic pathways, such as glycolysis, binds to proteins or nucleic acids and forms advanced glycation end products. MG is efficiently metabolized by the glyoxalase system where MG is converted by glyoxalase I (GLO I) to S-D-lactoylglutathione. Although the glyoxalase system has been shown to play a pathological role in various diseases, including diabetic complications, its detailed pathophysiological function remains to be elucidated. We are interested in renal hypoxic diseases, but very little information is available regarding the association between the glyoxalase system and renal hypoxic diseases. Therefore, we investigated the biological role of GLO I in renal hypoxic diseases by using the rat ischemia/reperfusion (I/R) injury model. I/R induced the reduction of renal GLO I activity associated with morphological changes and renal dysfunction. Interestingly, the rats that overexpress human GLO I (GLO I Tg rats) showed amelioration of these manifestations in renal I/R (e.g., improvement of the tubulointerstitial injury and renal function). Accumulation of renal MG adducts, carboxyethyllysine, induced by I/R also decreased in GLO I Tg rats compared to wild-type rats. These results demonstrate that GLO I has renoprotective effects in I/R injury via reduction of protein modification by MG.

  6. 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.

  7. Protecting the heart from ischemia/reperfusion injury: an update on remote ischemic preconditioning and postconditioning.

    PubMed

    Donato, Martín; Evelson, Pablo; Gelpi, Ricardo J

    2017-11-01

    The most effective strategy for reducing acute myocardial ischemic injury is timely and effective reperfusion. However, myocardial reperfusion can induce further cardiomyocyte death (reperfusion injury). Interventions that protect the heart from ischemia/reperfusion injury, reducing infarct size, can involve remote ischemic preconditioning and postconditioning. These interventions have a promising potential clinical application, and have been the focus of recent research. In this review, we provide an update of remote ischemic preconditioning and postconditioning mechanisms. Remote ischemic preconditioning cardioprotection can occur via a humoral pathway and/or a neural pathway. These two pathways have been described as mechanistically different, but it has been suggested that they could be interdependent. However, remote ischemic postconditioning mainly involves the humoral pathway. In this review, we will discuss the different pathways and mechanisms involved in remote ischemic preconditioning and postconditioning. Remote ischemic preconditioning and postconditioning is possible to perform in a clinical setting by intermittent ischemia of an upper or lower limb. Furthermore, clinical trials using this procedure in the context of predictable ischemia-reperfusion have produced promising results, and other studies to define the potential clinical use of these strategies are ongoing.

  8. 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.

  9. 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

  10. Defective neuropeptide processing and ischemic brain injury: a study on proprotein convertase 2 and its substrate neuropeptide in ischemic brains

    PubMed Central

    Zhan, Shuqin; Zhao, Hongbo; White, Aaron J; Minami, Manabu; Pignataro, Giuseppe; Yang, Tao; Zhu, Xiaorong; Lan, Jingquan; Xiong, Zhigang; Steiner, Donald F; Simon, Roger P; Zhou, An

    2010-01-01

    Using a focal cerebral ischemia model in rats, brain ischemia-induced changes in expression levels of mRNA and protein, and activities of proprotein convertase 2 (PC2) in the cortex were examined. In situ hybridization analyses revealed a transient upregulation of the mRNA level for PC2 at an early reperfusion hour, at which the level of PC2 protein was also high as determined by immunocytochemistry and western blotting. When enzymatic activities of PC2 were analyzed using a synthetic substrate, a significant decrease was observed at early reperfusion hours at which levels of PC2 protein were still high. Also decreased at these reperfusion hours were tissue levels of dynorphin-A(1–8) (DYN-A(1–8)), a PC2 substrate, as determined by radioimmunoassay. Further examination of PC2 protein biosynthesis by metabolic labeling in cultured neuronal cells showed that in ischemic cells, the proteolytic processing of PC2 was greatly attenuated. Finally, in mice, an intracerebroventricular administration of synthetic DYN-A(1–8) significantly reduced the extent of ischemic brain injury. In mice those lack an active PC2, exacerbated brain injury was observed after an otherwise non-lethal focal ischemia. We conclude that brain ischemia attenuates PC2 and PC2-mediated neuropeptide processing. This attenuation may play a role in the pathology of ischemic brain injury. PMID:19142196

  11. 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.

  12. Successful Nonoperative Management of High-Grade Blunt Renal Injuries

    PubMed Central

    Darwish, Oussama; Dang, Brian; Monda, John J.; Adsul, Prajakta; Syed, Johar; Siddiqui, Sameer A.

    2016-01-01

    Current management of high-grade blunt renal trauma favors a nonoperative approach when possible. We performed a retrospective study of high grade blunt renal injuries at our level I trauma center to determine the indications and success of nonoperative management (NOM). 47 patients with blunt grade IV or V injuries were identified between October 2004 and December 2013. Immediate operative patients (IO) were compared to nonoperatively managed (NOM). Of the 47 patients, 3 (6.4%) were IO and 44 (95.6%) NOM. IO patients had a higher heart rate on admission, 133 versus 100 in NOM (P = 0.01). IO patients had a higher rate of injury to the renal vein or artery (100%) compared to NOM group (18%) (P = 0.01). NOM failed in 3 of 44 patients (6.8%). Two required nonemergent nephrectomy and one required emergent exploration resulting in nephrectomy. Six NOM patients had kidney-related complications (13.6%). The renal salvage rate for the entire cohort was 87.2% and 93.2% for NOM. Nonoperative management for hemodynamically stable patients with high-grade blunt renal trauma is safe with a low risk of complications. Management decisions should consider hemodynamic status and visualization of active renal bleeding as well as injury grade in determining operative management. PMID:28018427

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

    PubMed

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

    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.

  14. 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

  15. Sulodexide pretreatment attenuates renal ischemia-reperfusion injury in rats.

    PubMed

    Yin, Jianyong; Chen, Weibin; Ma, Fenfen; Lu, Zeyuan; Wu, Rui; Zhang, Guangyuan; Wang, Niansong; Wang, Feng

    2017-02-07

    Sulodexide is a potent antithrombin agent, however, whether it has beneficial effects on renal ischemia-reperfusion injury (IRI) remains unknown. In the present study, we assessed the therapeutic effects of sulodexide in renal IRI and tried to investigate the potential mechanism. One dose of sulodexide was injected intravenously in Sprague-Dawley rats 30 min before bilateral kidney ischemia for 45 min. The animals were sacrificed at 3h and 24h respectively. Our results showed that sulodexide pretreatment improved renal dysfunction and alleviated tubular pathological injury at 24h after reperfusion, which was accompanied with inhibition of oxidative stress, inflammation and cell apoptosis. Moreover, we noticed that antithrombin III (ATIII) was activated at 3h after reperfusion, which preceded the alleviation of renal injury. For in vitro study, hypoxia/reoxygenation (H/R) injury model for HK2 cells was carried out and apoptosis and reactive oxygen species (ROS) levels were evaluated after sulodexide pretreatment. Consistently, sulodexide pretreatment could reduce apoptosis and ROS level in HK2 cells under H/R injury. Taken together, sulodexide pretreatment might attenuate renal IRI through inhibition of inflammation, oxidative stress and apoptosis, and activation of ATIII.

  16. Protective effects of glycine during hypothermic renal ischemia-reperfusion injury.

    PubMed

    Mangino, M J; Murphy, M K; Grabau, G G; Anderson, C B

    1991-11-01

    The objective of this investigation was to test the effects of glycine, a cytoprotectant in normothermic in vitro models of renal ischemia, in a model of hypothermic renal preservation injury. This study also probes possible physiological mechanisms of glycine protection during renal hypothermic ischemia-reperfusion injury. Canine kidneys were subjected to 48 h of hypothermic ischemia (4 degrees C) after intravascular flush with cold conventional Collins solution (G. H. Collins, M. B. Bravo-Shugarman, and P. I. Terasaki, Lancet 2: 1219-1223, 1969) and were subsequently revascularized for 1 h. After 1 h of reperfusion, glomerular filtration rate, urine production, and electrolyte excretion were dramatically higher when the Collins flush contained 5 mM glycine, compared with the 0 mM glycine controls. Renal tissue adenine nucleotides and glutathione levels progressively declined with graded cold ischemia times, and glycine had no effect on these levels. However, renal tissue ATP levels (but not glutathione) were significantly higher when kidneys were flushed with glycine, stored for 48 h, and reoxygenated in vitro for 1 h at 37 degrees C, compared with kidneys flushed without glycine. Analysis of CoA esters from ischemic renal tissue indicated altered production of only butyryl CoA after 48 and 72 h of cold ischemia, but no differences were detected in glycine or control kidneys. In conclusion, this study reports dramatic functional preservation with glycine in kidneys subjected to hypothermic ischemia and in vivo reperfusion. The mechanisms of these effects appear not to be attributable to the maintenance of cellular adenine nucleotide or glutathione levels nor to the scavenging of accumulated amphipathic acyl CoA esters.

  17. 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

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

    PubMed

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

    2016-01-01

    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. 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. 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. N. sativa and its components are beneficial in prevention and curing of renal diseases including nephrolithiasis and renal damages.

  19. 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

  20. Dietary intake of sugar substitutes aggravates cerebral ischemic injury and impairs endothelial progenitor cells in mice.

    PubMed

    Dong, Xiao-Hui; Sun, Xin; Jiang, Guo-Jun; Chen, Alex F; Xie, He-Hui

    2015-06-01

    In our current food supply, sugar substitutes are widely used in beverages and other food products. However, there is limited information about the link between dietary consumption of sugar substitutes and stroke to date. This study sought to determine the effect of various sugar substitutes on the cerebral ischemic injury and endothelial progenitor cells, which have been implicated to play an important role in vascular repair and revascularization in ischemic brain tissues, in mice. After treatment with sucrose and various sugar substitutes (the doses are in the range of corresponding acceptable daily intake levels) and vehicle for 6 weeks, mice were subjected to permanent left middle cerebral artery occlusion, and the infarct volumes, angiogenesis, and neurobehavioral outcomes were determined. In addition, the number and function of endothelial progenitor cells were also examined. After long-term treatment with fructose, erythritol (sugar alcohols), acesulfame K (artificial sweeteners), or rebaudioside A (rare sugars), the cerebral ischemic injury (both infarct volumes and neurobehavioral outcomes) was significantly aggravated, angiogenesis in ischemic brain was reduced, and endothelial progenitor cell function was impaired in mice compared with control. However, the similar impairments were not found in sucrose (with the same dose as fructose's)-treated mice. Long-term consumption of sugar substitutes aggravated cerebral ischemic injury in mice, which might be partly attributed to the impairment of endothelial progenitor cells and the reduction of angiogenesis in ischemic brain. This result implies that dietary intake of sugar substitutes warrants further attention in daily life. © 2015 American Heart Association, Inc.

  1. Growth and development alter susceptibility to acute renal injury.

    PubMed

    Zager, Richard A; Johnson, Ali C M; Naito, Masayo; Lund, Steve R; Kim, Nayeon; Bomsztyk, Karol

    2008-09-01

    Many of the studies of acute renal injury have been conducted in young mice usually during their rapid growth phase; yet, the impact of age or growth stage on the degree of injury is unknown. To address this issue, we studied three forms of injury (endotoxemic-, glycerol-, and maleate-induced) in mice ranging in age from adolescence (3 weeks) to maturity (16 weeks). The severity of injury within each model significantly correlated with weight and age. We also noticed a progressive age-dependent reduction in renal cholesterol content, a potential injury modifier. As the animals grew and aged they also exhibited stepwise decrements in the mRNAs of HMG CoA reductase and the low density lipoprotein receptor, two key cholesterol homeostatic genes. This was paralleled by decreased amounts of RNA polymerase II and the transcription factor SREBP1/2 at the reductase and lipoprotein receptor gene loci as measured by chromatin immunoprecipitation. Our study shows that the early phase of mouse growth can profoundly alter renal susceptibility to diverse forms of experimental acute renal injury.

  2. Renal functional reserve and renal recovery after acute kidney injury.

    PubMed

    Sharma, Aashish; Mucino, Marìa Jimena; Ronco, Claudio

    2014-01-01

    Renal functional reserve (RFR) represents the capacity of the kidney to increase glomerular filtration rate (GFR) in response to certain physiological or pathological stimuli or conditions. Once baseline GFR is determined, RFR can be assessed clinically after an oral protein load or intravenous amino acid infusion. In clinical practice, baseline GFR displays variable levels due to diet or other factors. RFR is the difference between peak 'stress' GFR induced by the test (p.o. or i.v.) and the baseline GFR. In clinical scenarios where hyperfiltration is present (high baseline GFR due to pregnancy, hypertension or diabetic nephropathy, in solitary kidney or kidney donors), RFR may be fully or partially used to achieve normal or supranormal renal function. Since commonly used renal function markers, such as GFR, may remain within normal ranges until 50% of nephrons are lost or in patients with a single remnant kidney, the RFR test may represent a sensitive and early way to assess the functional decline in the kidney. RFR assessment may become an important tool to evaluate the ability of the kidney to recover completely or partially after a kidney attack. In case of healing with a defect and progressive fibrosis, recovery may appear complete clinically, but a reduced RFR may be a sign of a maladaptive repair or subclinical loss of renal mass. Thus, a reduction in RFR may represent the equivalent of renal frailty or susceptibility to insults. The main aim of this article is to review the concept of RFR, its utility in different clinical scenarios, and future perspective for its use.

  3. 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

  4. Multiple carcinomas in the hemodialysis access induced ischemic hand of a renal transplant patient.

    PubMed

    Van Hoek, Frank; Van Tits, Herm W; Van Lijnschoten, Ineke; De Haas, Boudewijn D; Scheltinga, Marc R

    2010-01-01

    Long term immunosuppression following organ transplantation promotes the onset of skin cancers. A renal transplant patient developed multiple hyperkeratotic nodi in the left hand and digital pain following prolonged immunosuppression. Several skin abnormalities were observed in an ischemic and atrophic left hand in the presence of a patent Cimino-Brescia arteriovenous fistula previously used for hemodialysis. Severe hand ischemia was confirmed by digital plethysmography. Pathological examination of all 7 excised skin lesions indicated manifestations of well differentiated squamous cell carcinomas (SCC). Severe loco-regional ischemia due to an intact hemodialysis access may enhance the toxic effects of chronic immunosuppressive medication. Oxidative stress may act as a co-carcinogenic factor for the development of SCC in renal transplant patients receiving immunosuppressive agents.

  5. 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.

  6. 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.

  7. Epicatechin limits renal injury by mitochondrial protection in cisplatin nephropathy.

    PubMed

    Tanabe, Katsuyuki; Tamura, Yoshifuru; Lanaspa, Miguel A; Miyazaki, Makoto; Suzuki, Norihiko; Sato, Waichi; Maeshima, Yohei; Schreiner, George F; Villarreal, Francisco J; Johnson, Richard J; Nakagawa, Takahiko

    2012-11-01

    Cisplatin nephropathy can be regarded as a mitochondrial disease. Intervention to halt such deleterious injury is under investigation. Recently, the flavanol (-)-epicatechin emerges as a novel compound to protect the cardiovascular system, owing in part to mitochondrial protection. Here, we have hypothesized that epicatechin prevents the progression of cisplatin-induced kidney injury by protecting mitochondria. Epicatechin was administered 8 h after cisplatin injury was induced in the mouse kidney. Cisplatin significantly induced renal dysfunction and tubular injury along with an increase in oxidative stress. Mitochondrial damages were also evident as a decrease in loss of mitochondrial mass with a reduction in the oxidative phosphorylation complexes and low levels of MnSOD. The renal damages and mitochondrial injuries were significantly prevented by epicatechin treatment. Consistent with these observations, an in vitro study using cultured mouse proximal tubular cells demonstrated that cisplatin-induced mitochondrial injury, as revealed by a decrease in mitochondrial succinate dehydrogenase activity, an induction of cytochrome c release, mitochondrial fragmentation, and a reduction in complex IV protein, was prevented by epicatechin. Such a protective effect of epicatechin might be attributed to decreased oxidative stress and reduced ERK activity. Finally, we confirmed that epicatechin did not perturb the anticancer effect of cisplatin in HeLa cells. In conclusion, epicatechin exhibits protective effects due in part to its ability to prevent the progression of mitochondrial injury in mouse cisplatin nephropathy. Epicatechin may be a novel option to treat renal disorders associated with mitochondrial dysfunction.

  8. Epicatechin limits renal injury by mitochondrial protection in cisplatin nephropathy

    PubMed Central

    Tanabe, Katsuyuki; Tamura, Yoshifuru; Lanaspa, Miguel A.; Miyazaki, Makoto; Suzuki, Norihiko; Sato, Waichi; Maeshima, Yohei; Schreiner, George F.; Villarreal, Francisco J.; Johnson, Richard J.

    2012-01-01

    Cisplatin nephropathy can be regarded as a mitochondrial disease. Intervention to halt such deleterious injury is under investigation. Recently, the flavanol (–)-epicatechin emerges as a novel compound to protect the cardiovascular system, owing in part to mitochondrial protection. Here, we have hypothesized that epicatechin prevents the progression of cisplatin-induced kidney injury by protecting mitochondria. Epicatechin was administered 8 h after cisplatin injury was induced in the mouse kidney. Cisplatin significantly induced renal dysfunction and tubular injury along with an increase in oxidative stress. Mitochondrial damages were also evident as a decrease in loss of mitochondrial mass with a reduction in the oxidative phosphorylation complexes and low levels of MnSOD. The renal damages and mitochondrial injuries were significantly prevented by epicatechin treatment. Consistent with these observations, an in vitro study using cultured mouse proximal tubular cells demonstrated that cisplatin-induced mitochondrial injury, as revealed by a decrease in mitochondrial succinate dehydrogenase activity, an induction of cytochrome c release, mitochondrial fragmentation, and a reduction in complex IV protein, was prevented by epicatechin. Such a protective effect of epicatechin might be attributed to decreased oxidative stress and reduced ERK activity. Finally, we confirmed that epicatechin did not perturb the anticancer effect of cisplatin in HeLa cells. In conclusion, epicatechin exhibits protective effects due in part to its ability to prevent the progression of mitochondrial injury in mouse cisplatin nephropathy. Epicatechin may be a novel option to treat renal disorders associated with mitochondrial dysfunction. PMID:22933302

  9. Acute renal injury induced by valacyclovir hydrochloride: A case report

    PubMed Central

    Zhang, Yanning; Cong, Yuxi; Teng, Yan

    2016-01-01

    Acyclovir has been a frequently used antiviral agent in the clinical treatment of leukemia, acute encephalitis, malignant tumor and herpes simplex. The adverse effects of this drug have been widely described in clinical practice. In the present study, a case of a 35-year-old female patient diagnosed with herpes simplex, who developed acute renal injury following treatment with valacyclovir hydrochloride, is described. Kidney biopsy, light microscopy and laboratory examination were performed, and all findings revealed the signs of evident vacuolar degeneration of capillary endothelial and renal tubular epithelial cells, erythrocyte aggregation in partial renal tubule and microvilli exfoliation from epithelial cells. Renal interstitial edema was clearly identified. The clinical evidence observed from this female patient indicated that renal functions should be closely monitored during valacyclovir hydrochloride administration. A variety of effective measures, such as hydration, alkalizing urine, promoting the discharge of medication and the use of antagonists are recommended following the administration of antiviral agents. PMID:28101180

  10. Effect of renal function status on the prognostic value of heart rate in acute ischemic stroke patients.

    PubMed

    Zhu, Zhengbao; Zhong, Chongke; Xu, Tian; Wang, Aili; Peng, Yanbo; Xu, Tan; Peng, Hao; Chen, Chung-Shiuan; Wang, Jinchao; Ju, Zhong; Li, Qunwei; Geng, Deqin; Sun, Yingxian; Du, Qingjuan; Li, Yongqiu; Chen, Jing; Zhang, Yonghong; He, Jiang

    2017-08-01

    The association between heart rate and prognosis of ischemic stroke remains debatable, and whether renal function status influences the relationship between them is still not elucidated. A total of 3923 ischemic stroke patients were included in this prospective multicenter study from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke. Secondary outcomes were, separately, death and major disability. The association between heart rate tertiles and primary outcome was appreciably modified by renal function status (pinteraction = 0.037). After multivariate adjustment, high heart rate was associated with increased risk of primary outcome in patients with abnormal renal function (odds ratio, 1.61; 95% confidence interval, 1.02-2.54; ptrend = 0.039) but not in patients with normal renal function (odds ratio, 0.96; 95% confidence interval, 0.75-1.23; ptrend = 0.741), when two extreme tertiles were compared. Each 10 bpm increase of heart rate was associated with 21% (95% CI: 1%-44%) increased risk of primary outcome, and a linear association between heart rate and risk of primary outcome was observed among patients with abnormal renal function (p for linearity = 0.002). High heart rate may be merely a strong predictor of poor prognosis in acute ischemic stroke patients with abnormal renal function, suggesting that heart rate reduction should be applied to ischemic stroke patients with abnormal renal function to improve their prognosis. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. IL-37 inhibits IL-18-induced tubular epithelial cell expression of pro-inflammatory cytokines and renal ischemia-reperfusion injury.

    PubMed

    Yang, Yunbo; Zhang, Zhu-Xu; Lian, Dameng; Haig, Aaron; Bhattacharjee, Rabindra N; Jevnikar, Anthony M

    2015-02-01

    Cytokines and chemokines produced by tubular epithelial and infiltrating cells are critical to inflammation in renal ischemia-reperfusion injury. IL-37, a newly described IL-1 family member, inhibits IL-18-dependent pro-inflammatory cytokine production by its binding to IL-18 receptors and IL-18 binding protein. The potential role of IL-37 in renal ischemia-reperfusion injury is unknown. Here we found that exposure of tubular epithelial cells to exogenous IL-37 downregulated hypoxia and the IL-18-induced expression of TNFα, IL-6, and IL-1β. Importantly, human PT-2 tubular epithelial cells have inducible expression of IL-37. Moreover, pro-inflammatory cytokine expression was augmented in IL-37 mRNA-silenced tubular epithelial cells and inhibited by transfection with pCMV6-XL5-IL-37. In a mouse ischemic injury model, transgenic expression of human IL-37 inhibited kidney expression of TNFα, IL-6, and IL-1β and improved mononuclear cell infiltration, kidney injury, and function. Thus, human tubular epithelial cells express the IL-18 contra-regulatory protein IL-37 as an endogenous control mechanism to reduce inflammation. Augmenting kidney IL-37 may represent a novel strategy to suppress renal injury responses and promote kidney function after renal ischemic injury and transplantation.

  12. Erythropoietin-enhanced endothelial progenitor cell recruitment in peripheral blood and renal vessels during experimental acute kidney injury in rats.

    PubMed

    Cakiroglu, Figen; Enders-Comberg, Sora Maria; Pagel, Horst; Rohwedel, Jürgen; Lehnert, Hendrik; Kramer, Jan

    2016-03-01

    Beneficial effects of erythropoietin (EPO) have been reported in acute kidney injury (AKI) when administered prior to induction of AKI. We studied the effects of EPO administration on renal function shortly after ischemic AKI. For this purpose, rats were subjected to renal ischemia for 30 min and EPO was administered at a concentration of 500 U/kg either i.v. as a single shot directly after ischemia or with an additional i.p. dose until 3 days after surgery. The results were compared with AKI rats without EPO application and a sham-operated group. Renal function was assessed by measurement of serum biochemical markers, histological grading, and using an isolated perfused kidney (IPK) model. Furthermore, we performed flow cytometry to analyze the concentration of endothelial progenitor cells (EPCs) in the peripheral blood and renal vessels. Following EPO application, there was only a statistically non-significant tendency of serum creatinine and urea to improve, particularly after daily EPO application. Renal vascular resistance and the renal perfusion rate were not significantly altered. In the histological analysis, acute tubular necrosis was only marginally ameliorated following EPO administration. In summary, we could not demonstrate a significant improvement in renal function when EPO was applied after AKI. Interestingly, however, EPO treatment resulted in a highly significant increase in CD133- and CD34-positive EPC both in the peripheral blood and renal vessels.

  13. ALDOSE REDUCTASE PATHWAY CONTRIBUTES TO VULNERABILITY OF AGING MYOCARDIUM TO ISCHEMIC INJURY

    PubMed Central

    Ananthakrishnan, Radha; Li, Qing; Gomes, Teodoro; Schmidt, Ann Marie; Ramasamy, Ravichandran

    2011-01-01

    Aging men and women display both increased incidence of cardiovascular disease and complications of myocardial infarction and heart failure. We hypothesized that altered glucose metabolism, in particular, flux of glucose via the polyol pathway (PP) may be responsible, in part, for the enhanced vulnerability of aging myocardium to ischemic injury, even in the absence of superimposed disease processes linked to PP flux, such as diabetes. To test our hypothesis, we determined the expression and products of PP enzymes aldose reductase (AR) and sorbitol dehydrogenase (SDH) in hearts from Fischer 344 aged (26 month) and young (4 month) rats subjected to global ischemia followed by reperfusion in the presence or absence of blockers of PP and the measures of ischemic injury and functional recovery were determined. Expression and activities of AR and SDH were significantly higher in aged vs. young hearts, and induction of ischemia further increased AR and SDH activity in the aged hearts. Myocardial ischemic injury was significantly greater in aged vs. young hearts, and blockade of AR reduced ischemic injury and improved cardiac functional recovery on reperfusion in aged hearts. These data indicate that innate increases in activity of the PP enzymes augment myocardial vulnerability to I/R injury in aging, and that blockers of PP protect the vulnerable aging hearts. PMID:21600277

  14. Betaxolol, a beta1-adrenoceptor antagonist, protects a transient ischemic injury of the retina.

    PubMed

    Woo Cheon, Eun; Hee Kim, Young; Yun Cho, Yi; Joon Kim, Hyun; Soo Kang, Sang; Jae Cho, Gyeong; Myong Yoo, Ji; Kyung Song, Joon; Sung Choi, Wan

    2002-11-01

    In the present study, we investigated the protective effects of the topical beta-adrenoceptor antagonist Betoptic((R)) (0.25% betaxolol) in the rat retina following the ischemic injury induced by a transient increase of intraocular pressure (IOP). Like other areas of the central nervous system, the retina is highly vulnerable to ischemic-induced injury. Ischemia was induced in the rat retina by raising the IOP above the systolic blood pressure for 60min. After an ischemia/reperfusion, the thickness of the retinal layers and the immunoreactivities of choline acetyltransferase (ChAT), gamma-amino butyric acid (GABA) and tyrosine hydroxylase (TH) were examined. After a reperfusion period of 7 days, the thickness of both the inner plexiform layer and inner nuclear layer was much decreased. After a reperfusion period of 14-28 days, the thickness of the outer nuclear layer decreased markedly. Moreover, the ChAT and TH immunoreactivity had almost completely disappeared in the retinas after 7 days, while GABA immunoreactivity remained for 28 days. These results suggest that the inner retinal layers are more susceptible to ischemic-induced injury than the outer retinal layer.Histological examination demonstrated protective effects of betaxolol on ischemic-induced retinal damage, which was more substantial in the inner retinal layer. When two drops of betaxolol, once before ischemic injury and twice daily for 28 days after ischemia, were continuously administered, the reductions in the retinal ChAT, GABA and TH immunoreactivities were significantly attenuated. The present study suggests that topically applied betaxolol is an efficient neuroprotective agent and prevents the retinal cell damage induced by ischemic injury in rats.

  15. Delayed treatment with ADAMTS13 ameliorates cerebral ischemic injury without hemorrhagic complication.

    PubMed

    Nakano, Takafumi; Irie, Keiichi; Hayakawa, Kazuhide; Sano, Kazunori; Nakamura, Yoshihiko; Tanaka, Masayoshi; Yamashita, Yuta; Satho, Tomomitsu; Fujioka, Masayuki; Muroi, Carl; Matsuo, Koichi; Ishikura, Hiroyasu; Futagami, Kojiro; Mishima, Kenichi

    2015-10-22

    Tissue plasminogen activator (tPA) is the only approved therapy for acute ischemic stroke. However, delayed tPA treatment increases the risk of cerebral hemorrhage and can result in exacerbation of nerve injury. ADAMTS13, a von Willebrand factor (VWF) cleaving protease, has a protective effect against ischemic brain injury and may reduce bleeding risk by cleaving VWF. We examined whether ADAMTS13 has a longer therapeutic time window in ischemic stroke than tPA in mice subjected to middle cerebral artery occlusion (MCAO). ADAMTS13 (0.1mg/kg) or tPA (10mg/kg) was administered i.v., immediately after reperfusion of after 2-h or 4-h MCAO for comparison of the therapeutic time windows in ischemic stroke. Infarct volume, hemorrhagic volume, plasma high-mobility group box1 (HMGB1) levels and cerebral blood flow were measured 24h after MCAO. Both ADAMTS13 and tPA improved the infarct volume without hemorrhagic complications in 2-h MCAO mice. On the other hand, ADAMTS13 reduced the infarct volume and plasma HMGB1 levels, and improved cerebral blood flow without hemorrhagic complications in 4-h MCAO mice, but tPA was not effective and these animals showed massive intracerebral hemorrhage. These results indicated that ADAMTS13 has a longer therapeutic time window in ischemic stroke than tPA, and ADAMTS13 may be useful as a new therapeutic agent for ischemic stroke.

  16. Protective roles of puerarin and Danshensu on acute ischemic myocardial injury in rats.

    PubMed

    Wu, L; Qiao, H; Li, Y; Li, L

    2007-10-01

    Ischemic heart diseases have been the leading cause of death in both developed and developing countries over the past decades. The aim of this study was to investigate the cardioprotective effects of the complex preparation (called Shenge), made of puerarin (isolated from Pueraria lobata Ohwi., also called Kudzu) and Danshensu (isolated from the Chinese herb, Salvia miltiorrhiza), on acute ischemic myocardial injury in rats and its underlying mechanisms. The left anterior descending (LAD) coronary artery was occluded to induce myocardial ischemia in the hearts of SD rats. Shenge was injected into the tail vein 15 min after occlusion at doses of 0, 30, 60, or 120 mg/kg body wt. ST elevation was then measured at 60, 120, and 240 min after Shenge administration. The ischemic size, serum levels of creatine kinase isoenzyme-MB (CK-MB), lactate dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA), and ST elevation were measured after the rats were sacrificed. Shenge decreased ST elevation induced by acute myocardial ischemia, reduced ischemic size, serum levels of CK-MB, LDH and MDA, and increased serum activity of SOD in a dose-dependent manner. The combined use of puerarin and Danshensu at a ratio of 1:1 showed the most effective activity. In conclusion, Shenge exerts significant cardioprotective effects against acute ischemic myocardial injury in rats, likely through its antioxidant and anti-lipid peroxidation properties, and thus may be an effective and promising medicine for both prophylaxis and treatment of ischemic heart disease.

  17. Carnosine protects the brain of rats and Mongolian gerbils against ischemic injury: after-stroke-effect.

    PubMed

    Dobrota, Dusan; Fedorova, Tatiana; Stvolinsky, Sergey; Babusikova, Eva; Likavcanova, Katarina; Drgova, Anna; Strapkova, Adriana; Boldyrev, Alexander

    2005-10-01

    Carnosine, a specific constituent of excitable tissues of vertebrates, exhibits a significant antioxidant protecting effect on the brain damaged by ischemic-reperfusion injury when it was administered to the animals before ischemic episode. In this study, the therapeutic effect of carnosine was estimated on animals when this drug was administered intraperitoneally (100 mg/kg body weight) after ischemic episode induced by experimental global brain ischemia. Treatment of the animals with carnosine after ischemic episode under long-term (7-14 days) reperfusion demonstrated its pronounced protective effect on neurological symptoms and animal mortality. Carnosine also prevented higher lipid peroxidation of brain membrane structures and increased a resistance of neuronal membranes to the in vitro induced oxidation. Measurements of malonyl dialdehyde (MDA) in brain homogenates showed its increase in the after brain stroke animals and decreased MDA level in the after brain stroke animals treated with carnosine. We concluded that carnosine compensates deficit in antioxidant defense system of brain damaged by ischemic injury. The data presented demonstrate that carnosine is effective in protecting the brain in the post-ischemic period.

  18. 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

  19. A3 adenosine receptor agonist reduces brain ischemic injury and inhibits inflammatory cell migration in rats.

    PubMed

    Choi, In-Young; Lee, Jae-Chul; Ju, Chung; Hwang, Sunyoung; Cho, Geum-Sil; Lee, Hyuk Woo; Choi, Won Jun; Jeong, Lak Shin; Kim, Won-Ki

    2011-10-01

    A3 adenosine receptor (A3AR) is recognized as a novel therapeutic target for ischemic injury; however, the mechanism underlying anti-ischemic protection by the A3AR agonist remains unclear. Here, we report that 2-chloro-N(6)-(3-iodobenzyl)-5'-N-methylcarbamoyl-4'-thioadenosine (LJ529), a selective A3AR agonist, reduces inflammatory responses that may contribute to ischemic cerebral injury. Postischemic treatment with LJ529 markedly reduced cerebral ischemic injury caused by 1.5-hour middle cerebral artery occlusion, followed by 24-hour reperfusion in rats. This effect was abolished by the simultaneous administration of the A3AR antagonist MRS1523, but not the A2AAR antagonist SCH58261. LJ529 prevented the infiltration/migration of microglia and monocytes occurring after middle cerebral artery occlusion and reperfusion, and also after injection of lipopolysaccharides into the corpus callosum. The reduced migration of microglia by LJ529 could be related with direct inhibition of chemotaxis and down-regulation of spatiotemporal expression of Rho GTPases (including Rac, Cdc42, and Rho), rather than by biologically relevant inhibition of inflammatory cytokine/chemokine release (eg, IL-1β, TNF-α, and MCP-1) or by direct inhibition of excitotoxicity/oxidative stress (not affected by LJ529). The present findings indicate that postischemic activation of A3AR and the resultant reduction of inflammatory response should provide a promising therapeutic strategy for the treatment of ischemic stroke.

  20. 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

  1. Ischemic and Nephrotoxic Acute Renal Failure are Distinguished by their Broad Transcriptomic Responses (102/160 char)

    PubMed Central

    Yuen, Peter S.T.; Jo, Sang-Kyung; Holly, Mikaela K.; Hu, Xuzhen; Star, Robert A.

    2006-01-01

    Acute renal failure (ARF) has a high morbidity and mortality. In animal ARF models, effective treatments must be administered before or shortly after the insult, limiting their clinical potential. We used microarrays to identify early biomarkers that distinguish ischemic from nephrotoxic ARF, or biomarkers that detect both injury types. We compared rat kidney transcriptomes 2 and 8 hours after ischemia/reperfusion and after mercuric chloride. Quality control and statistical analyses were necessary to normalize microarrays from different lots, eliminate outliers, and exclude unaltered genes. Principal component analysis revealed distinct ischemic and nephrotoxic trajectories, and clear array groupings. Therefore, we used supervised analysis, t-tests and fold changes, to compile gene lists for each group, exclusive or non-exclusive, alone or in combination. There was little network connectivity, even in the largest group. Some microarray-identified genes were validated by TaqMan assay, ruling out artifacts. Western blotting confirmed that HO-1 and ATF3 proteins were upregulated; however, unexpectedly, their localization changed within the kidney. HO-1 staining shifted from cortical (early) to outer stripe of the outer medulla (late), primarily in detaching cells, after mercuric chloride, but not ischemia/reperfusion. ATF3 staining was similar, but with additional early transient expression in the outer stripe after ischemia/reperfusion. We conclude that microarray-identified genes must be evaluated not only for protein levels, but also for anatomical distribution among different zones, nephron segments, or cell types. Although protein detection reagents are limited, microarray data lay a rich foundation to explore biomarkers, therapeutics, and pathophysiology of ARF. PMID:16507785

  2. Keratins are novel markers of renal epithelial cell injury.

    PubMed

    Djudjaj, Sonja; Papasotiriou, Marios; Bülow, Roman D; Wagnerova, Alexandra; Lindenmeyer, Maja T; Cohen, Clemens D; Strnad, Pavel; Goumenos, Dimitrios S; Floege, Jürgen; Boor, Peter

    2016-04-01

    Keratins, the intermediate filaments of the epithelial cell cytoskeleton, are up-regulated and post-translationally modified in stress situations. Renal tubular epithelial cell stress is a common finding in progressive kidney diseases, but little is known about keratin expression and phosphorylation. Here, we comprehensively describe keratin expression in healthy and diseased kidneys. In healthy mice, the major renal keratins, K7, K8, K18, and K19, were expressed in the collecting ducts and K8, K18 in the glomerular parietal epithelial cells. Tubular expression of all 4 keratins increased by 20- to 40-fold in 5 different models of renal tubular injury as assessed by immunohistochemistry, Western blot, and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The up-regulation became significant early after disease induction, increased with disease progression, was found de novo in distal tubules and was accompanied by altered subcellular localization. Phosphorylation of K8 and K18 increased under stress. In humans, injured tubules also exhibited increased keratin expression. Urinary K18 was only detected in mice and patients with tubular cell injury. Keratins labeled glomerular parietal epithelial cells forming crescents in patients and animals. Thus, all 4 major renal keratins are significantly, early, and progressively up-regulated upon tubular injury regardless of the underlying disease and may be novel sensitive markers of renal tubular cell stress. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  3. [Pathophysiology of brain injury and targets of treatment in acute ischemic stroke].

    PubMed

    Tanaka, Kortaro

    2013-01-01

    Brain is very vulnerable to ischemia, and exhibits various functional impairments in a flow-dependent manner. After onset of ischemia, the following cascade ensues propagating from the ischemic core to the surrounding area; ischemic depolarization, excitatory cellular injury induced by Ca(2+) and glutamate, oxidative injury induced by reactive oxygen species including various free radicals, secondary microcirculatory disturbance, edema formation, apoptosis and inflammation. Intrinsic protective responses are also activated at the periphery of ischemic area. From the clinical view point, urgent detection of "penumbra" area by imaging modalities such as diffusion-perfusion mismatch and rescuing this area from evolving into irreversible damage (infarction) are the most important issues. Therapeutic targets in the acute phase of cerebral infarction consist of vascular therapy including acute thrombolysis, prevention of microcirculatory disturbance, protection of blood brain barrier and promotion of collateral blood flow, and cellular therapy such as neuroprotective measures aiming at neurovascular unit.

  4. Glomerular haematuria, renal interstitial haemorrhage and acute kidney injury.

    PubMed

    Martín Cleary, Catalina; Moreno, Juan Antonio; Fernández, Beatriz; Ortiz, Alberto; Parra, Emilio G; Gracia, Carolina; Blanco-Colio, Luis M; Barat, Antonio; Egido, Jesús

    2010-12-01

    Macroscopic haematuria of glomerular origin has been associated with acute kidney injury. We report a patient with IgA nephropathy, macroscopic haematuria and acute kidney injury. Systemic anticoagulation may have aggravated haematuria. There was extensive interstitial and intratubular red blood cell extravasation, and interstitial haemosiderin deposits. The abundant presence of macrophages expressing the haemoglobin scavenger receptor CD163 and of cells stained for oxidative stress markers (NADPH-p22 phox and heme-oxigenase-1) in areas of interstitial haemorrhage and red blood cell cast-containing tubules provided evidence for a role for free haemoglobin in tubulointerstitial renal injury in human glomerular disease.

  5. Alcohol-induced exacerbation of ischemic brain injury: role of NAD(P)H oxidase.

    PubMed

    Zhao, Honggang; Mayhan, William G; Arrick, Denise M; Xiong, Wanfen; Sun, Hong

    2010-11-01

     Chronic alcohol consumption increases ischemic stroke and exacerbates ischemic brain injury. We determined the role of NAD(P)H oxidase in exacerbated ischemic brain injury during chronic alcohol consumption.  Sprague Dawley rats were fed a liquid diet with or without alcohol (6.4% v/v) for 8 weeks. We measured the effect of apocynin on 2-hour middle cerebral artery occlusion (MCAO)/24-hour reperfusion-induced brain injury. In addition, superoxide production and expression of NAD(P)H oxidase subunit, gp91phox, in the peri-infarct area were assessed. Chronic alcohol consumption produced a larger infarct volume, worse neurological score, and higher superoxide production. Acute (5 mg/kg, ip, 30 minutes before MCAO) and chronic treatment with apocynin (7.5 mg/kg/d in the diet, 4 weeks prior to MCAO) reduced infarct volume, improved neurological outcome, and attenuated superoxide production in alcohol-fed rats. Expression of gp91phox at basal conditions and following ischemia/reperfusion was greater in alcohol-fed rats compared to non-alcohol-fed rats. In addition, neurons are partially responsible for upregulated gp91phox during alcohol consumption. Our findings suggest that NAD(P)H oxidase may play an important role in exacerbated ischemic brain injury during chronic alcohol consumption. Copyright © 2010 by the Research Society on Alcoholism.

  6. 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

  7. 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.

  8. Blunt renal artery injury: incidence, diagnosis, and management.

    PubMed

    Bruce, L M; Croce, M A; Santaniello, J M; Miller, P R; Lyden, S P; Fabian, T C

    2001-06-01

    Renal artery injury is a rare complication of blunt abdominal trauma. Increasing use of CT scans to evaluate blunt abdominal trauma identifies more blunt renal artery injuries (BRAIs) that may have otherwise been missed. We identified patients with BRAI to examine the incidence and to evaluate the current diagnosis and management strategies. Patients admitted from 1986 to 2000 at a regional Level I trauma center sustaining BRAI were evaluated. Patients undergoing revascularization or nonoperative management were followed for renovascular hypertension. Twenty-eight patients with BRAI were identified out of 36,938 blunt trauma admissions between 1986 and 2000 (incidence 0.08%). Most renal artery injuries were diagnosed by CT scans (93%) with seven confirmatory angiograms. Nine patients had nephrectomy (one bilateral), and three patients with unilateral injuries were revascularized. Sixteen were managed nonoperatively including one patient who had endovascular stent placement. Three patients died from shock and sepsis. Follow-up for all patients ranged from one month to 8 years. Two patients developed hypertension: one who was revascularized (33%) and one was managed nonoperatively (6%). The frequency of diagnosis of BRAI is increasing because of the increased use of CT. Nonoperative management of unilateral injuries can be successful with a 6 per cent risk for developing renovascular hypertension. The role of endovascular stenting is promising, and further study is necessary.

  9. The effect of thymoquinone on the renal functions following ischemia-reperfusion injury in the rat

    PubMed Central

    Hammad, Fayez T; Lubbad, Loay

    2016-01-01

    Introduction: The aim of this study was to investigate the effect of thymoquinone, an antioxidant phytochemical compound found in the plant Nigella sativa, on the alterations in renal functional parameters following warm renal ischemia-reperfusion injury (IRI) in the rat. Methods: Wistar rats underwent left renal ischemia for 35 minutes. Group-TQ (n=15) received thymoquinone 10 mg/kg/day (dissolved in a vehicle (corn oil) orally by gavage starting 4 days prior to IRI and continued 6 days thereafter when the hemodynamic and tubular renal functions of the right and left kidneys were measured using clearance techniques. Group-Vx (n=15) underwent similar protocol but received only the vehicle. Results: IRI affected all hemodynamic and tubular parameters in the affected kidney. Thymoquinone attenuated the IRI-related alteration in renal functions so when the left ischemic kidney in Group-TQ and Group-Vx were compared, the left RBF and GFR were significantly higher in Group-TQ (2.02±0.39 vs. 1.27±0.21, P=0.04 and 0.33±0.08 vs. 0.18±0.03, P=0.03, respectively). Thymoquinone also improved left renal FENa (1.59±0.28 vs. 2.40±0.35, P=0.04). In addition, it decreased the gene expressions of KIM-1, NGAL, TNF-α, TGF-β1 and PAI-1 (143±20 vs. 358±49, 16±3 vs. 34±6, (1.1±0.2 vs. 2.8±0.4, 1.6±0.1 vs. 2.8±0.1, and 2.4±0.3 vs. 5.8±1.0, P<0.05 for all). Conclusion: Thymoquinone ameliorated the IRI effect on the hemodynamic and tubular renal functional parameters as well as the expression of some kidney injury markers and pro-inflammatory and pro-fibrotic cytokines indicating a renoprotective effect of this agent on the IRI-induced renal dysfunction with potential clinical implications. PMID:28078054

  10. Chronic nicotine exposure augments renal oxidative stress and injury through transcriptional activation of p66shc.

    PubMed

    Arany, Istvan; Clark, Jeb; Reed, Dustin K; Juncos, Luis A

    2013-06-01

    Chronic nicotine (Ch-NIC) exposure exacerbates ischemia/reperfusion (I/R)-induced oxidative stress and acute kidney injury (AKI), and mitochondrial production of reactive oxygen species (ROS) in cultured renal proximal tubule cells (RPTCs). Because Ser36-phosphorylated p66shc modulates mitochondrial ROS production and injury of RPTCs, we hypothesized that Ch-NIC exacerbates AKI by increasing stress-induced phosphorylation of p66shc. We first tested whether Ch-NIC augments I/R-AKI-induced expression and phosphorylation of p66shc in vivo. We then examined whether knocking down p66shc, or impairing its Ser36 phosphorylation or binding to cytochrome c, alters the effects of Ch-NIC on oxidative stress (H₂O₂)-induced production of ROS, mitochondrial depolarization and injury in RPTCs in vitro. We found that Ch-NIC increased the expression of p66shc in the control and ischemic kidneys, but only increased its Ser36 phosphorylation after renal I/R. Knocking down p66shc or impairing phosphorylation of its Ser36 residue, via the S36A mutation (but not the phosphomimetic S36D mutation), blunted Ch-NIC + H2O2-dependent ROS production, mitochondrial depolarization and injury in RPTCs. Additionally, Ch-NIC + H2O2-dependent binding of p66shc to mitochondrial cytochrome c was attenuated by S36A mutation of p66shc, and impairing cytochrome c binding (via W134F mutation) abolished ROS production, mitochondrial depolarization and injury, while ectopic overexpression of p66shc (which mimics Ch-NIC treatment) augmented oxidant injury. We determined that Ch-NIC stimulates the p66shc promoter through p53- and epigenetic modification (promoter hypomethylation). Ch-NIC worsens oxidative stress-dependent acute renal injury by increasing expression and consequent oxidative stress-dependent Ser36 phosphorylation of p66shc. Thus, targeting this pathway may have therapeutic relevance in preventing/ameliorating tobacco-related kidney injury.

  11. Chronic nicotine exposure augments renal oxidative stress and injury through transcriptional activation of p66shc

    PubMed Central

    Arany, Istvan; Clark, Jeb; Reed, Dustin K.; Juncos, Luis A.

    2013-01-01

    Background Chronic nicotine (Ch-NIC) exposure exacerbates ischemia/reperfusion (I/R)-induced oxidative stress and acute kidney injury (AKI), and mitochondrial production of reactive oxygen species (ROS) in cultured renal proximal tubule cells (RPTCs). Because Ser36-phosphorylated p66shc modulates mitochondrial ROS production and injury of RPTCs, we hypothesized that Ch-NIC exacerbates AKI by increasing stress-induced phosphorylation of p66shc. Methods We first tested whether Ch-NIC augments I/R-AKI-induced expression and phosphorylation of p66shc in vivo. We then examined whether knocking down p66shc, or impairing its Ser36 phosphorylation or binding to cytochrome c, alters the effects of Ch-NIC on oxidative stress (H2O2)-induced production of ROS, mitochondrial depolarization and injury in RPTCs in vitro. Results We found that Ch-NIC increased the expression of p66shc in the control and ischemic kidneys, but only increased its Ser36 phosphorylation after renal I/R. Knocking down p66shc or impairing phosphorylation of its Ser36 residue, via the S36A mutation (but not the phosphomimetic S36D mutation), blunted Ch-NIC + H2O2-dependent ROS production, mitochondrial depolarization and injury in RPTCs. Additionally, Ch-NIC + H2O2-dependent binding of p66shc to mitochondrial cytochrome c was attenuated by S36A mutation of p66shc, and impairing cytochrome c binding (via W134F mutation) abolished ROS production, mitochondrial depolarization and injury, while ectopic overexpression of p66shc (which mimics Ch-NIC treatment) augmented oxidant injury. We determined that Ch-NIC stimulates the p66shc promoter through p53- and epigenetic modification (promoter hypomethylation). Conclusions Ch-NIC worsens oxidative stress-dependent acute renal injury by increasing expression and consequent oxidative stress-dependent Ser36 phosphorylation of p66shc. Thus, targeting this pathway may have therapeutic relevance in preventing/ameliorating tobacco-related kidney injury. PMID:23328708

  12. Effects of Renal Ischemic Postconditioning on Myocardial Ultrastructural Organization and Myocardial Expression of Bcl-2/Bax in Rabbits

    PubMed Central

    Zhang, Wen-zhong; Li, Rong; Liu, Song; Ning, Xian-feng; Cai, Shang-lang

    2016-01-01

    We investigated the cardioprotective effect of renal ischemic postconditioning (RI-PostC) and its mechanisms in a rabbit model. Rabbits underwent 60 min of left anterior descending coronary artery occlusion (LADO) and 6 h of reperfusion. The ischemia-reperfusion (IR) group underwent LADO and reperfusion only. In the RI-PostC group, the left renal artery underwent 3 cycles of occlusion for 30 seconds and release for 30 seconds, before the coronary artery was reperfused. In the RI-PostC + GF109203X group, the rabbits received 0.05 mg/kg GF109203X (protein kinase C inhibitor) intravenously for 10 min followed by RI-PostC. Light microscopy and electron microscopy demonstrated that the RI-PostC group showed less pronounced changes, a smaller infarct region, and less apoptosis than the other two groups. Bcl-2 and Bax protein expression did not differ between the IR and RI-PostC + GF109203X groups. However, in the RI-PostC group, Bcl-2 protein expression was significantly higher and Bax protein expression was significantly lower than in the other two groups (P < 0.05). Changes in heart rate and mean arterial pressure were also smaller in the RI-PostC group than in the other two groups. These results indicate that RI-PostC can ameliorate myocardial ischemia-reperfusion injury and increase the Bcl-2/Bax ratio through a mechanism involving protein kinase C. PMID:28097153

  13. 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

  14. Peripheral administration of fetuin-A attenuates early cerebral ischemic injury in rats

    PubMed Central

    Wang, Haichao; Li, Wei; Zhu, Shu; Li, Jianhua; D'Amore, Jason; Ward, Mary F; Yang, Huan; Wu, Rongqian; Jahnen-Dechent, Willi; Tracey, Kevin J; Wang, Ping; Sama, Andrew E

    2010-01-01

    Cerebral ischemia-elicited inflammatory responses are driven by inflammatory mediators produced both by central (e.g., neurons and microglia) and infiltrating peripheral immune cells (e.g., macrophage/monocyte), and contribute to the evolution of tissue injury. A ubiquitous molecule, spermine, is released from injured cells, and counter-regulates release of various proinflammatory cytokines. However, the spermine-mediated anti-inflammatory activities are dependent on the availability of fetuin-A, a liver-derived negative acute-phase protein. Using an animal model of focal cerebral ischemia (i.e., permanent middle cerebral artery occlusion, MCAo), we found that levels of fetuin-A in the ischemic brain tissue were elevated in a time-dependent manner, starting between 2 and 6 h, peaking around 24 to 48 h, and returning to baseline 72 h after MCAo. When administered peripherally, exogenous fetuin-A gained entry across the BBB into the ischemic brain tissue, and dose dependently reduced brain infarct volume at 24 h after MCAo. Meanwhile, fetuin-A effectively attenuated (i) ischemia-induced HMGB1 depletion from the ischemic core; (ii) activation of centrally (e.g., microglia) and peripherally derived immune cells (e.g., macrophage/monocytes); and (iii) TNF production in ischemic brain tissue. Taken together, these experimental data suggest that fetuin-A protects against early cerebral ischemic injury partly by attenuating the brain inflammatory response. PMID:19953099

  15. Ischemic Bowel Syndrome in Patients with Spinal Cord Injury: A Nationwide Study

    PubMed Central

    Tseng, Chih-Wei; Lin, Cheng-Li; Chen, Yu-Tso; Jeng, Long-Bin

    2017-01-01

    Purpose The aim of this study was to determine whether spinal cord injuries (SCI) is associated with increased risk of ischemic bowel syndrome (IBS) in an Asian population by analyzing data from the National Health Insurance Research Database (NHIRD) in Taiwan. Methods Patients aged ≥20 years in the inpatient database with newly identified SCI from 2000 to 2011 were selected as the SCI cohort. For the non-SCI cohort, patients were selected based on a 1:4 risk-set sampling. Hospitalization with a new diagnosis of IBS during the follow-up was the main outcome measure. We used the standard univariable and multivariable Cox proportional hazard regression models to determine adjusted subhazard ratios (SHR) and 95% confidence interval (CI) in the SCI and non-SCI cohorts. Results Patients with SCI were at significant risk for IBS, with an adjusted SHR (aSHR) of 1.25, 95% CI = 1.04–1.51. Multivariable analysis showed individuals with SCI were associated with a greater risk of IBS than individuals without SCI among males (aSHR = 1.47, 95% CI = 1.16–1.86), all age groups (≤49 y: aSHR = 2.15, 95% CI = 1.24–3.74; 50–65 y: aSHR = 1.82, 95% CI = 1.15–2.88; >65 y: aSHR = 1.39, 95% CI = 1.11–1.74) and those without comorbidities (aSHR = 1.41, 95% CI = 1.04–1.93). Comorbidities including diabetes, hypertension, heart failure, coronary artery disease (CAD), Stroke, and end stage renal disease (ESRD) significantly increased the risk of IBS. Conclusion Patients hospitalized for SCI have increased risks of developing IBS. Though the mechanism that predisposes SCI patients to IBS is unclear, we suggest that physicians promptly identify and treat correctable risk factors. PMID:28056095

  16. Mitochondrial dysfunction in inherited renal disease and acute kidney injury.

    PubMed

    Emma, Francesco; Montini, Giovanni; Parikh, Samir M; Salviati, Leonardo

    2016-05-01

    Mitochondria are increasingly recognized as key players in genetic and acquired renal diseases. Most mitochondrial cytopathies that cause renal symptoms are characterized by tubular defects, but glomerular, tubulointerstitial and cystic diseases have also been described. For example, defects in coenzyme Q10 (CoQ10) biosynthesis and the mitochondrial DNA 3243 A>G mutation are important causes of focal segmental glomerulosclerosis in children and in adults, respectively. Although they sometimes present with isolated renal findings, mitochondrial diseases are frequently associated with symptoms related to central nervous system and neuromuscular involvement. They can result from mutations in nuclear genes that are inherited according to classic Mendelian rules or from mutations in mitochondrial DNA, which are transmitted according to more complex rules of mitochondrial genetics. Diagnosis of mitochondrial disorders involves clinical characterization of patients in combination with biochemical and genetic analyses. In particular, prompt diagnosis of CoQ10 biosynthesis defects is imperative because of their potentially reversible nature. In acute kidney injury (AKI), mitochondrial dysfunction contributes to the physiopathology of tissue injury, whereas mitochondrial biogenesis has an important role in the recovery of renal function. Potential therapies that target mitochondrial dysfunction or promote mitochondrial regeneration are being developed to limit renal damage during AKI and promote repair of injured tissue.

  17. Mitochondrial dysfunction in inherited renal disease and acute kidney injury

    PubMed Central

    Emma, Francesco; Montini, Giovanni; Parikh, Samir M.; Salviati, Leonardo

    2017-01-01

    Mitochondria are increasingly recognized as key players in genetic and acquired renal diseases. Most mitochondrial cytopathies that cause renal symptoms are characterized by tubular defects, but glomerular, tubulointerstitial and cystic diseases have also been described. For example, defects in coenzyme Q10 (CoQ10) biosynthesis and the mitochondrial DNA 3243 A>G mutation are important causes of focal segmental glomerulosclerosis in children and in adults, respectively. Although they sometimes present with isolated renal findings, mitochondrial diseases are frequently associated with symptoms related to central nervous system and neuromuscular involvement. They can result from mutations in nuclear genes that are inherited according to classic Mendelian rules or from mutations in mitochondrial DNA, which are transmitted according to more complex rules of mitochondrial genetics. Diagnosis of mitochondrial disorders involves clinical characterization of patients in combination with biochemical and genetic analyses. In particular, prompt diagnosis of CoQ10 biosynthesis defects is imperative because of their potentially reversible nature. In acute kidney injury (AKI), mitochondrial dysfunction contributes to the physiopathology of tissue injury, whereas mitochondrial biogenesis has an important role in the recovery of renal function. Potential therapies that target mitochondrial dysfunction or promote mitochondrial regeneration are being developed to limit renal damage during AKI and promote repair of injured tissue. PMID:26804019

  18. Preventive Effects of a Natural Anti-Inflammatory Agent, Astragaloside IV, on Ischemic Acute Kidney Injury in Rats

    PubMed Central

    Tan, Shufeng; Wang, Guofu; Guo, Yongping; Gui, Dingkun; Wang, Niansong

    2013-01-01

    This study investigated the anti-inflammatory effects of astragaloside IV(AS-IV) on ischemia/reperfusion (IR) induced acute kidney injury (AKI) in rats. Experimental model of ischemic AKI was induced in rats by bilateral renal artery clamp for 45 min followed by reperfusion of 12 h and 24 h, respectively. AS-IV was orally administered once a day to rats at 10 and 20 mg·kg−1·d−1 for 7 days prior to ischemia. AS-IV pretreatment significantly decreased serum urea, creatinine, and cystatin C levels at 12 h and 24 h of reperfusion in AKI rats. AS-IV pretreatment also ameliorated tubular damage and suppressed the phosphorylation of p65 subunit of NF-κB in AKI rats. Moreover, NF-κB and MPO activity as well as serum and tissue levels of TNF-α, MCP-1, and ICAM-1 were elevated in AKI rats. All of these abnormalities were prevented by AS-IV. Furthermore, AS-IV downregulated the mRNA expression of NF-κB, TNF-α, MCP-1, and ICAM-1 in AKI rats. These results suggest that AS-IV might be developed as a novel therapeutic approach to prevent ischemic AKI through inhibition of NF-κB mediated inflammatory genes expression. PMID:23853656

  19. Cytoprotective Actions of FTY720 Modulate Severe Preservation Reperfusion Injury in Rat Renal Transplants.

    PubMed

    Fuller, T Florian; Hoff, Uwe; Kong, Linghua; Naether, Melanie; Wagner, Philine; Nieminen-Kelhä, Melina; Nolting, Jochen; Luft, Friedrich C; Hegner, Björn; Dragun, Duska

    2010-02-27

    Fingolimod (FTY720) is a potent agonist of sphingosine 1 phosphate receptors and thereby interferes with lymphocyte trafficking. We previously showed that FTY720 protects from mild preservation reperfusion injury induced by 4 hr of cold ischemia. The purpose of this study was to explore the role of FTY720 in ischemic injury and regeneration using a clinically relevant rat renal transplant model with 24 hr of cold ischemia. Donor kidneys were cold stored in the University of Wisconsin solution for 24 hr before transplantation into bilaterally nephrectomized syngeneic recipients (n=6 per group), which received 0.5 mg/kg/d FTY720 or vehicle through oral gavage. Grafts were harvested 2 or 7 days posttransplantation. Renal tissue was examined histologically, stained for apoptosis, proliferation, inflammatory cell infiltrates, and studied for transforming growth factor-beta, and tumor necrosis factor-alpha expression. Rat proximal tubular cells were incubated with 0.1 to 30 micromol/L of phosphorylated FTY720 to test for in vitro cytopathic effects. FTY720 induced peripheral lymphopenia and significantly reduced intragraft CD3 and ED1 infiltrates. Acute tubular damage scores and graft function were not influenced by FTY720. Tubular apoptosis was significantly reduced, whereas the number of proliferating cell nuclear antigen-positive tubular cells were markedly increased. FTY720 attenuated renal tumor necrosis factor-alpha and transforming growth factor-beta expression. In vitro, pharmacologic concentrations up to 1 micromol/L of phosphorylated FTY720 did not affect tubular cell viability. FTY720 confers tubular epithelial protection in the presence of severe preservation reperfusion injury. Beneficial effects may in part be due to reduction in cell-mediated immune mechanisms. Furthermore, FTY720 could be helpful in patients with delayed graft function.

  20. A Metabolic Index of Ischemic Injury for Perfusion-Recovery of Cadaveric Rat Livers

    PubMed Central

    Tolboom, Herman; Uygun, Basak; Berthiaume, Francois; Yarmush, Martin L.; Uygun, Korkut

    2011-01-01

    With over 110,000 patients waiting for organ transplantation, the current crisis in organ transplantation is based on a lack of donors after brain-death (DBD). A very large alternative pool of donor organs that remain untapped are the donors after cardiac death (DCD), recovered after cardiac activity has ceased and therefore sustained some ischemic injury. Machine perfusion has been proposed as a novel modality of organ preservation and treatment to render such cadaveric organs, and in particular livers, transplantable. Two key issues that remain unaddressed are how to assess whether a DCD liver is damaged beyond repair, and whether machine perfusion has rendered an injured organ sufficiently viable for transplantation. In this work, we present a metabolic analysis of the transient responses of cadaveric rat livers during normothermic machine perfusion (NMP), and develop an index of ischemia that enables evaluation of the organ ischemic injury level. Further, we perform a discriminant analysis to construct a classification algorithm with >0.98 specificity to identify whether a given perfused liver is ischemic or fresh, in effect a precursor for an index of transplantability and a basis for the use of statistical process control measures for automated feedback control of treatment of ischemic injury in DCD livers. The analyses yield an index based on squared prediction error (SPE) as log(SPE) >1.35 indicating ischemia. The differences between metabolic functions of fresh and ischemic livers during perfusion are outlined and the metabolites that varied significantly for ischemic livers are identified as ornithine, arginine, albumin and tyrosine. PMID:22194843

  1. 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

  2. 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

  3. 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.

  4. Diallyl disulfide attenuates acetaminophen-induced renal injury in rats.

    PubMed

    Shin, Jin-Young; Han, Ji-Hee; Ko, Je-Won; Park, Sung-Hyeuk; Shin, Na-Rae; Jung, Tae-Yang; Kim, Hyun-A; Kim, Sung-Hwan; Shin, In-Sik; Kim, Jong-Choon

    2016-12-01

    This study investigated the protective effects of diallyl disulfide (DADS) against acetaminophen (AAP)-induced acute renal injury in male rats. We also investigated the effects of DADS on kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), which are novel biomarkers of nephrotoxicity in renal tissues, in response to AAP treatment. The following four experimental groups were evaluated: (1) vehicle control, (2) AAP (1,000 mg/kg), (3) AAP&DADS, and (4) DADS (50 mg/kg/day). AAP treatment caused acute kidney injury evidenced by increased serum blood urea nitrogen (BUN) levels and histopathological alterations. Additionally, Western blot and immunohistochemistry analysis showed increased expression of KIM-1 and NGAL proteins in renal tissues of AAP-treated rats. In contrast, DADS pretreatment significantly attenuated the AAP-induced nephrotoxic effects, including serum BUN level and expression of KIM-1 and NGAL proteins. Histopathological studies confirmed the renoprotective effect of DADS. The results suggest that DADS prevents AAP-induced acute nephrotoxicity, and that KIM-1 and NGAL may be useful biomarkers for the detection and monitoring of acute kidney injury associated with AAP exposure.

  5. Diallyl disulfide attenuates acetaminophen-induced renal injury in rats

    PubMed Central

    Shin, Jin-Young; Han, Ji-Hee; Ko, Je-Won; Park, Sung-Hyeuk; Shin, Na-Rae; Jung, Tae-Yang; Kim, Hyun-A; Kim, Sung-Hwan; Shin, In-Sik

    2016-01-01

    This study investigated the protective effects of diallyl disulfide (DADS) against acetaminophen (AAP)-induced acute renal injury in male rats. We also investigated the effects of DADS on kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), which are novel biomarkers of nephrotoxicity in renal tissues, in response to AAP treatment. The following four experimental groups were evaluated: (1) vehicle control, (2) AAP (1,000 mg/kg), (3) AAP&DADS, and (4) DADS (50 mg/kg/day). AAP treatment caused acute kidney injury evidenced by increased serum blood urea nitrogen (BUN) levels and histopathological alterations. Additionally, Western blot and immunohistochemistry analysis showed increased expression of KIM-1 and NGAL proteins in renal tissues of AAP-treated rats. In contrast, DADS pretreatment significantly attenuated the AAP-induced nephrotoxic effects, including serum BUN level and expression of KIM-1 and NGAL proteins. Histopathological studies confirmed the renoprotective effect of DADS. The results suggest that DADS prevents AAP-induced acute nephrotoxicity, and that KIM-1 and NGAL may be useful biomarkers for the detection and monitoring of acute kidney injury associated with AAP exposure. PMID:28053613

  6. 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

  7. Transient receptor potential melastatin 2 channels (TRPM2) mediate neonatal hypoxic-ischemic brain injury in mice.

    PubMed

    Huang, Sammen; Turlova, Ekaterina; Li, Feiya; Bao, Mei-Hua; Szeto, Vivian; Wong, Raymond; Abussaud, Ahmed; Wang, Haitao; Zhu, Shuzhen; Gao, Xinzheng; Mori, Yasuo; Feng, Zhong-Ping; Sun, Hong-Shuo

    2017-10-01

    Transient receptor potential melastatin 2 (TRPM2), a calcium-permeable non-selective cation channel, is reported to mediate brain damage following ischemic insults in adult mice. However, the role of TRPM2 channels in neonatal hypoxic-ischemic brain injury remains unknown. We hypothesize that TRPM2(+/-) and TRPM2(-/-) neonatal mice have reduced hypoxic-ischemic brain injury. To study the effect of TRPM2 on neonatal brain damage, we used 2,3,5-triphenyltetrazolium chloride (TTC) staining to assess the infarct volume and whole brain imaging to assess morphological changes in the brain. In addition, we also evaluated neurobehavioral outcomes for sensorimotor function 7days following hypoxic-ischemic brain injury. We report that the infarct volumes were significantly smaller and behavioral outcomes were improved in both TRPM2(+/-) and TRPM2(-/-) mice compared to that of wildtype mice. Next, we found that TRPM2-null mice showed reduced dephosphorylation of GSK-3β following hypoxic ischemic injury unlike sham mice. TRPM2(+/-) and TRPM2(-/-) mice also had reduced activation of astrocytes and microglia in ipsilateral hemispheres, compared to wildtype mice. These findings suggest that TRPM2 channels play an essential role in mediating hypoxic-ischemic brain injury in neonatal mice. Genetically eliminating TRPM2 channels can provide neuroprotection against hypoxic-ischemic brain injury and this effect is elicited in part through regulation of GSK-3β. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. 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

  9. Grape seed proanthocyanidin extract reduces renal ischemia/reperfusion injuries in rats.

    PubMed

    Wei, Ribao; Ding, Rui; Wang, Yongxin; Tang, Li

    2012-06-01

    Activation of reactive oxygen species and inflammation are implicated in renal ischemia/reperfusion (I/R) injuries. This study investigated whether grape seed proanthocyanidin extract (GSPE) protects against renal I/R injury by its effect on reactive oxygen species and the inflammation pathway. Wistar rats were administered GSPE before renal ischemia, followed by reperfusion for 24 hours. Plasma concentrations of urea, creatinine and cystatin C were measured for renal dysfunction. Serum and tissue superoxide dismutase activity and glutathione peroxidase and malondialdehyde levels were measured. Renal sections were analyzed for histological grading of renal injury, and nuclear factor-ĸB activity was determined. GSPE significantly reduced increases in urea, creatinine and cystatin C; increased kidney superoxide dismutase activity and glutathione peroxidase levels and reduced malondialdehyde levels. GSPE reduced histological renal damage and nuclear factor-ĸB activity. These results suggest that GSPE reduces renal dysfunction and injury caused by renal I/R.

  10. Cortical neurogenesis in adult rats after ischemic brain injury: most new neurons fail to mature.

    PubMed

    Li, Qing-Quan; Qiao, Guan-Qun; Ma, Jun; Fan, Hong-Wei; Li, Ying-Bin

    2015-02-01

    The present study examines the hypothesis that endogenous neural progenitor cells isolated from the neocortex of ischemic brain can differentiate into neurons or glial cells and contribute to neural regeneration. We performed middle cerebral artery occlusion to establish a model of cerebral ischemia/reperfusion injury in adult rats. Immunohistochemical staining of the cortex 1, 3, 7, 14 or 28 days after injury revealed that neural progenitor cells double-positive for nestin and sox-2 appeared in the injured cortex 1 and 3 days post-injury, and were also positive for glial fibrillary acidic protein. New neurons were labeled using bromodeoxyuridine and different stages of maturity were identified using doublecortin, microtubule-associated protein 2 and neuronal nuclei antigen immunohistochemistry. Immature new neurons coexpressing doublecortin and bromodeoxyuridine were observed in the cortex at 3 and 7 days post-injury, and semi-mature and mature new neurons double-positive for microtubule-associated protein 2 and bromodeoxyuridine were found at 14 days post-injury. A few mature new neurons coexpressing neuronal nuclei antigen and bromodeoxyuridine were observed in the injured cortex 28 days post-injury. Glial fibrillary acidic protein/bromodeoxyuridine double-positive astrocytes were also found in the injured cortex. Our findings suggest that neural progenitor cells are present in the damaged cortex of adult rats with cerebral ischemic brain injury, and that they differentiate into astrocytes and immature neurons, but most neurons fail to reach the mature stage.

  11. Enhanced recovery from chronic ischemic injury by bone marrow cells in a rat model of ischemic stroke.

    PubMed

    Yoo, Jongman; Seo, Jin-Ju; Eom, Jang-Hyeon; Hwang, Dong-Youn

    2015-01-01

    Even after decades of intensive studies, therapeutic options for patients with stroke are rather limited. Thrombolytic drugs effectively treat the very acute stage of stroke, and several neuroprotectants that are designed to treat secondary injury following stroke are being tested in clinical trials. However, these pharmacological approaches primarily focus on acute stroke recovery, and few options are available for treating chronic stroke patients. In recent years, stem cell-mediated regenerative approaches have emerged as promising therapeutic strategies for treating the chronic stage of stroke. In this study, we examined whether systemically administered bone marrow cells (BMCs) could have beneficial effects in a rat model of chronic ischemia. Our transplantation experiments using BMCs obtained from ischemic donor rats showed functional and structural recovery during the chronic stage of stroke. BMC-mediated neural proliferation was prominent in the brains of rats with chronic stroke, and most of the new cells eventually became neurons instead of astrocytes. BMC-mediated enhanced neural proliferation coincided with a significant reduction (∼50%) in the number of activated microglia, which is consistent with previous reports of enhanced neural proliferation being linked to microglial inactivation. Strikingly, approximately 57% of the BMCs that infiltrated the chronic ischemic brain were CD25(+) cells, suggesting that these cells may exert the beneficial effects associated with BMC transplantation. Based on the reported anti-inflammatory role of CD25(+) regulatory T-cells in acute experimental stroke, we propose a working model delineating the positive effects of BMC transplantation during the chronic phase of stroke; infiltrating BMCs (mostly CD25(+) cells) reduce activated microglia, which leads to enhanced neural proliferation and enhanced recovery from neuronal damage in this rat model of chronic stroke. This study provides valuable insights into the effect

  12. Application of principal component analysis to study topography of hypoxic-ischemic brain injury.

    PubMed

    Singhal, Shaloo; Chen, Jian; Beare, Richard; Ma, Henry; Ly, John; Phan, Thanh G

    2012-08-01

    The regions at risk of ischemia following cardio-respiratory arrest have not been systematically analysed. This knowledge may be of use in determining the mechanism of ischemic injury at vulnerable sites. The aim of this study is to evaluate the use of principal component analysis to analyse the covariance patterns of hypoxic ischemic injury. The inclusion criteria were: age ≥ 17 years, cardio-respiratory arrest and coma on admission (2003-2011). Regions of ischemic injury were manually segmented on fluid attenuated inversion recovery (FLAIR) and diffusion weighted (DWI) sequences and linearly registered into common stereotaxic coordinate space. Topography of ischemic injury was assessed using principal component analysis (covariance data) and compared qualitatively against current method of topography analysis, the probabilistic method (frequency data). For the probabilistic data, subgroup analyses were performed using t-statistics while for the covariance data, subgroup analyses were performed by calculating the angle between the principle components. To account for bias due to a higher frequency of coma survivors in the studied group, we performed sensitivity analysis by sequentially removing coma survivors such that the final data set contained higher rate of death. Quantitative analysis between these methods could not be performed as they have different units of measurement. Forty one patients were included in this series (mean age ± SD=51.5 ± 18.9 years). In our probabilistic map, the highest frequency of ischemic injury on the DWI and FLAIR sequences was putamen (0.250), caudate (0.225), temporal lobes (0.175), occipital (0.150) and hippocampus (0.125). The first 6 principal components contained 77.7% of the variance of the data. The first component showed covariance between the deep grey matter nuclei and posterior cortical structures (contains 50.2% of the variance of the data). There was similarity in the findings of the subgroup analyses by the

  13. Protective Effects of Hydrocortisone, Vitamin C and E Alone or in Combination against Renal Ischemia-Reperfusion Injury in Rat

    PubMed Central

    Azari, Omid; Kheirandish, Reza; Azizi, Shahrzad; Farajli Abbasi, Mohammad; Ghahramani Gareh Chaman, Shahin; Bidi, Masoud

    2015-01-01

    Background: Renal ischemia reperfusion injury may occur in a variety of clinical situations, following a transient drop in total or regional blood flow to the kidney. This study was performed to investigate the protective effects of different antioxidants such as vitamin C, vitamin E, hydrocortisone and combination of these agents against experimental renal ischemia-reperfusion injury. Method: Thirty male rats were divided into six groups. Group Sham, Group I/R: (45 min of ischemia followed by 1h of reperfusion), Group I/R+Vit C: (50 mg/kg Vit C, IV, immediately after reperfusion), Group I/R+Vit E: (20 mg/kg Vit E, IM, 15 min before reperfusion), Group I/R+Hydrocortisone: (50 mg/kg, IV, immediately after reperfusion), and Group Combination: Ischemia-reperfusion plus combination of Vit C, E and hydrocortisone. After the experiments, the left kidney was removed and the tissues were processed for histopathological examination. Result: Severe injuries such as necrosis of tubules, atrophy of glomerulus, and hemorrhage were observed in group I/R. Histological scores indicating tissue injury significantly decreased in all treatment groups compared to the group I/R. The renal tissue in group treatment was preserved in comparison with the group I/R. Comparison between the treatment groups showed that group combination was more effective and group vit E was less effective in protecting of renal tissue against I/R injuries. Conclusion: The results demonstrated simultaneous administration of combination of Vit C, E and hydrocortisone before reperfusion of blood flow to the ischemic tissue could show a synergy against deleterious effects of I/R injuries in kidney. PMID:26351497

  14. Slit2 ameliorates renal inflammation and fibrosis after hypoxia-and lipopolysaccharide-induced epithelial cells injury in vitro.

    PubMed

    Zhou, Xiangjun; Yao, Qisheng; Sun, Xinbo; Gong, Xiaoxin; Yang, Yong; Chen, Congbo; Shan, Guang

    2017-03-01

    Hypoxic acute kidney injury (AKI) is often incompletely repaired and leads to chronic kidney disease (CKD), which is characterized by tubulointerstitial inflammation and fibrosis. The Slit2 family of secreted glycoproteins is expressed in the kidney, it has been shown to exert an anti-inflammatory activity and prevent ischemic renal injury in vivo. However, whether Slit2 reduces renal fibrosis and inflammation after hypoxic and inflammatory epithelial cells injury in vitro remains unknown. In this study, we aimed to evaluate whether Slit2 ameliorated fibrosis and inflammation in two renal epithelial cells line challenged with hypoxia and lipopolysaccharide (LPS). Renal epithelial cells were treated with hypoxia and LPS to induce cell injury. Hoechst staining and Western blot analysis was conducted to examine epithelial cells injury. Immunofluorescence staining and Western blot analysis was performed to evaluate tubulointerstitial fibrosis. Real-time polymerase chain reaction (PCR) tested the inflammatory factor interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and Western blot analysis determined the hypoxia-inducible factor (HIF)-1α, Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB. Results revealed that hypoxia induced epithelial cells apoptosis, inflammatory factor IL-1β and TNF-α release and tubulointerstitial fibrosis. LPS could exacerbate hypoxia -induced epithelial cells apoptosis, IL-1β and TNF-α release and fibrosis. Slit2 reduced the expression of fibronectin, the rate of epithelial cell apoptosis, and the expression of inflammatory factor. Slit2 could also inhibit the expression of TLR4 and NF-κB, but not the expression of HIF-1α. Therefore, Slit2 attenuated inflammation and fibrosis after LPS- and hypoxia-induced epithelial cells injury via the TLR4/NF-κB signaling pathway, but not depending on the HIF-1α signaling pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Salt restriction inhibits renal growth and stabilizes injury in rats with established renal disease.

    PubMed

    Dworkin, L D; Benstein, J A; Tolbert, E; Feiner, H D

    1996-03-01

    Salt restriction inhibits renal growth and stabilizes injury in rats with established renal disease. Male Munich-Wistar rats that underwent right nephrectomy and segmental infarction of two thirds of the left kidney were fed standard chow for 4 wk and then randomly assigned to ingest standard or low-salt chow for an additional 4 wk. Four wk after ablation, rats had systemic hypertension, proteinuria, and glomerular sclerosis. The prevalence of sclerosis, protein excretion rate, and glomerular volume increased between the fourth and eighth week in rats that were fed standard chow, however, in rats that were fed low-salt chow, the increase in glomerular volume and development of further glomerular sclerosis was prevented whereas the protein excretion rate actually declined. Micropuncture studies performed 8 wk after ablation revealed that the glomerular hydraulic pressure was elevated in remnant kidneys and was not affected by salt restriction. This study demonstrates that dietary salt restriction can prevent further glomerular injury and reduce proteinuria even when instituted in rats with established renal disease. These findings are also consistent with the hypothesis that glomerular hypertrophy promotes injury in this model of hypertension and progressive renal disease.

  16. 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.

  17. Efficacy of Ficus spp. on renal injury induced by hypercholesterolaemia.

    PubMed

    Awad, Nagwa E; Hamed, Manal A; Seida, Ahmed A; Elbatanony, Marwa M

    2012-01-01

    The ethanol and hexane extracts of Ficus microcarpa, Ficus religiosa and Ficus mysorensis leaves were evaluated against renal injury induced by hypercholesterolaemia. Phytochemical screening of the investigated plants was undertaken. For the in vivo study, all rats were orally given cholesterol (30 mg kg⁻¹ body weight, BW) and leaves extract (500 mg kg⁻¹ BW) five times per week for 9 weeks. Hypercholesterolaemic rats showed significant increases in urea nitrogen and creatinine while serum protein and albumin levels, nitric oxide (NO), Na⁺-K⁺-ATPase and phospholipids in kidney tissue were all decreased. Treatment with leaves extract improved kidney function indices (urea nitrogen, creatinine, serum protein and albumin), kidney disorder biochemical parameters (NO, Na⁺-K⁺-ATPase and phospholipids), haematological profile (haemoglobin, RBCs and WBCs) and kidney histopathology. In conclusion, Ficus spp. succeeded in improving renal injury induced by hypercholesterolaemia, with the most potent effects seen while using Ficus microcarpa hexane extract.

  18. GSK-3β inhibitors suppressed neuroinflammation in rat cortex by activating autophagy in ischemic brain injury.

    PubMed

    Zhou, Xiaogang; Zhou, Jian; Li, Xilei; Guo, Chang'an; Fang, Taolin; Chen, Zhengrong

    2011-07-29

    Previous studies have shown that GSK-3β inhibitor could reduce infarct volume after ischemia brain injury. However, the underlying mechanisms of GSK-3β inhibitor involving neuroprotection remain poorly understood. In the present study, we demonstrated that GSK-3β inhibitor suppressed insult-induced neuroinflammation in rat cortex by increasing autophagy activation in ischemic injury. Male rats were subjected to pMCAO (permanent middle cerebral artery occlusion) followed by treating with SB216763, a GSK-3β inhibitor. We found that insult-induced inflammatory response was significantly decreased by intraperitoneal infusion of SB216763 in rat cortex. A higher level of autophagy was also detected after SB216763 treatment. In the cultured primary microglia, SB216763 activated autophagy and suppressed inflammatory response. Importantly, inhibition of autophagy by Beclin1-siRNA increased inflammatory response in the SB216763-treated microglia. These data suggest that GSK-3β inhibitor suppressed neuroinflammation by activating autophagy after ischemic brain injury, thus offering a new target for prevention of ischemic brain injury.

  19. Renalase protects against ischemic AKI.

    PubMed

    Lee, H Thomas; Kim, Joo Yun; Kim, Mihwa; Wang, Peili; Tang, Lieqi; Baroni, Sara; D'Agati, Vivette D; Desir, Gary V

    2013-02-01

    Elevated levels of plasma catecholamines accompany ischemic AKI, possibly contributing the inflammatory response. Renalase, an amine oxidase secreted by the proximal tubule, degrades circulating catecholamines and reduces myocardial necrosis, suggesting that it may protect against renal ischemia reperfusion injury. Here, mice subjected to renal ischemia reperfusion injury had significantly lower levels of renalase in the plasma and kidney compared with sham-operated mice. Consistent with this, plasma NE levels increased significantly after renal ischemia reperfusion injury. Furthermore, renal tubular inflammation, necrosis, and apoptosis were more severe and plasma catecholamine levels were higher in renalase-deficient mice subjected to renal ischemia reperfusion compared with wild-type mice. Administration of recombinant human renalase reduced plasma catecholamine levels and ameliorated ischemic AKI in wild-type mice. Taken together, these data suggest that renalase protects against ischemic AKI by reducing renal tubular necrosis, apoptosis, and inflammation, and that plasma renalase might be a biomarker for AKI. Recombinant renalase therapy may have potential for the prevention and treatment of AKI.

  20. Lose dose genistein inhibits glucocorticoid receptor and ischemic brain injury in female rats.

    PubMed

    Shi, Rengfei; Wang, Shunli; Qi, Xiang; Chen, Si; Chen, Peijie; Zhang, Quanguang

    2014-01-01

    Although acute bolus of genistein treatment has been shown to protect against neuronal damage in experimental brain injury animal models, chronic continuous low dose treatment of genistein on ischemic brain injury has not been well elucidated. In the present study, female rats were received either pure genistein (0.1mg/kg/day via osmotic minipumps) or placebo at the time of ovariectomy, and transient forebrain ischemia was induced 7days later. Results demonstrated that genistein treatment for 14days significantly improved ischemic neuronal survival in hippocampal CA1 region of ovariectomized rats. Glucocorticoid receptor (GR) is a member of the adrenal steroid hormone receptor, which is highly expressed in the rat hippocampus. Activation of the GR plays a critical role in the neuronal stress responses, including ischemic brain damage. This study therefore examined the potential mechanisms by which genistein regulates GR signaling, including the protein distribution and receptor activation in hippocampus following ischemic reperfusion (I/R). Results showed that GR expression in the ovariectomized rats was excessively increased both in neurons (I/R 6h) and activated microglial cells (I/R 7d) in hippocampal CA1 region. Genistein treatment significantly attenuated GR induction and the enhanced GR nuclear translocation and DNA-binding capacity. The effects of genistein on the GR levels was accompanied with decreased blood plasma levels of corticosterone (primary glucocorticoid in rodents) and coupled to an E3 ubiquitin ligase Mdm2 targeted proteasomal degradation of GR, because genistein treatment could enhance the GR-Mdm2 interaction and the ubiquitination level of GR protein. In addition, our results indicated that genistein markedly prevented the excessive activation of microglia in CA1 sector. These results demonstrate the neuroprotective action of chronic low dose genistein replacement against ischemic brain damage, and a potential mechanism associated with the

  1. 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.

  2. Immune suppression blocks sodium-sensitive hypertension following recovery from ischemic acute renal failure.

    PubMed

    Pechman, Kimberly R; Basile, David P; Lund, Hayley; Mattson, David L

    2008-04-01

    The present study determined the effect of immune suppression with mycophenolate mofetil (MMF) on sodium-sensitive hypertension following recovery from ischemia reperfusion (I/R)-induced acute renal failure. Male Sprague-Dawley rats fed 0.4% NaCl chow were subjected to 40 min bilateral I/R or control sham surgery. After 35 days of recovery, when plasma creatinine levels had returned to normal, the rats were switched to 4.0% NaCl chow for 28 days and administered vehicle or MMF (20 mg.kg(-1).day(-1) ip). High-salt mean arterial pressure was significantly higher in I/R rats (144 +/- 16 mmHg) compared with vehicle-treated sham rats (122 +/- 2 mmHg). Treatment of I/R rats with MMF during the period of high salt intake prevented the salt-induced increase in arterial pressure (114 +/- 3 mmHg). Conscious creatinine clearance was lower in I/R rats (0.27 +/- 0.07 ml.min(-1).100 g body wt(-1)) compared with vehicle-treated sham rats (0.58 +/- 0.04 ml.min(-1).100 g body wt(-1)); MMF treatment prevented the decrease in creatinine clearance in I/R rats (0.64 +/- 0.07 ml.min(-1).100 g body wt(-1)). I/R injury also significantly increased glomerular tissue damage and increased the presence of ED-1 positive (macrophages) and S100A4 positive cells (fibroblasts) in the renal interstitium. The I/R rats treated with MMF exhibited a significant reduction in infiltrating macrophages and fibroblasts and decreased histological damage. The present data indicate that infiltrating immune cells mediate or participate in the development of sodium-sensitive hypertension and renal damage in rats apparently recovered from renal I/R injury.

  3. Treatment protocols to reduce renal injury during shock wave lithotripsy

    PubMed Central

    McAteer, James A.; Evan, Andrew P.; Williams, James C.; Lingeman, James E.

    2010-01-01

    Purpose of review Growing concern over the acute and long-term adverse effects associated with shock wave lithotripsy calls for treatment strategies to reduce renal injury and improve the efficiency of stone breakage in shock wave lithotripsy. Recent findings Experimental studies in the pig model show that lithotripter settings for power and shock wave rate and the sequence of shock wave delivery can be used to reduce trauma to the kidney. Step-wise power ramping as is often used to acclimate the patient to shock waves causes less tissue trauma when the initial dose is followed by a brief (3–4 min) pause in shock wave delivery. Slowing the firing rate of the lithotripter to 60 shock waves/min or slower is also effective in reducing renal injury and has the added benefit of improving stone breakage outcomes. Neither strategy to reduce renal injury – not power ramping with ‘pause-protection’ nor delivering shock waves at reduced shock wave rate – have been tested in clinical trials. Summary Technique in lithotripsy is critically important, and it is encouraging that simple, practical steps can be taken to improve the safety and efficacy of shock wave lithotripsy. PMID:19195131

  4. Activation of cannabinoid CB2 receptor-mediated AMPK/CREB pathway reduces cerebral ischemic injury.

    PubMed

    Choi, In-Young; Ju, Chung; Anthony Jalin, Angela M A; Lee, Da In; Prather, Paul L; Kim, Won-Ki

    2013-03-01

    The type 2 cannabinoid receptor (CB2R) was recently shown to mediate neuroprotection in ischemic injury. However, the role of CB2Rs in the central nervous system, especially neuronal and glial CB2Rs in the cortex, remains unclear. We, therefore, investigated anti-ischemic mechanisms of cortical CB2R activation in various ischemic models. In rat cortical neurons/glia mixed cultures, a CB2R agonist, trans-caryophyllene (TC), decreased neuronal injury and mitochondrial depolarization caused by oxygen-glucose deprivation/re-oxygenation (OGD/R); these effects were reversed by the selective CB2R antagonist, AM630, but not by a type 1 cannabinoid receptor antagonist, AM251. Although it lacked free radical scavenging and antioxidant enzyme induction activities, TC reduced OGD/R-evoked mitochondrial dysfunction and intracellular oxidative stress. Western blot analysis demonstrated that TC enhanced phosphorylation of AMP-activated protein kinase (AMPK) and cAMP responsive element-binding protein (CREB), and increased expression of the CREB target gene product, brain-derived neurotrophic factor. However, TC failed to alter the activity of either Akt or extracellular signal-regulated kinase, two major CB2R signaling pathways. Selective AMPK and CREB inhibitors abolished the neuroprotective effects of TC. In rats, post-ischemic treatment with TC decreased cerebral infarct size and edema, and increased phosphorylated CREB and brain-derived neurotrophic factor expression in neurons. All protective effects of TC were reversed by co-administration with AM630. Collectively, these data demonstrate that cortical CB2R activation by TC ameliorates ischemic injury, potentially through modulation of AMPK/CREB signaling, and suggest that cortical CB2Rs might serve as a putative therapeutic target for cerebral ischemia.

  5. Use of Fluorescein Isothiocyanate-Inulin as a Marker for Intestinal Ischemic Injury.

    PubMed

    AlKukhun, Abedalrazaq; Caturegli, Giorgio; Munoz-Abraham, Armando Salim; Judeeba, Sami; Patron-Lozano, Roger; Morotti, Raffaella; Rodriguez-Davalos, Manuel I; Geibel, John P

    2017-06-01

    Intestinal ischemia is observed in conditions such as mesenteric ischemia, or during traumatic events such as intestinal transplantation. Intestinal ischemia leads to pathophysiologic disruptions that present as increased fluid secretion into the intestinal lumen. We propose a novel method to detect real-time ischemic injury that is used in an in vitro model applicable to intestinal transplantation. Small intestine segments from rats were procured. The segments were attached to customized perfusion chambers. Both intestines were perfused on the vascular side with a Ringer buffer solution. The experimental buffer solution was bubbled with 100% nitrogen to mimic ischemia. Both lumens were perfused with 3 mL HEPES-Ringer solution containing 50 μM fluorescein isothiocyanate (FITC)-inulin. Intraluminal samples were collected at 15-minute intervals to measure FITC-inulin concentration using a nanofluorospectrophotometer. Intestinal tissue samples were processed and evaluated by a blinded pathologist using the Park/Chiu scoring system for grading intestinal ischemia. Samples collected from the ischemic intestine showed a significant decrease in FITC-inulin fluorescence compared with the control intestine, indicating enhanced fluid secretion. Histopathologic samples from the experimental arm exhibited higher scores of ischemic injury in comparison with the control arm, confirming the FITC-inulin as a correlation to ischemia. Fluorescein isothiocyanate-inulin can be used as a real-time volume marker to monitor the ischemic state of intestinal tissue. A positive correlation between the degree of fluid shift and presence of ischemic injury. The changes in fluorescence signal provide a potential selective method to measure real-time fluid changes inside an intestinal graft to evaluate viability. Copyright © 2016 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

  6. P43/pro-EMAPII: A Potential Biomarker for Discriminating Traumatic Versus Ischemic Brain Injury

    PubMed Central

    Yao, Changping; Williams, Anthony J.; Ottens, Andrew K.; Lu, X.-C. May; Liu, Ming Cheng; Hayes, Ronald L.; Wang, Kevin K.; Tortella, Frank C.

    2009-01-01

    Abstract To gain additional insights into the pathogenic cellular and molecular mechanisms underlying different types of brain injury (e.g., trauma versus ischemia), recently attention has focused on the discovery and study of protein biomarkers. In previous studies, using a high-throughput immunoblotting (HTPI) technique, we reported changes in 29 out of 998 proteins following acute injuries to the rat brain (penetrating traumatic versus focal ischemic). Importantly, we discovered that one protein, endothelial monocyte-activating polypeptide II precursor (p43/pro-EMAPII), was differentially expressed between these two types of brain injury. Among other functions, p43/pro-EMAPII is a known pro-inflammatory cytokine involved in the progression of apoptotic cell death. Our current objective was to verify the changes in p43/pro-EMAPII expression, and to evaluate the potentially important implications that the differential regulation of this protein has on injury development. At multiple time points following either a penetrating ballistic-like brain injury (PBBI), or a transient middle cerebral artery occlusion (MCAo) brain injury, tissue samples (6–72 h), CSF samples (24 h), and blood samples (24 h) were collected from rats for analysis. Changes in protein expression were assessed by Western blot analysis and immunohistochemistry. Our results indicated that p43/pro-EMAPII was significantly increased in brain tissues, CSF, and plasma following PBBI, but decreased after MCAo injury compared to their respective sham control samples. This differential expression of p43/pro-EMAPII may be a useful injury-specific biomarker associated with the underlying pathologies of traumatic versus ischemic brain injury, and provide valuable information for directing injury-specific therapeutics. PMID:19317603

  7. 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.

  8. 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.

  9. Oxidized LDL accumulation in experimental renal ischemia reperfusion injury model.

    PubMed

    Kulah, Eyup; Tascilar, Oge; Acikgoz, Serefden; Tekin, Ishak Ozel; Karadeniz, Guldeniz; Can, Murat; Gun, Banu; Barut, Figen; Comert, Mustafa

    2007-01-01

    The aim of this study was to identify oxidative damage of kidney during ischemia reperfusion injury (IRI) by evaluating changes in lipid peroxidation markers in tissue and blood by an experimental model. Oxidized LDL (ox-LDL) was used as an oxidative stress biomarker, whereas paraoxonase (PON-1) activity was used as an antioxidative biomarker. Sixty-three male Wistar rats were randomly assigned into three groups: renal IRI, sham, and control. In the renal IRI group, the right kidney was removed and the artery and vein of the left kidney were clamped for 90 minutes. The presence of ox-LDL in the kidney tissue sections was determined by using an immunofluorescent staining method. The plasma ox-LDL levels did not increase significantly at the 24th hour following IRI, made a peak at the 48th hour, and declined at the 72nd hour. Accumulation of ox-LDL was detected in the kidney tissue on the 24th, 48th, and 72nd hours of the renal IRI. Serum PON-1 levels have peaked on the 24th hour and then declined. This study demonstrates the accumulation of ox-LDL molecules in the renal tissues of the IRI model. Future strategies aimed to reduce the lipid peroxidation during the initial hours of renal IRI may be useful to prevent complications of ischemia.

  10. Renal parenchymal oxygenation and hypoxia adaptation in acute kidney injury.

    PubMed

    Rosenberger, Christian; Rosen, Seymour; Heyman, Samuel N

    2006-10-01

    The pathogenesis of acute kidney injury (AKI), formally termed acute tubular necrosis, is complex and, phenotypically, may range from functional dysregulation without overt morphological features to literal tubular destruction. Hypoxia results from imbalanced oxygen supply and consumption. Increasing evidence supports the view that regional renal hypoxia occurs in AKI irrespective of the underlying condition, even under circumstances basically believed to reflect 'direct' tubulotoxicity. However, at present, it is remains unclear whether hypoxia per se or, rather, re-oxygenation (possibly through reactive oxygen species) causes AKI. Data regarding renal hypoxia in the clinical situation of AKI are lacking and our current concepts regarding renal oxygenation during acute renal failure are presumptive and largely derived from experimental studies. There is robust experimental evidence that AKI is often associated with altered intrarenal microcirculation and oxygenation. Furthermore, renal parenchymal oxygen deprivation seems to participate in the pathogenesis of experimental AKI, induced by exogenous nephrotoxins (such as contrast media, non-steroidal anti-inflammatory drugs or amphotericin), sepsis, pigment and obstructive nephropathies. Sub-lethal cellular hypoxia engenders adaptational responses through hypoxia-inducible factors (HIF). Forthcoming technologies to modulate the HIF system form a novel potential therapeutic approach for AKI.

  11. Neuroprotection in hypoxic-ischemic brain injury targeting glial cells.

    PubMed

    Herrera, María Inés; Mucci, Sofia; Barreto, George E; Kolliker-Frers, Rodolfo; Capani, Francisco

    2017-07-27

    Brain injury constitutes a disabling health condition of several etiologies. One of the major causes of brain injury is hypoxia-ischemia. Until recently, pharmacological treatments were solely focused on neurons. In the last decades, glial cells started to be considered as alternative targets for neuroprotection. Novel treatments for hypoxia-ischemia intend to modulate reactive forms of glial cells, and/or potentiate their recovery response. In this review, we summarize these neuroprotective strategies in hypoxia-ischemia and discuss their mechanisms of action. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. Repeated exposure to methamphetamine induces sex-dependent hypersensitivity to ischemic injury in the adult rat heart

    PubMed Central

    Seeley, Sarah L.; Stoops, Thorne S.; D’Souza, Manoranjan S.

    2017-01-01

    Background We previously reported that adult female, but not male rats that were prenatally exposed to methamphetamine exhibit myocardial hypersensitivity to ischemic injury. However, it is unknown whether hypersensitivity to ischemic injury develops when rats are exposed to methamphetamine during adulthood. The goal of this study was to determine whether methamphetamine exposure during adulthood sensitizes the heart to ischemic injury. Methods Adult male and female rats received daily injections of methamphetamine (5 mg/kg) or saline for 10 days. Their hearts were isolated on day 11 and subjected to a 20 min ischemic insult on a Langendorff isolated heart apparatus. Cardiac contractile function was measured by an intraventricular balloon, and infarct size was measured by triphenyltetrazolium chloride staining. Results Hearts from methamphetamine-treated females exhibited significantly larger infarcts and suppressed postischemic recovery of contractile function compared to hearts from saline-treated females. In contrast, methamphetamine had no effect on infarct size or contractile recovery in male hearts. Subsequent experiments demonstrated that hypersensitivity to ischemic injury persisted in female hearts following a 1 month period of abstinence from methamphetamine. Myocardial protein kinase C-ε expression, Akt phosphorylation, and ERK phosphorylation were unaffected by adult exposure to methamphetamine. Conclusions Exposure of adult rats to methamphetamine sex-dependently increases the extent of myocardial injury following an ischemic insult. These data suggest that women who have a heart attack might be at risk of more extensive myocardial injury if they have a recent history of methamphetamine abuse. PMID:28575091

  13. Repeated exposure to methamphetamine induces sex-dependent hypersensitivity to ischemic injury in the adult rat heart.

    PubMed

    Rorabaugh, Boyd R; Seeley, Sarah L; Stoops, Thorne S; D'Souza, Manoranjan S

    2017-01-01

    We previously reported that adult female, but not male rats that were prenatally exposed to methamphetamine exhibit myocardial hypersensitivity to ischemic injury. However, it is unknown whether hypersensitivity to ischemic injury develops when rats are exposed to methamphetamine during adulthood. The goal of this study was to determine whether methamphetamine exposure during adulthood sensitizes the heart to ischemic injury. Adult male and female rats received daily injections of methamphetamine (5 mg/kg) or saline for 10 days. Their hearts were isolated on day 11 and subjected to a 20 min ischemic insult on a Langendorff isolated heart apparatus. Cardiac contractile function was measured by an intraventricular balloon, and infarct size was measured by triphenyltetrazolium chloride staining. Hearts from methamphetamine-treated females exhibited significantly larger infarcts and suppressed postischemic recovery of contractile function compared to hearts from saline-treated females. In contrast, methamphetamine had no effect on infarct size or contractile recovery in male hearts. Subsequent experiments demonstrated that hypersensitivity to ischemic injury persisted in female hearts following a 1 month period of abstinence from methamphetamine. Myocardial protein kinase C-ε expression, Akt phosphorylation, and ERK phosphorylation were unaffected by adult exposure to methamphetamine. Exposure of adult rats to methamphetamine sex-dependently increases the extent of myocardial injury following an ischemic insult. These data suggest that women who have a heart attack might be at risk of more extensive myocardial injury if they have a recent history of methamphetamine abuse.

  14. Assessment of Acute Kidney Injury and Renal Fibrosis after Renal Ischemia Protocols in Cats

    PubMed Central

    Dickerson, Vanna M; Rissi, Daniel R; Brown, Cathy A; Brown, Scott A; Schmiedt, Chad W

    2017-01-01

    In an attempt to identify a feline model of acute or chronic kidney disease, this study was designed to evaluate the effects of 15 or 30 min of bilateral renal ischemia (RI) and 60 min of unilateral RI with delayed contralateral nephrectomy as models of acute kidney injury and chronic interstitial fibrosis in cats. Adult, purpose-bred, USDA Class A cats (n = 14) were randomly assigned to receive bilateral RI for 15 min (n = 3) or 30 min (n = 3), unilateral RI for 60 min with a delayed (2 wk) contralateral nephrectomy (n = 5), or sham unilateral RI with a delayed contralateral nephrectomy (n = 3). Serum creatinine concentration, urine specific gravity, and plasma clearance of iohexol were assessed at several time points throughout the study. Renal interstitial inflammatory cell counts and descriptive histopathology were acquired in all cats. Histomorphometry was used to quantify renal interstitial fibrosis and collagen at 120 d after RI in cats undergoing unilateral RI. Renal histopathology was evaluated at 21 and 120 d after bilateral and unilateral RI, respectively. Neither duration of bilateral RI resulted in appreciable histologic renal damage at 21 d after ischemia. At 120 d after ischemia, variable amounts of renal fibrosis were noted after 60 min of unilateral RI with delayed contralateral nephrectomy. Neither of the tested methods is a suitable model of consistent renal interstitial fibrosis in cats. Healthy cats appear able to sustain bilateral RI for as long as 30 min with no apparent effects on renal morphology or function at 21 d after ischemia. PMID:28222840

  15. 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

  16. Endogenous level of TIGAR in brain is associated with vulnerability of neurons to ischemic injury.

    PubMed

    Cao, Lijuan; Chen, Jieyu; Li, Mei; Qin, Yuan-Yuan; Sun, Meiling; Sheng, Rui; Han, Feng; Wang, Guanghui; Qin, Zheng-Hong

    2015-10-01

    In previous studies, we showed that TP53-induced glycolysis and apoptosis regulator (TIGAR) protects neurons against ischemic brain injury. In the present study, we investigated the developmental changes of TIGAR level in mouse brain and the correlation of TIGAR expression with the vulnerability of neurons to ischemic injury. We found that the TIGAR level was high in the embryonic stage, dropped at birth, partially recovered in the early postnatal period, and then continued to decline to a lower level in early adult and aged mice. The TIGAR expression was higher after ischemia/reperfusion in mouse brain 8 and 12 weeks after birth. Four-week-old mice had smaller infarct volumes, lower neurological scores, and lower mortality rates after ischemia than 8- and 12-week-old mice. TIGAR expression also increased in response to oxygen glucose deprivation (OGD)/reoxygenation insult or H2O2 treatment in cultured primary neurons from different embryonic stages (E16 and E20). The neurons cultured from the early embryonic period had a greater resistance to OGD and oxidative insult. Higher TIGAR levels correlated with higher pentose phosphate pathway activity and less oxidative stress. Older mice and more mature neurons had more severe DNA and mitochondrial damage than younger mice and less mature neurons in response to ischemia/reperfusion or OGD/reoxygenation insult. Supplementation of cultured neurons with nicotinamide adenine dinuclectide phosphate (NADPH) significantly reduced ischemic injury. These results suggest that TIGAR expression changes during development and its expression level may be correlated with the vulnerability of neurons to ischemic injury.

  17. Five-Year Retrospective Review of Blunt Renal Injuries at a Level I Trauma Center.

    PubMed

    Burns, Jessica; Brown, Megan; Assi, Zakaria I; Ferguson, Eric J

    2017-02-01

    We report the experience of a Level I trauma center in the management of blunt renal injury during a 5-year period, with special attention to those treated using angiography with embolization. The institutional trauma registry was queried for all patients with blunt renal injury between September 1, 2009 and August 30, 2014. Each injury was graded using the American Association for the Surgery of Trauma guidelines. Patients that underwent angiography with embolization were reviewed for case-specific information including imaging findings, treatment, materials used, clinical course, and mortality. The registry identified 48 blunt renal injury patients. Median Injury Severity Score was higher and hospital length of stay was significantly longer in those with blunt renal injury when compared with those without blunt renal injury (P < 0.001). The majority of patients with blunt renal injury were managed nonoperatively. Mortality was three out of 48 patients (5%). Nine patients underwent exploratory laparotomy. These operations were always performed for reasons other than the renal trauma (e.g., splenic injury, free fluid, free air). No patient underwent invasive renal operation. Six patients were treated using angiography with embolization. Of the six, one patient died of pulmonary septic complications. We conclude that selective nonoperative management is the mainstay of treatment for blunt renal injury. Angiography with embolization is a useful modality for cases of ongoing bleeding, and is typically preferable to nephrectomy in our experience.

  18. 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.

  19. Enriched Endogenous Omega-3 Polyunsaturated Fatty Acids Protect Cortical Neurons from Experimental Ischemic Injury.

    PubMed

    Shi, Zhe; Ren, Huixia; Luo, Chuanming; Yao, Xiaoli; Li, Peng; He, Chengwei; Kang, Jing-X; Wan, Jian-Bo; Yuan, Ti-Fei; Su, Huanxing

    2016-11-01

    Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert therapeutic potential in a variety of neurological disorders, including ischemic stroke. However, the underlying mechanisms still lack investigation. Here, we report that cultured cortical neurons isolated from fat-1 mice with high endogenous n-3 PUFAs were tolerant to oxygen-glucose deprivation/reperfusion (OGD/R) injury. Fat-1 neurons exhibited significantly attenuated reactive oxygen species (ROS) activation induced by OGD/R injury, upregulated antiapoptotic proteins Bcl-2 and Bcl-xL, and reduced cleaved caspase-3. Exogenous administration of docosahexaenoic acid (DHA), a major component of the n-3 PUFA family, resulted in similar protective effects on cultured cortex neurons. We further verified the protective effects of n-3 PUFAs in vivo, using a mini ischemic model with a reproducible cortical infarct and manifest function deficits by occlusion of the distal branch of the middle cerebral artery with focused femtosecond laser pulses. The Fat-1 animals showed decreased ROS expression and higher level of glutathione in the injured brain, associated with improved functional recovery. We therefore provide evidence that n-3 PUFAs exert their protective effects against ischemic injury both in vitro and in vivo, partly through inhibiting ROS activation.

  20. Ameliorative effects of Gualou Guizhi decoction on inflammation in focal cerebral ischemic-reperfusion injury

    PubMed Central

    ZHANG, YUQIN; ZHANG, SHENGNAN; LI, HUANG; HUANG, MEI; XU, WEI; CHU, KEDAN; CHEN, LIDIAN; CHEN, XIANWEN

    2015-01-01

    Gualou Guizhi decoction (GLGZD) is a well-established Traditional Chinese Medicinal formulation which has long been used to treat stroke in a clinical setting in China. The present study investigated the ameliorative effects of GLGZD on inflammation in focal cerebral ischemic-reperfusion injury. A rat model of middle cerebral artery occlusion (MCAO) was employed. Rats were administrated GLGZD (7.2 and 14.4 g/kg per day) or saline as control 2 h after reperfusion and daily over the following seven days. Neurological deficit score and screen test were evaluated at 1, 3, 5 and 7 days after MCAO. Brain infarct size and brain histological changes were observed via 2,3,5-triphenyltetrazolium chloride staining and regular hematoxylin & eosin staining. Furthermore, inflammation mediators and nuclear factor-κB (NF-κB) were investigated using ELISA and immunohistochemistry. GLGZD treatment significantly improved neurological function, ameliorated histological changes to the brain and decreased infarct size in focal cerebral ischemic-reperfusion injury. GLGZD was found to significantly reduce interleukin (IL)-1, tumor necrosis factor-α and NF-κB levels, while increasing levels of IL-10. In conclusion, the present study suggested that GLGZD has a neuroprotective effect on focal cerebral ischemic-reperfusion injury and this effect is likely to be associated with the anti-inflammatory function of GLGZD. PMID:25815894

  1. Regulation of PINK1 by NR2B-containing NMDA receptors in ischemic neuronal injury.

    PubMed

    Shan, Yuexin; Liu, Baosong; Li, Lijun; Chang, Ning; Li, Lei; Wang, Hanbin; Wang, Dianshi; Feng, Hua; Cheung, Carol; Liao, Mingxia; Cui, Tianyuan; Sugita, Shuzo; Wan, Qi

    2009-12-01

    Dysfunction of PTEN-induced kinase-1 (PINK1) is implicated in neurodegeneration. We report here that oxygen-glucose deprivation (OGD), an in vitro insult mimicking ischemic neuron injury, resulted in a significant reduction of PINK1 protein expression in cultured cortical neurons. The decrease of PINK1 expression was blocked by the antagonists of NMDA receptors. We revealed that the overactivation of NR2B-containing NMDA receptors (NR2BRs) was responsible for the OGD-induced PINK1 reduction. The overactivated NR2BRs also inhibited the phosphorylation, but not the protein expression, of the cell survival-promoting kinase Akt after OGD insult, indicating that OGD-induced reduction of PINK1 protein is specific in the injury paradigm. We further showed that enhancing the protein expression of PINK1 antagonized OGD-induced reduction of Akt phosphorylation, suggesting that Akt may be a downstream target of PINK1 in ischemic neuron injury. Importantly, we provided evidence that both NR2BR antagonist and PINK1 over-expression protected against OGD-induced neuronal death. These results suggest that the overactivation of NR2BRs may contribute to ischemic neuron death through suppressing PINK1-dependent survival signaling. Thus, selectively antagonizing NR2BR signal pathway-induced neurotoxicity may be a potential neuroprotection strategy.

  2. 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. Copyright © 2016 the American Physiological Society.

  3. P2X7 receptor inhibition protects against ischemic acute kidney injury in mice.

    PubMed

    Yan, Yanli; Bai, Jianwen; Zhou, Xiaoxu; Tang, Jinhua; Jiang, Chunming; Tolbert, Evelyn; Bayliss, George; Gong, Rujun; Zhao, Ting C; Zhuang, Shougang

    2015-03-15

    Activation of the purinergic P2X7 receptor (P2X7R) has been associated with the development of experimental nephritis and diabetic and hypertensive nephropathy. However, its role in acute kidney injury (AKI) remains unknown. In this study, we examined the effects of P2X7R inhibition in a murine model of ischemia-reperfusion (I/R)-induced AKI using A438079, a selective inhibitor of P2X7R. At 24 h after I/R, mice developed renal dysfunction and renal tubular damage, which was accompanied by elevated expression of P2X7R. Early administration of A438079 immediately or 6 h after the onset of reperfusion protected against renal dysfunction and attenuated kidney damage whereas delayed administration of A438079 at 24 h after restoration of perfusion had no protective effects. The protective actions of A438079 were associated with inhibition of renal tubule injury and cell death and suppression of renal expression of monocyte chemotactic protein-1 and regulated upon expression normal T cell expressed and secreted (RANTES). Moreover, I/R injury led to an increase in phosphorylation (activation) of extracellular signal-regulated kinases 1/2 in the kidney; treatment with A438079 diminished this response. Collectively, these results indicate that early P2X7R inhibition is effective against renal tubule injury and proinflammatory response after I/R injury and suggest that targeting P2X7R may be a promising therapeutic strategy for treatment of AKI.

  4. 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.

  5. Downregulation of miRNA-134 protects neural cells against ischemic injury in N2A cells and mouse brain with ischemic stroke by targeting HSPA12B.

    PubMed

    Chi, W; Meng, F; Li, Y; Wang, Q; Wang, G; Han, S; Wang, P; Li, J

    2014-09-26

    MicroRNAs (miRNAs) have emerged as a major regulator in neurological diseases, and understanding their molecular mechanism in modulating cerebral ischemic injury may provide potential therapeutic targets for ischemic stroke. However, as one of 19 differentially expressed miRNAs in mouse brain with middle cerebral artery occlusion (MCAO), the role of miR-134 in ischemic injury is not well understood. In this study, the miR-134 expression level was manipulated both in oxygen-glucose deprivation (OGD)-treated N2A neuroblastoma cells in vitro and mouse brain with MCAO-induced ischemic stroke in vivo, and its possible targets of heat shock protein A5 (HSPA5) and HSPA12B were determined by bioinformatics analysis and dual luciferase assay. The results showed that overexpression of miR-134 exacerbated cell death and apoptosis both in vitro and in vivo. Conversely, downregulating miR-134 levels reduced cell death and apoptosis. Furthermore, non-expression of miR-134 enhanced HSPA12B protein levels in OGD-treated N2A cells as well as in the ischemic region. It could attenuate brain infarction size and neural cell damage, and improve neurological outcomes in mice with ischemic stroke, whereas upregulation of miR-134 had the opposite effect. In addition, HSPA12B was validated to be a target of miR-134 and its short interfering RNAs (siRNAs) could block miR-134 inhibitor-induced neuroprotection in OGD-treated N2A cells. In conclusion, downregulation of miR-134 could induce neuroprotection against ischemic injury in vitro and in vivo by negatively upregulating HSPA12B protein expression.

  6. Tat-glyoxalase protein inhibits against ischemic neuronal cell damage and ameliorates ischemic injury.

    PubMed

    Shin, Min Jea; Kim, Dae Won; Lee, Yeom Pyo; Ahn, Eun Hee; Jo, Hyo Sang; Kim, Duk-Soo; Kwon, Oh-Shin; Kang, Tae-Cheon; Cho, Yong-Jun; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2014-02-01

    Methylglyoxal (MG), a metabolite of glucose, is the major precursor of protein glycation and induces apoptosis. MG is associated with neurodegeneration, including oxidative stress and impaired glucose metabolism, and is efficiently metabolized to S-D-lactoylglutathione by glyoxalase (GLO). Although GLO has been implicated as being crucial in various diseases including ischemia, its detailed functions remain unclear. Therefore, we investigated the protective effect of GLO (GLO1 and GLO2) in neuronal cells and an animal ischemia model using Tat-GLO proteins. Purified Tat-GLO protein efficiently transduced into HT-22 neuronal cells and protected cells against MG- and H2O2-induced cell death, DNA fragmentation, and activation of caspase-3 and mitogen-activated protein kinase. In addition, transduced Tat-GLO protein increased D-lactate in MG- and H2O2-treated cells whereas glycation end products (AGE) and MG levels were significantly reduced in the same cells. Gerbils treated with Tat-GLO proteins displayed delayed neuronal cell death in the CA1 region of the hippocampus compared with a control. Furthermore, the combined neuroprotective effects of Tat-GLO1 and Tat-GLO2 proteins against ischemic damage were significantly higher than those of each individual protein. Those results demonstrate that transduced Tat-GLO protein protects neuronal cells by inhibiting MG- and H2O2-mediated cytotoxicity in vitro and in vivo. Therefore, we suggest that Tat-GLO proteins could be useful as a therapeutic agent for various human diseases related to oxidative stress including brain diseases. © 2013 Elsevier Inc. All rights reserved.

  7. PHLPP1 gene deletion protects the brain from ischemic injury

    PubMed Central

    Chen, Bo; Van Winkle, Jessica A; Lyden, Patrick D; Brown, Joan H; Purcell, Nicole H

    2013-01-01

    A recently discovered protein phosphatase PHLPP (PH domain Leucine-rich repeat Protein Phosphatase) has been shown to dephosphorylate Akt on its hydrophobic motif (Ser473) thereby decreasing Akt kinase activity. We generated PHLPP1 knockout (KO) mice and used them to explore the ability of enhanced in vivo Akt signaling to protect the brain against ischemic insult. Brains from KO mice subjected to middle cerebral artery occlusion (MCAO) for 2 hours showed significantly greater increases in Akt activity and less neurovascular damage after reperfusion than wild-type (WT) mice. Remarkably, infarct volume in the PHLPP1 KO was significantly reduced compared with WT (12.7±2.7% versus 22.9±3.1%) and this was prevented by Akt inhibition. Astrocytes from KO mice and neurons in which PHLPP1 was downregulated showed enhanced Akt activation and diminished cell death in response to oxygen-glucose deprivation. Thus, deletion of PHLPP1 can enhance Akt activation in neurons and astrocytes, and can significantly increase cell survival and diminish infarct size after MCAO. Inhibition of PHLPP could be a therapeutic approach to minimize damage after focal ischemia. PMID:23072745

  8. Iloprost reduces colonic injury in ischemic colitis in rats.

    PubMed

    Karatepe, Oguzhan; Cakir, Affan; Unal, Orçun; Battal, Muharrem; Adas, Gokhan; Kamali, Gülcin; Kemik, Ahu; Aydin, Timucin; Kamali, Sedat; Karahan, Servet R; Aksoy, Murat

    2011-06-01

    Evaluate the effects of iloprost administration in the early period of ischemic colitis and the mechanism that how these effects develop. Thirty two Wistar albino female rats with an average weight of 220g were divided into four groups of eight rats. In group 1 the rats were given iloprost and sacrificed after 24 hours and in group 2 they were sacrificed after 24 hours without any iloprost. The rats in group 3 were administrated iloprost and sacrificed after 72 hours and in group 4 they were sacrificed at 72th hour without iloprost. The differences between the groups as tissue damage, vascularization or apoptosis were assessed statistically. Oxidative damage and apoptosis were less pronounced and vascularization was better developed in rats that were given iloprost and sacrificed at 24th hour later in contrast to the rats that were not treated with iloprost. But there was no statistical difference among the groups at 72th hour. Iloprost inhibited leucocyte infiltration, decreased proinflammatory cytokines and enhanced angiogenesis so that the oxidative stress and inflammatory response decreased resulting in lesser tissue damage.

  9. Bryostatin improves survival and reduces ischemic brain injury in aged rats following acute ischemic stroke

    PubMed Central

    Tan, Zhenjun; Turner, Ryan C.; Leon, Rachel L.; Li, Xinlan; Hongpaisan, Jarin; Zheng, Wen; Logsdon, Aric F.; Naser, Zachary J.; Alkon, Daniel L.; Rosen, Charles L.; Huber, Jason D.

    2014-01-01

    Background and Purpose Bryostatin, a potent protein kinase C (PKC) activator, has demonstrated therapeutic efficacy in preclinical models of associative memory, Alzheimer's disease, global ischemia, and traumatic brain injury. In this study, we tested the hypothesis that administration of bryostatin provides a therapeutic benefit in reducing brain injury and improving stroke outcome using a clinically relevant model of cerebral ischemia with tissue plasminogen activator (tPA) reperfusion in aged rats. Methods Acute cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery (MCAO) in 18-20 month old female Sprague-Dawley rats using an autologous blood clot with tPA-mediated reperfusion. Bryostatin was administered at 6 h post-MCAO then at 3, 6, 9, 12, 15, and 18 d after MCAO. Functional assessment was conducted at 2, 7, 14, and 21 d after MCAO. Lesion volume and hemispheric swelling/atrophy were performed at 2, 7, and 21 d post-MCAO. Histological assessment of PKC isozymes was performed at 24 h post-MCAO. Results Bryostatin-treated rats showed improved survival post-MCAO, especially during the first 4 d. Repeated administration of bryostatin post-MCAO resulted in reduced infarct volume, hemispheric swelling/atrophy, and improved neurological function at 21 d post-MCAO. Changes in PKC alpha expression and PKC epsilon expression in neurons were noted in bryostatin-treated rats at 24 h post-MCAO. Conclusions Repeated bryostatin administration post-MCAO protected the brain from severe neurological injury post-MCAO. Bryostatin treatment improved survival rate, reduced lesion volume, salvaged tissue in infarcted hemisphere by reducing necrosis and peri-infarct astrogliosis, and improved functional outcome following MCAO. PMID:24172582

  10. Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke.

    PubMed

    Tan, Zhenjun; Turner, Ryan C; Leon, Rachel L; Li, Xinlan; Hongpaisan, Jarin; Zheng, Wen; Logsdon, Aric F; Naser, Zachary J; Alkon, Daniel L; Rosen, Charles L; Huber, Jason D

    2013-12-01

    Bryostatin, a potent protein kinase C (PKC) activator, has demonstrated therapeutic efficacy in preclinical models of associative memory, Alzheimer disease, global ischemia, and traumatic brain injury. In this study, we tested the hypothesis that administration of bryostatin provides a therapeutic benefit in reducing brain injury and improving stroke outcome using a clinically relevant model of cerebral ischemia with tissue plasminogen activator reperfusion in aged rats. Acute cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery (MCAO) in 18- to 20-month-old female Sprague-Dawley rats using an autologous blood clot with tissue plasminogen activator-mediated reperfusion. Bryostatin was administered at 6 hours post-MCAO, then at 3, 6, 9, 12, 15, and 18 days after MCAO. Functional assessment was conducted at 2, 7, 14, and 21 days after MCAO. Lesion volume and hemispheric swelling/atrophy were performed at 2, 7, and 21 days post-MCAO. Histological assessment of PKC isozymes was performed at 24 hours post-MCAO. Bryostatin-treated rats showed improved survival post-MCAO, especially during the first 4 days. Repeated administration of bryostatin post-MCAO resulted in reduced infarct volume, hemispheric swelling/atrophy, and improved neurological function at 21 days post-MCAO. Changes in αPKC expression and εPKC expression in neurons were noted in bryostatin-treated rats at 24 hours post-MCAO. Repeated bryostatin administration post-MCAO protected the brain from severe neurological injury post-MCAO. Bryostatin treatment improved survival rate, reduced lesion volume, salvaged tissue in infarcted hemisphere by reducing necrosis and peri-infarct astrogliosis, and improved functional outcome after MCAO.

  11. Ascorbic acid against reperfusion injury in human renal transplantation.

    PubMed

    Norio, Karri; Wikström, Mårten; Salmela, Kaija; Kyllönen, Lauri; Lindgren, Leena

    2003-08-01

    The cadaveric renal graft is exposed to ischaemic injury during preservation and to oxidative damage during reperfusion. Both these mechanisms are known to cause cell damage, which may impair graft function. Reperfusion injury (RPI) is mediated by reactive oxygen species (ROS). Ascorbic acid (AA) is a potent physiological extracellular scavenger of ROS. We perfused 31 renal grafts immediately before implantation with a solution of Euro-Collins containing 0.5 mg/ml of AA to diminish RPI. From every donor, the contralateral kidney served as a control. The control grafts were perfused with the same perfusion as those of the AA group, only without the AA substitution. We assessed the effect of AA by recording serum creatinine, creatinine clearance, initial graft function and early rejections. The incidence of delayed graft function (DGF) was 32% in the AA group, and 29% in the control group. Other parameters were also similar in both groups, except for the length of DGF, which showed a trend towards a shorter duration in the AA group. The pre-operative systemic AA concentration was significantly ( P=0.01) lower in the haemodialysis patients than in those on peritoneal dialysis. In conclusion, this clinical study could not demonstrate significant benefits of AA in renal transplantation.

  12. Multipotent adult progenitor cells for hypoxic-ischemic injury in the preterm brain.

    PubMed

    Jellema, Reint K; Ophelders, Daan R M G; Zwanenburg, Alex; Nikiforou, Maria; Delhaas, Tammo; Andriessen, Peter; Mays, Robert W; Deans, Robert; Germeraad, Wilfred T V; Wolfs, Tim G A M; Kramer, Boris W

    2015-12-23

    Preterm infants are at risk for hypoxic-ischemic encephalopathy. No therapy exists to treat this brain injury and subsequent long-term sequelae. We have previously shown in a well-established pre-clinical model of global hypoxia-ischemia (HI) that mesenchymal stem cells are a promising candidate for the treatment of hypoxic-ischemic brain injury. In the current study, we investigated the neuroprotective capacity of multipotent adult progenitor cells (MAPC®), which are adherent bone marrow-derived cells of an earlier developmental stage than mesenchymal stem cells and exhibiting more potent anti-inflammatory and regenerative properties. Instrumented preterm sheep fetuses were subjected to global hypoxia-ischemia by 25 min of umbilical cord occlusion at a gestational age of 106 (term ~147) days. During a 7-day reperfusion period, vital parameters (e.g., blood pressure and heart rate; baroreceptor reflex) and (amplitude-integrated) electroencephalogram were recorded. At the end of the experiment, the preterm brain was studied by histology. Systemic administration of MAPC therapy reduced the number and duration of seizures and prevented decrease in baroreflex sensitivity after global HI. In addition, MAPC cells prevented HI-induced microglial proliferation in the preterm brain. These anti-inflammatory effects were associated with MAPC-induced prevention of hypomyelination after global HI. Besides attenuation of the cerebral inflammatory response, our findings showed that MAPC cells modulated the peripheral splenic inflammatory response, which has been implicated in the etiology of hypoxic-ischemic injury in the preterm brain. In a pre-clinical animal model MAPC cell therapy improved the functional and structural outcome of the preterm brain after global HI. Future studies should establish the mechanism and long-term therapeutic effects of neuroprotection established by MAPC cells in the developing preterm brain exposed to HI. Our study may form the basis for future

  13. Detection of renal ischemic lesions using Gd-DTPA enhanced turbo FLASH MRI: Experimental and clinical results

    SciTech Connect

    Vosshenrich, R.; Fischer, U.; Funke, M.; Kopka, L.; Grabbe, E.

    1996-03-01

    Our goal was to investigate the role of Gd-DTPA-enhanced dynamic MRI in the evaluation of renal ischemic lesions. With a turbo FLASH sequence before and after injection of Gd-DTPA, nine foxhound dogs after 60-120 min of renal ischemia underwent MR examination. In addition, five patients with a tumor in a solitary kidney were examined before and after nephron-sparing renal surgery to evaluate renal perfusion and function. The experimental and clinical findings were correlated with conventional measurements of kidney function and with histological findings. Complete renal ischemia leads to a poor corticomedullary differentiation in Gd-DTPA-enhanced turbo FLASH MRI. The signal-intensity-versus-time plots of kidneys with significant postischemic changes show a less steep increase of signal intensity in the cortex and a steeper increase of signal intensity in the medulla than those of normal kidneys. Dynamic MRI demonstrate renal morphology and reflect the functional status of the renal vasculature. 21 refs., 8 figs., 1 tab.

  14. Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a "two-hit" model.

    PubMed

    Sekhon, Mypinder S; Ainslie, Philip N; Griesdale, Donald E

    2017-04-13

    Hypoxic ischemic brain injury (HIBI) after cardiac arrest (CA) is a leading cause of mortality and long-term neurologic disability in survivors. The pathophysiology of HIBI encompasses a heterogeneous cascade that culminates in secondary brain injury and neuronal cell death. This begins with primary injury to the brain caused by the immediate cessation of cerebral blood flow following CA. Thereafter, the secondary injury of HIBI takes place in the hours and days following the initial CA and reperfusion. Among factors that may be implicated in this secondary injury include reperfusion injury, microcirculatory dysfunction, impaired cerebral autoregulation, hypoxemia, hyperoxia, hyperthermia, fluctuations in arterial carbon dioxide, and concomitant anemia.Clarifying the underlying pathophysiology of HIBI is imperative and has been the focus of considerable research to identify therapeutic targets. Most notably, targeted temperature management has been studied rigorously in preventing secondary injury after HIBI and is associated with improved outcome compared with hyperthermia. Recent advances point to important roles of anemia, carbon dioxide perturbations, hypoxemia, hyperoxia, and cerebral edema as contributing to secondary injury after HIBI and adverse outcomes. Furthermore, breakthroughs in the individualization of perfusion targets for patients with HIBI using cerebral autoregulation monitoring represent an attractive area of future work with therapeutic implications.We provide an in-depth review of the pathophysiology of HIBI to critically evaluate current approaches for the early treatment of HIBI secondary to CA. Potential therapeutic targets and future research directions are summarized.

  15. 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

  16. Renal Artery Injury Secondary to Blunt Abdominal Trauma – Two Case Reports

    PubMed Central

    Ahmed, Zahoor; Nabir, Syed; Ahmed, Mohamed Nadeem; Al Hilli, Shatha; Ravikumar, Vajjala; Momin, Umais Zaid

    2016-01-01

    Summary Background Blunt abdominal trauma is routinely encountered in the Emergency Department. It is one of the main causes of morbidity and mortality amongst the population below the age of 35 years worldwide. Renal artery injury secondary to blunt abdominal trauma however, is a rare occurrence. Here, we present two such cases, encountered in the emergency department sustaining polytrauma following motor vehicle accidents. Case Report We hereby report two interesting cases of renal artery injury sustained in polytrauma patients. In these two cases we revealed almost the entire spectrum of findings that one would expect in renal arterial injuries. Conclusions Traumatic renal artery occlusion is a rare occurrence with devastating consequences if missed on imaging. Emergency radiologists need to be aware of the CT findings so as to accurately identify renal artery injury. This case report stresses the need for immediate CT assessment of polytrauma patients with suspected renal injury, leading to timely diagnosis and urgent surgical or endovascular intervention. PMID:28058071

  17. Treatment with Evasin-3 reduces atherosclerotic vulnerability for ischemic stroke, but not brain injury in mice

    PubMed Central

    Copin, Jean-Christophe; da Silva, Rafaela F; Fraga-Silva, Rodrigo A; Capettini, Luciano; Quintao, Silvia; Lenglet, Sébastien; Pelli, Graziano; Galan, Katia; Burger, Fabienne; Braunersreuther, Vincent; Schaller, Karl; Deruaz, Maud; Proudfoot, Amanda E; Dallegri, Franco; Stergiopulos, Nikolaos; Santos, Robson A S; Gasche, Yvan; Mach, François; Montecucco, Fabrizio

    2013-01-01

    Neutrophilic inflammation might have a pathophysiological role in both carotid plaque rupture and ischemic stroke injury. Here, we investigated the potential benefits of the CXC chemokine-binding protein Evasin-3, which potently inhibits chemokine bioactivity and related neutrophilic inflammation in two mouse models of carotid atherosclerosis and ischemic stroke, respectively. In the first model, the chronic treatment with Evasin-3 as compared with Vehicle (phosphate-buffered saline (PBS)) was investigated in apolipoprotein E-deficient mice implanted of a ‘cast' carotid device. In the second model, acute Evasin-3 treatment (5 minutes after cerebral ischemia onset) was assessed in mice subjected to transient left middle cerebral artery occlusion. Although CXCL1 and CXCL2 were upregulated in both atherosclerotic plaques and infarcted brain, only CXCL1 was detectable in serum. In carotid atherosclerosis, treatment with Evasin-3 was associated with reduction in intraplaque neutrophil and matrix metalloproteinase-9 content and weak increase in collagen as compared with Vehicle. In ischemic stroke, treatment with Evasin-3 was associated with reduction in ischemic brain neutrophil infiltration and protective oxidants. No other effects in clinical and histological outcomes were observed. We concluded that Evasin-3 treatment was associated with reduction in neutrophilic inflammation in both mouse models. However, Evasin-3 administration after cerebral ischemia onset failed to improve poststroke outcomes. PMID:23250107

  18. Remote ischemic preconditioning for prevention of contrast-induced acute kidney injury in diabetic patients.

    PubMed

    Savaj, Shokoufeh; Savoj, Javad; Jebraili, Ismail; Sezavar, Seyed Hashem

    2014-11-01

    There are some clinical trials showing that short-term ischemia in one organ can protect different organs against higher intensity and longer ischemic insult. We designed a study to assess whether remote ischemic preconditioning (RIPC) on one organ can decrease the rate of contrast-induced acute kidney injury (AKI) in diabetic patients who undergo coronary artery angiography (CAA). This randomized control trial included 96 diabetic patients who were candidates for CAA. Exclusion criteria were congestive heart failure and complications during CAA. All of the patients received 1000 mL of normal saline before CAA. The RIPC group underwent 3 cycles of 5-minute ischemia in their right arm. Serum creatinine was measured before and 24 hours after CAA. Contrast-induced AKI was reported in 5 cases in the control group and 1 case in the RIPC group (P = .13, odds ratio, 5.4). The differences in serum creatinine level before and after the procedure was significantly lower in RIPC group than that in the control group (P = .04, odds ratio, 0.08). Serum creatinine rise significantly correlated with contrast dose (P = .02) and a history of hypertension (P = .02) in both groups. Ischemic preconditioning had a protective effect on contrast-induced AKI in our study. Since this method is harmless and cost effective, further studies on patients with chronic kidney disease is required to evaluate addition of ischemic preconditioning to our clinical practice for prevention of contrast-induced AKI.

  19. Preventive effect of specific antioxidant on oxidative renal cell injury associated with renal crystal formation.

    PubMed

    Fishman, Andrew I; Green, David; Lynch, Alexandria; Choudhury, Muhammad; Eshghi, Majid; Konno, Sensuke

    2013-08-01

    To investigate whether calcium oxalate monohydrate (COM), a key element of hyperoxaluria, would induce renal cell injury through oxidative stress and also whether certain antioxidants could prevent chemically induced renal crystal formation in rats. COM-exerted oxidative stress on the kidney epithelial Madin-Darby canine kidney cells was assessed using the lipid peroxidation assay. Glyoxalase I (Gly-I) activity was also determined. Two antioxidants, vitamin C and N-acetylcysteine (NAC), were then tested to determine whether they could abolish such oxidative stress in Madin-Darby canine kidney cells. Both antioxidants were also tested to determine whether they might prevent or reduce renal crystal formation induced with ethylene glycol (EG) and vitamin D3 (VD3) in Wistar rats. COM (200 μg/mL) demonstrated ∼1.3-fold greater oxidative stress with a significant reduction in cell viability and Gly-I activity compared with controls. However, such adverse events were almost completely prevented with NAC but not with vitamin C. In the animal study, no renal crystals were seen in the sham group. However, numerous crystals, with reduced Gly-I activity and elevated oxidative stress, were found in the EG-VD3 group. However, markedly (>70%) fewer crystals, with full Gly-I activity and diminished oxidative stress, were detected in the EG-VD3+NAC group. COM exerted oxidative stress on Madin-Darby canine kidney cells, leading to cell viability reduction and Gly-I inactivation, with NAC fully preventing such adverse consequences. Similarly, numerous crystals with Gly-I inactivation and elevated oxidative stress seen in the rats (EG-VD3) were also significantly prevented with NAC supplement. Thus, NAC might have clinical implications in preventing oxidative renal cell injury and, ultimately, kidney stone formation. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Evidence of uncoupling between renal dysfunction and injury in cardiorenal syndrome: insights from the BIONICS study.

    PubMed

    Legrand, Matthieu; De Berardinis, Benedetta; Gaggin, Hanna K; Magrini, Laura; Belcher, Arianna; Zancla, Benedetta; Femia, Alexandra; Simon, Mandy; Motiwala, Shweta; Sambhare, Rasika; Di Somma, Salvatore; Mebazaa, Alexandre; Vaidya, Vishal S; Januzzi, James L

    2014-01-01

    The objective of the study was to assess urinary biomarkers of renal injury for their individual or collective ability to predict Worsening renal function (WRF) in patients with acutely decompensated heart failure (ADHF). In a prospective, blinded international study, 87 emergency department (ED) patients with ADHF were evaluated with biomarkers of cardiac stretch (B type natriuretic peptide [BNP] and its amino terminal equivalent [NT-proBNP], ST2), biomarkers of renal function (creatinine, estimated glomerular filtration rate [eGFR]) and biomarkers of renal injury (plasma neutrophil gelatinase associated lipocalin [pNGAL], urine kidney injury molecule-1 [KIM-1], urine N-acetyl-beta-D-glucosaminidase [NAG], urine Cystatin C, urine fibrinogen). The primary endpoint was WRF. 26% developed WRF; baseline characteristics of subjects who developed WRF were generally comparable to those who did not. Biomarkers of renal function and urine biomarkers of renal injury were not correlated, while urine biomarkers of renal injury correlated between each other. Biomarker concentrations were similar between patients with and without WRF except for baseline BNP. Although plasma NGAL was associated with the combined endpoint, none of the biomarker showed predictive accuracy for WRF. In ED patients with ADHF, urine biomarkers of renal injury did not predict WRF. Our data suggest that a weak association exists between renal dysfunction and renal injury in this setting (Clinicaltrials.gov NCT#0150153).

  1. Evidence of Uncoupling between Renal Dysfunction and Injury in Cardiorenal Syndrome: Insights from the BIONICS Study

    PubMed Central

    Legrand, Matthieu; De Berardinis, Benedetta; Gaggin, Hanna K.; Magrini, Laura; Belcher, Arianna; Zancla, Benedetta; Femia, Alexandra; Simon, Mandy; Motiwala, Shweta; Sambhare, Rasika; Di Somma, Salvatore; Mebazaa, Alexandre; Vaidya, Vishal S.; Januzzi, James L.; (GREAT), from the Global Research on Acute Conditions Team

    2014-01-01

    Objective The objective of the study was to assess urinary biomarkers of renal injury for their individual or collective ability to predict Worsening renal function (WRF) in patients with acutely decompensated heart failure (ADHF). Methods In a prospective, blinded international study, 87 emergency department (ED) patients with ADHF were evaluated with biomarkers of cardiac stretch (B type natriuretic peptide [BNP] and its amino terminal equivalent [NT-proBNP], ST2), biomarkers of renal function (creatinine, estimated glomerular filtration rate [eGFR]) and biomarkers of renal injury (plasma neutrophil gelatinase associated lipocalin [pNGAL], urine kidney injury molecule-1 [KIM-1], urine N-acetyl-beta-D-glucosaminidase [NAG], urine Cystatin C, urine fibrinogen). The primary endpoint was WRF. Results 26% developed WRF; baseline characteristics of subjects who developed WRF were generally comparable to those who did not. Biomarkers of renal function and urine biomarkers of renal injury were not correlated, while urine biomarkers of renal injury correlated between each other. Biomarker concentrations were similar between patients with and without WRF except for baseline BNP. Although plasma NGAL was associated with the combined endpoint, none of the biomarker showed predictive accuracy for WRF. Conclusions In ED patients with ADHF, urine biomarkers of renal injury did not predict WRF. Our data suggest that a weak association exists between renal dysfunction and renal injury in this setting (Clinicaltrials.gov NCT#0150153). PMID:25386851

  2. Oxygenation of the cerebrospinal fluid with artificial cerebrospinal fluid can ameliorate a spinal cord ischemic injury in a rabbit model.

    PubMed

    Kanda, Keisuke; Adachi, Osamu; Kawatsu, Satoshi; Sakatsume, Ko; Kumagai, Kiichiro; Kawamoto, Shunsuke; Saiki, Yoshikatsu

    2016-11-01

    We evaluated the effect of cerebrospinal fluid oxygenation for the prevention of spinal cord ischemic injury after infrarenal aortic occlusion in a rabbit model. Twenty white Japanese rabbits were categorized into the following 4 groups (5 in each): group S (sham), balloon catheter insertion on to the aorta; group C (control), spinal cord ischemic injury by infrarenal abdominal aortic balloon occlusion for 15 minutes; group N (nonoxygenated), spinal cord ischemic injury with cerebrospinal fluid replacement by nonoxygenated artificial cerebrospinal fluid; and group O (oxygenated), spinal cord ischemic injury with cerebrospinal fluid replacement by nanobubble-oxygenated artificial cerebrospinal fluid. The changes in cerebrospinal fluid partial pressure of oxygen during the peri-ischemic period, modified Tarlov score, and histopathology of the spinal cord 48 hours after aortic maneuvers were evaluated. Cerebrospinal fluid partial pressure of oxygen significantly increased in group O compared with group N after cerebrospinal fluid replacement (254.5 ± 54.8 mm Hg vs 136.1 ± 43.5 mm Hg, P = .02). After 15 minutes of spinal cord ischemic injury, cerebrospinal fluid partial pressure of oxygen in group C decreased to 65.8 ± 18.6 mm Hg compared with baseline (148.8 ± 20.6 mm Hg, P < .01), whereas cerebrospinal fluid partial pressure of oxygen in group O was maintained at remarkably high levels after spinal cord ischemic injury (291.9 ± 51.8 mm Hg), which was associated with improved neurologic function, with 20% of spinal cord ischemic injury having a Tarlov score less than 5 compared with 100% of spinal cord ischemic injury in group C. Preservation of anterior horn neurons in groups N and O was confirmed by histopathologic analysis with significant reduction of degenerated neurons compared with group C. Cerebrospinal fluid oxygenation with artificial cerebrospinal fluid can exert a protective effect against spinal cord ischemic injury in rabbits

  3. Prognostic Relationships between Microbleed, Lacunar Infarction, White Matter Lesion, and Renal Dysfunction in Acute Ischemic Stroke Survivors.

    PubMed

    Jeon, Jae Woong; Jeong, Hye Seon; Choi, Dae Eun; Ham, Young Rok; Na, Ki Ryang; Lee, Kang Wook; Shin, Jong Wook; Kim, Jei

    2017-02-01

    It is well known that renal dysfunction and cerebral small-vessel disease (SVD), including microbleed, lacunar infarction, and white matter lesion (WML), are associated with poor prognosis after ischemic stroke. However, the prognostic relationship between renal dysfunction and SVD has not been well evaluated in acute ischemic stroke survivors. Therefore, in this study, we evaluated the prognostic relationships between estimated glomerular filtration rate (eGFR) and cerebral SVD after acute ischemic stroke. We retrospectively reviewed the clinical and radiological data of acute ischemic stroke survivors with decreased eGFR (<60 mL/min/1.73 m(2), n = 128) and controls (eGFR ≥60 mL/min/1.73 m(2), n = 128). The presence of SVD was evaluated according to magnetic resonance imaging performed on admission. Mortality data were obtained from medical chart reviews and telephone interviews. Patients with silent lacunar infarction, WML, or microbleed had lower eGFR than patients without such lesions (60.4 ± 34.8 versus 87.5 ± 28.4 mL/min/1.73 m(2), 60.5 ± 37.1 versus 73.9 ± 33.3 mL/min/1.73 m(2), and 57.6 ± 33.3 versus 73.9 ± 32.9 mL/min/1.73 m(2), respectively). In addition, the multivariate adjusted odds ratio for the presence of SVD increased inversely with eGFR. Three-year survival was lower in patients with renal dysfunction and each type of SVD. The presence of WML was an independent risk factor for cardiovascular death. Renal impairment was associated with the presence of SVD in acute ischemic stroke survivors. Both renal impairment and the presence of SVD were predictors of poor poststroke survival. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  4. Examination of the impact of airbags on renal injury using a national database.

    PubMed

    Smith, Thomas G; Wessells, Hunter B; Mack, Chris D; Kaufman, Robert; Bulger, Eileen M; Voelzke, Bryan B

    2010-09-01

    Little is known about preventative measures to lessen solid organ injury in motor vehicle collisions (MVCs). To evaluate the efficacy of airbags in reducing renal injuries in MVC, we analyzed renal injury rates in vehicles with and without airbags using the Crash Injury Research and Engineering Network (CIREN) database. The CIREN database was queried for MVC and renal injury from 1996 to September 2008. CIREN is weighted toward late model vehicles and selects more severely injured patients. Search fields were primary direction of force (PDOF), presence of airbags, and location of airbags (steering wheel, instrument panel, seat back, door panel, and roof-side curtain). Abdominal Abbreviated Injury Score was converted to AAST renal injury grade. Renal injury rates were compared between vehicles with and without frontal and side airbags. We reviewed 2,864 records and identified 139 renal injuries (28.9% AAST grade III to V). In MVCs with renal injuries, frontal impact was 54.7% of total (n = 76) and side impact was 45.3% of total (n = 63). Most occupants in frontal impact MVCs had exposure to a steering wheel airbag (74.9%); 16.6% had an instrument panel (passenger) airbags. In side impact MVCs, 32.2% of occupants had a side airbag. Compared with the non-airbags cohort, frontal airbags and side airbags were associated with a 45.3% and 52.8% reduction in renal injury, respectively. Passengers in automobiles with frontal and side airbags have a reduced rate of renal injury compared with those without airbags. Our data support further study of the role of airbags in reducing renal injury after MVC. Copyright 2010 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

  5. Calcium Oxalate Induces Renal Injury through Calcium-Sensing Receptor

    PubMed Central

    Li, Xiaoran; Ma, Junhai; Shi, Wei; Su, Yu; Fu, Xu; Yang, Yanlin; Lu, Jianzhong

    2016-01-01

    Objective. To investigate whether calcium-sensing receptor (CaSR) plays a role in calcium-oxalate-induced renal injury. Materials and Methods. HK-2 cells and rats were treated with calcium oxalate (CaOx) crystals with or without pretreatment with the CaSR-specific agonist gadolinium chloride (GdCl3) or the CaSR-specific antagonist NPS2390. Changes in oxidative stress (OS) in HK-2 cells and rat kidneys were assessed. In addition, CaSR, extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal protein kinase (JNK), and p38 expression was determined. Further, crystal adhesion assay was performed in vitro, and the serum urea and creatinine levels and crystal deposition in the kidneys were also examined. Results. CaOx increased CaSR, ERK, JNK, and p38 protein expression and OS in vitro and in vivo. These deleterious changes were further enhanced upon pretreatment with the CaSR agonist GdCl3 but were attenuated by the specific CaSR inhibitor NPS2390 compared with CaOx treatment alone. Pretreatment with GdCl3 further increased in vitro and in vivo crystal adhesion and renal hypofunction. In contrast, pretreatment with NPS2390 decreased in vitro and in vivo crystal adhesion and renal hypofunction. Conclusions. CaOx-induced renal injury is related to CaSR-mediated OS and increased mitogen-activated protein kinase (MAPK) signaling, which subsequently leads to CaOx crystal adhesion. PMID:27965733

  6. Transforming growth factor-β1 promotes homing of bone marrow mesenchymal stem cells in renal ischemia-reperfusion injury

    PubMed Central

    Si, Xiaoyun; Liu, Ximing; Li, Jingjing; Wu, Xiaoyan

    2015-01-01

    Backgrounds: Acute ischemia reperfusion-induced kidney injury is a common cause of acute renal failure, and it is also an important cause of delayed recovery of transplanted kidney functions and even loss of function. However, there is no effective treatment method in clinical applications presently. Objective: The objective was to investigate effects of transforming growth factor-β1 on homing of bone marrow mesenchymal stem cells in renal ischemia-reperfusion injury. Methods: Effects of TGF-β1 over-expression in MSCs on expression of CXCR4 and chemotactic effect to SDF-1 were investigated by in vitro transmembrane chemotaxis. Anti-TGF-β1 antibody was incubated with ischemia reperfusion injury renal tissue homogenate and effects of anti-TGF-β1 antibody were observed. In addition, effects of TGF-β1 gene transfection and anti-CXCR4 antibody treatment in MSCs on expression of SDF-1/CXCR4 axis of renal tissues and damage repair were further explored. Results: Expression of TGF-β1 mRNA in the IRI group increased significantly, and MSCs transplantation could enhance expression of CXCR4 mRNA in rats of the IRI group, the expression of CXCR4 can be decreased by the anti-TGF-β1 antibody and the anti-CXCR4 antibody. TGF-β1 induced homing of MSCs in repair of renal ischemic reperfusion injury by regulating expression of CXCR4 on cell membranes. Blue fluorescence of DAPI-positive MSCs cells of renal parenchyma in the IRI+MSC group was enhanced significantly, which was significantly inhibited by anti-TGF-β1 and anti-CXCR4 antibody, and the inhibitory effect of anti-CXCR4 antibody was more obvious than that of anti-TGF-β1 antibody. Conclusion: Transforming growth factor-β1 promotes homing of bone marrow mesenchymal stem cells in renal ischemia-reperfusion injury, which will provide useful data on role of TGF-β1 in regulating SDF-1/CXCR4 axis-induced MSCs homing. PMID:26722423

  7. 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

  8. The feasibility of imaging myocardial ischemic/reperfusion injury using (99m)Tc-labeled duramycin in a porcine model.

    PubMed

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

    2015-02-01

    When pathologically externalized, phosphatidylethanolamine (PE) is a potential surrogate marker for detecting tissue injuries. (99m)Tc-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 (99m)Tc-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. The clearance and distribution of intravenously injected (99m)Tc-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). (99m)Tc-duramycin (10-15mCi) was injected intravenously at 1hour after reperfusion. SPECT/CT was acquired at 1 and 3hours after injection. Cardiac tissues were analyzed for changes associated with acute cellular injuries. Autoradiography and gamma counting were used to determine radioactivity uptake. For the remaining animals, (99m)Tc-tetrafosamin scan was performed on the second day to identify the infarct site. Intravenously injected (99m)Tc-duramycin cleared from circulation predominantly via the renal/urinary tract with an α-phase half-life of 3.6±0.3minutes and β-phase half-life of 179.9±64.7minutes. 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 3hours 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 30min post-injection. The in vivo ischemic-to-normal uptake ratios were 3.57±0.74 and 3.69±0.91 at 1 and 3hours 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±0.78. The size of (99m)Tc-duramycin positive

  9. A Controversial Medicolegal Issue: Timing the Onset of Perinatal Hypoxic-Ischemic Brain Injury

    PubMed Central

    Frati, Paola

    2017-01-01

    Perinatal hypoxic-ischemic brain injury, as a result of chronic, subacute, and acute insults, represents the pathological consequence of fetal distress and birth or perinatal asphyxia, that is, “nonreassuring fetal status.” Hypoxic-ischemic injury (HII) is typically characterized by an early phase of damage, followed by a delayed inflammatory local response, in an apoptosis-necrosis continuum. In the early phase, the cytotoxic edema and eventual acute lysis take place; with reperfusion, additional damage should be assigned to excitotoxicity and oxidative stress. Finally, a later phase involves all the inflammatory activity and long-term neural tissue repairing and remodeling. In this model mechanism, loss of mitochondrial function is supposed to be the hallmark of secondary injury progression, and autophagy which is lysosome-mediated play a role in enhancing brain injury. Early-induced molecules driven by hypoxia, as chaperonins HSPs and ORP150, besides common markers for inflammatory responses, have predictive value in timing the onset of neonatal HII; on the other hand, clinical biomarkers for HII diagnosis, as CK-BB, LDH, S-100beta, and NSE, could be useful to predict outcomes. PMID:28883688

  10. Remote Ischemic Conditioning Prevents Lung and Liver Injury After Hemorrhagic Shock/Resuscitation: Potential Role of a Humoral Plasma Factor.

    PubMed

    Leung, Chung Ho; Caldarone, Christopher A; Wang, Feng; Venkateswaran, Seetha; Ailenberg, Menachem; Vadasz, Brian; Wen, Xiao-Yan; Rotstein, Ori D

    2015-06-01

    To evaluate the efficacy of remote ischemic conditioning (RIC) on organ protection after hemorrhagic shock/resuscitation (S/R) in a murine model. Ischemia/reperfusion resulting from S/R contributes to multiple organ dysfunction in trauma patients. We hypothesized that RIC before shock (remote ischemic preconditioning), during shock (remote ischemic "PER"conditioning), or during resuscitation (remote ischemic "POST"conditioning) could confer organ protection. We also tested the effect of ischemic conditioned plasma on neutrophil migration in vivo using transgenic zebrafish models. C57Bl/6 mice were subjected to S/R with or without hindlimb RIC. Serum levels of alanine aminotransferase and tumor necrosis factor-alpha, and liver tumor necrosis factor-alpha and interleukin 1β mRNA were evaluated. In some experiments, lung protein leakage, cytokines, and myeloperoxidase activity were investigated. Plasma from mice subjected to RIC was microinjected into zebrafish, and neutrophil migration was assessed after tailfin transection or copper sulfate treatment. In mice subjected to S/R, remote ischemic preconditioning, remote ischemic "PER"conditioning, and remote ischemic "POST"conditioning each significantly reduced serum alanine aminotransferase and liver mRNA expression of tumor necrosis factor-alpha and interleukin 1β and improved liver histology compared with control S/R mice. Lung injury and inflammation were also significantly reduced in mice treated with remote ischemic preconditioning. Zebrafish injected with plasma or dialyzed plasma (fraction >14 kDa) from ischemic conditioned mice had reduced neutrophil migration toward sites of injury compared with zebrafish injected with control plasma. RIC protects against S/R-induced organ injury, in part, through a humoral factor(s), which alters neutrophil function. The beneficial effects of RIC, performed during the S/R phase of care, suggest a role for its application early in the posttrauma period.

  11. Ambient Melamine Exposure and Urinary Biomarkers of Early Renal Injury

    PubMed Central

    Wu, Chia-Fang; Peng, Chiung-Yu; Liu, Chia-Chu; Lin, Wen-Yi; Pan, Chih-Hong; Cheng, Ching-Mei; Hsieh, Hui-Min; Hsieh, Tusty-Jiuan; Chen, Bai-Hsiun

    2015-01-01

    Information about environmental exposure to melamine and renal injury in adults is lacking. We investigated this relationship in 44 workers at two melamine tableware manufacturing factories in Taiwan (16 manufacturers, eight grinders, ten packers, and ten administrators) and 105 nonexposed workers (controls) at one shipbuilding company who were enrolled in August–December of 2012. For melamine workers, personal and area air samples were obtained at the worksite over 1 workweek (Monday–Friday). In the same week, pre- and post-shift one-spot urine samples were collected each workday and one first-spot urine sample was collected on each weekend morning and the following Monday morning. For each control, a one-spot urine sample was collected on Friday morning. A blood sample was also obtained from each participant at this time. Melamine levels were measured in air, urine, and serum, and early renal injury biomarkers were measured in urine. Urinary melamine concentrations in manufacturers increased sharply between pre- and post-shift measurements on Monday, remained significantly elevated throughout the workweek, and decreased over the weekend; changes in urinary melamine concentrations were substantially lower for other melamine workers. Manufacturers were exposed to the highest concentrations of ambient melamine and had significantly higher urinary and serum melamine concentrations than did the controls (P<0.001). Urinary melamine levels were positively associated with urinary N-acetyl β-d-glucosaminidase (NAG) levels but not microalbumin levels, and the detectable β2-microglobulin rate increased in the manufacturers group. In conclusion, ambient melamine exposure may increase the levels of urinary biomarkers of renal tubular injury in this occupational setting. PMID:26045090

  12. Ambient Melamine Exposure and Urinary Biomarkers of Early Renal Injury.

    PubMed

    Wu, Chia-Fang; Peng, Chiung-Yu; Liu, Chia-Chu; Lin, Wen-Yi; Pan, Chih-Hong; Cheng, Ching-Mei; Hsieh, Hui-Min; Hsieh, Tusty-Jiuan; Chen, Bai-Hsiun; Wu, Ming-Tsang

    2015-11-01

    Information about environmental exposure to melamine and renal injury in adults is lacking. We investigated this relationship in 44 workers at two melamine tableware manufacturing factories in Taiwan (16 manufacturers, eight grinders, ten packers, and ten administrators) and 105 nonexposed workers (controls) at one shipbuilding company who were enrolled in August-December of 2012. For melamine workers, personal and area air samples were obtained at the worksite over 1 workweek (Monday-Friday). In the same week, pre- and post-shift one-spot urine samples were collected each workday and one first-spot urine sample was collected on each weekend morning and the following Monday morning. For each control, a one-spot urine sample was collected on Friday morning. A blood sample was also obtained from each participant at this time. Melamine levels were measured in air, urine, and serum, and early renal injury biomarkers were measured in urine. Urinary melamine concentrations in manufacturers increased sharply between pre- and post-shift measurements on Monday, remained significantly elevated throughout the workweek, and decreased over the weekend; changes in urinary melamine concentrations were substantially lower for other melamine workers. Manufacturers were exposed to the highest concentrations of ambient melamine and had significantly higher urinary and serum melamine concentrations than did the controls (P<0.001). Urinary melamine levels were positively associated with urinary N-acetyl β-d-glucosaminidase (NAG) levels but not microalbumin levels, and the detectable β2-microglobulin rate increased in the manufacturers group. In conclusion, ambient melamine exposure may increase the levels of urinary biomarkers of renal tubular injury in this occupational setting. Copyright © 2015 by the American Society of Nephrology.

  13. Epoxyeicosatrienoic acids in cardioprotection: ischemic versus reperfusion injury.

    PubMed

    Nithipatikom, Kasem; Moore, Jeannine M; Isbell, Marilyn A; Falck, John R; Gross, Garrett J

    2006-08-01

    Cytochrome P-450 (CYP) epoxygenases and their arachidonic acid (AA) metabolites, the epoxyeicosatrienoic acids (EETs), have been shown to produce increases in postischemic function via ATP-sensitive potassium channels (K(ATP)); however, the direct effects of EETs on infarct size (IS) have not been investigated. We demonstrate that two major regioisomers of CYP epoxygenases, 11,12-EET and 14,15-EET, significantly reduced IS in dogs compared to control (22.1 +/- 1.8%), whether administered 15 min before 60 min of coronary occlusion (6.4 +/- 1.9%, 11,12-EET; and 8.4 +/- 2.4%, 14.15-EET) or 5 min before 3 h of reperfusion (8.8 +/- 2.1%, 11,12-EET; and 9.7 +/- 1.4%, 14,15-EET). Pretreatment with the epoxide hydrolase metabolite of 14,15-EET, 14,15-dihydroxyeicosatrienoic acid, had no effect. The protective effect of 11,12-EET was abolished (24.3 +/- 4.6%) by the K(ATP) channel antagonist glibenclamide. Furthermore, one 5-min period of ischemic preconditioning (IPC) reduced IS to a similar extent (8.7 +/- 2.8%) to that observed with the EETs. The selective CYP epoxygenase inhibitor, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH), did not block the effect of IPC. However, administration of MS-PPOH concomitantly with N-methylsulfonyl-12,12-dibromododec-11-enanide (DDMS), a selective inhibitor of endogenous CYP omega-hydroxylases, abolished the reduction in myocardial IS expressed as a percentage of area at risk (IS/AAR) produced by DDMS (4.6 +/- 1.2%, DDMS; and 22.2 +/- 3.4%, MS-PPOH + DDMS). These data suggest that 11,12-EET and 14,15-EET produce reductions in IS/AAR primarily at reperfusion. Conversely, inhibition of CYP epoxygenases and endogenous EET formation by MS-PPOH, in the presence of the CYP omega-hydroxylase inhibitor DDMS blocked cardioprotection, which suggests that endogenous EETs are important for the beneficial effects observed when CYP omega-hydroxylases are inhibited. Finally, the protective effects of EETs are mediated by cardiac K

  14. Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

    PubMed Central

    Li, Minshu; Li, Zhiguo; Yao, Yang; Jin, Wei-Na; Wood, Kristofer; Liu, Qiang; Shi, Fu-Dong; Hao, Junwei

    2017-01-01

    Astrocytes are believed to bridge interactions between infiltrating lymphocytes and neurons during brain ischemia, but the mechanisms for this action are poorly understood. Here we found that interleukin-15 (IL-15) is dramatically up-regulated in astrocytes of postmortem brain tissues from patients with ischemic stroke and in a mouse model of transient focal brain ischemia. We generated a glial fibrillary acidic protein (GFAP) promoter-controlled IL-15–expressing transgenic mouse (GFAP–IL-15tg) line and found enlarged brain infarcts, exacerbated neurodeficits after the induction of brain ischemia. In addition, knockdown of IL-15 in astrocytes attenuated ischemic brain injury. Interestingly, the accumulation of CD8+ T and natural killer (NK) cells was augmented in these GFAP–IL-15tg mice after brain ischemia. Of note, depletion of CD8+ T or NK cells attenuated ischemic brain injury in GFAP–IL-15tg mice. Furthermore, knockdown of the IL-15 receptor α or blockade of cell-to-cell contact diminished the activation and effector function of CD8+ T and NK cells in GFAP–IL-15tg mice, suggesting that astrocytic IL-15 is delivered in trans to target cells. Collectively, these findings indicate that astrocytic IL-15 could aggravate postischemic brain damage via propagation of CD8+ T and NK cell-mediated immunity. PMID:27994144

  15. 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.

  16. Ischemic postconditioning as a novel avenue to protect against brain injury after stroke

    PubMed Central

    Zhao, Heng

    2009-01-01

    Ischemic postconditioning initially referred to a stuttering reperfusion performed immediately after reperfusion, for preventing ischemia/reperfusion injury in both myocardial and cerebral infarction. It has evolved into a concept that can be induced by a broad range of stimuli or triggers, and may even be performed as late as 6 h after focal ischemia and 2 days after transient global ischemia. The concept is thought to be derived from ischemic preconditioning or partial/gradual reperfusion, but in fact the first experiment for postconditioning was carried out much earlier than that of preconditioning or partial/gradual reperfusion, in the research on myocardial ischemia. This review first examines the protective effects and parameters of postconditioning in various cerebral ischemic models. Thereafter, it provides insights into the protective mechanisms of postconditioning associated with reperfusion injury and the Akt, mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and ATP-sensitive K+ (KATP) channel cell signaling pathways. Finally, some open issues and future challenges regarding clinical translation of postconditioning are discussed. PMID:19240739

  17. Anti-inflammation effects of picroside 2 in cerebral ischemic injury rats

    PubMed Central

    2010-01-01

    Background Excitatory amino acid toxicity, oxidative stress, intracellular calcium overload, as well as inflammation and apoptosis are involved in the pathological process after cerebral ischemic reperfusion injury. Picrodide 2 could inhibit neuronal apoptosis and play anti-oxidant and anti-inflammation role in cerebral ischemia/reperfusion injuries, but the exact mechanism is not very clear. This study aims to explore the anti-inflammation mechanism of picroside 2 in cerebral ischemic reperfusion injury in rats. Methods The middle cerebral artery occlusion reperfusion models were established with intraluminal thread methods in 90 adult healthy female Wistar rats. Picroside 2 and salvianic acid A sodium were respectively injected from tail vein at the dosage of 10 mg/kg for treatment. The neurobehavioral function was evaluated with Bederson's test and the cerebral infarction volume was observed with tetrazolium chloride (TTC) staining. The apoptotic cells were counted by in situ terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling (TUNEL) assay. The immunohistochemistry stain was used to determine the expressions of toll-like receptor 4 (TLR4), nuclear transcription factor κB (NFκB) and tumor necrosis factor α (TNFα). The concentrations of TLR4, NFκB and TNFα in brain tissue were determined by enzyme linked immunosorbent assay (ELISA). Results After cerebral ischemic reperfusion, the rats showed neurobehavioral function deficit and cerebral infarction in the ischemic hemisphere. The number of apoptotic cells, the expressions and the concentrations in brain tissue of TLR4, NFκB and TNFα in ischemia control group increased significantly than those in the sham operative group (P < 0.01). Compared with the ischemia control group, the neurobehavioral scores, the infarction volumes, the apoptotic cells, the expressions and concentrations in brain tissue of TLR4, NFκB and TNFα were obviously decreased both in

  18. cPKCγ-Modulated Autophagy in Neurons Alleviates Ischemic Injury in Brain of Mice with Ischemic Stroke Through Akt-mTOR Pathway.

    PubMed

    Wei, Haiping; Li, Yun; Han, Song; Liu, Shuiqiao; Zhang, Nan; Zhao, Li; Li, Shujuan; Li, Junfa

    2016-12-01

    We have reported that neuron-specific conventional protein kinase C (cPKC)γ is involved in the development of cerebral hypoxic preconditioning (HPC) and the neuroprotection against ischemic injuries, but its molecular mechanism is unclear. In this study, the adult and postnatal 24 h C57BL/6J wild-type (cPKCγ(+/+)) and cPKCγ knockout (cPKCγ(-/-)) mice were respectively used to establish the models of middle cerebral artery occlusion (MCAO)-induced ischemic stroke in vivo and oxygen-glucose deprivation (OGD)-treated primarily cultured cortical neurons as cell ischemia in vitro. The results showed that cPKCγ knockout could increase the infarct volume and neuronal cell loss in the peri-infarct region, and enhance the neurological deficits, the impaired coordination, and the reduced muscle strength of mice following 1 h MCAO/1-7 days reperfusion. Meanwhile, cPKCγ knockout significantly increased the conversion of LC3-I to LC3-II and beclin-1 protein expression, and resulted in more reductions in P-Akt, P-mTOR, and P-S6 phosphorylation levels in the peri-infarct region of mice with ischemic stroke. The autophagy inhibitor BafA1 could enhance or reduce neuronal cell loss in the peri-infarct region of cPKCγ(+/+) and cPKCγ(-/-) mice after ischemic stroke. In addition, cPKCγ knockout and restoration could aggravate or alleviate OGD-induced neuronal ischemic injury in vitro through Akt-mTOR pathway-mediated autophagy. These results suggested that cPKCγ-modulated neuron-specific autophagy improves the neurological outcome of mice following ischemic stroke through the Akt-mTOR pathway, providing a potential therapeutic target for ischemic stroke.

  19. Role of the renal sympathetic nervous system in mediating renal ischaemic injury-induced reductions in renal haemodynamic and excretory functions.

    PubMed

    Salman, Ibrahim M; Ameer, Omar Z; Sattar, Munavvar A; Abdullah, Nor A; Yam, Mun F; Najim, Hafsa S; Khan, Abdul Hye; Johns, Edward J

    2010-04-01

    We investigated the role of renal sympathetic innervation in the deterioration of renal haemodynamic and excretory functions during the early post-ischaemic phase of renal ischaemia/reperfusion injury. Anaesthetised male Sprague-Dawley rats were subjected to unilateral renal ischaemia by clamping the left renal artery for 30 min followed by reperfusion. Following acute renal denervation clearance experiments were performed. In a different set of experiments, the renal nerves were electrically stimulated at increasing frequencies and responses in renal blood flow and renal vascular resistance were recorded. Denervated post-ischaemic acute renal failure (ARF) rats showed higher urine flow rate, absolute and fractional sodium excretions, urinary sodium to urinary potassium, glomerular filtration rate and basal renal blood flow but lower basal renal vascular resistance (all p < 0.05 vs innervated ARF rats). Potassium excretion was significantly lower in denervated group as per fractional (p < 0.05 vs innervated ARF rats) but not absolute potassium excretion (p > 0.05 vs innervated ARF rats). The rise in mean arterial pressure and renal vasoconstrictor response to renal nerve stimulation were blunted in denervated ischaemic ARF rats (all p < 0.05 vs innervated ARF rats). Renal histopathology in denervated ARF rats manifested a significantly lower medullary congestion, inflammation and tubular injury compared to innervated counterparts (p < 0.05 vs innervated ARF rats). The findings strongly suggest the involvement of renal sympathetic tone in the post-ischaemic events of ischaemic ARF, as the removal of its action to a degree ameliorated the post-ischaemic renal dysfunctions.

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

    PubMed Central

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

    2010-01-01

    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. PMID:24198613

  1. 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.

  2. Melatonin treatment against remote organ injury induced by renal ischemia reperfusion injury in diabetes mellitus.

    PubMed

    Fadillioglu, Ersin; Kurcer, Zehra; Parlakpinar, Hakan; Iraz, Mustafa; Gursul, Cebrail

    2008-06-01

    Oxidative stress may have a role in liver damage after acute renal injury due to various reasons such as ischemia reperfusion (IR). Diabetes mellitus (DM) is an important disease for kidneys and may cause nephropathy as a long term complication. The aim of this study was to investigate protective effect of melatonin, a potent antioxidant, against distant organ injury on liver induced by renal IR in rats with or without DM. The rats were divided into six groups: control (n=7), DM (n=5), IR (n=7), DM+IR (n=7), melatonin+IR (Mel+IR) (melatonin, 4 mg/ kg during 15 days) (n=7), and Mel+DM+IR groups (n=7). Diabetes developed 3 days after single i.p. dose of 45 mg/kg streptozotocin. After 15 day, the left renal artery was occluded for 30 min followed 24 h of reperfusion in IR performed groups. DM did not alter oxidative parameters alone in liver tissue. The levels of malondialdehyde, protein carbonyl and nitric oxide with activities of xanthine oxidase and myeloperoxidase were increased in liver tissues of diabetic and non-diabetic IR groups. Nitric oxide level in DM was higher than control. The activities of catalase and superoxide dismutase were increased in IR groups in comparison with control and DM. ALT and AST levels were higher in IR and DM+IR groups than control and DM. Melatonin treatment reversed all these oxidant and antioxidant parameters to control values as well as serum liver enzymes. We concluded that renal IR may affect distant organs such as liver and oxidative stress may play role on this injury, but DM has not an effect on kidney induced distant organ injury via oxidant stress. Also, it was concluded that melatonin treatment may prevent liver oxidant stress induced by distant injury of kidney IR.

  3. Remote Limb Ischemic Postconditioning Protects Against Neonatal Hypoxic–Ischemic Brain Injury in Rat Pups by the Opioid Receptor/Akt Pathway

    PubMed Central

    Zhou, Yilin; Fathali, Nancy; Lekic, Tim; Ostrowski, Robert P.; Chen, Chunhua; Martin, Robert D.; Tang, Jiping; Zhang, John H.

    2013-01-01

    Background and Purpose Remote ischemic postconditoning, a phenomenon in which brief ischemic stimuli of 1 organ protect another organ against an ischemic insult, has been demonstrated to protect the myocardium and adult brain in animal models. However, mediators of the protection and underlying mechanisms remain to be elucidated. In the present study, we tested the hypothesis that remote limb ischemic postconditioning applied immediately after hypoxia provides neuroprotection in a rat model of neonatal hypoxia–ischemia (HI) by mechanisms involving activation of the opioid receptor/phosphatidylinositol-3-kinase/Akt signaling pathway. Methods HI was induced in postnatal Day 10 rat pups by unilateral carotid ligation and 2 hours of hypoxia. Limb ischemic postconditioning was induced by 4 conditioning cycles of 10 minutes of ischemia and reperfusion on both hind limbs immediately after HI. The opioid antagonist naloxone, phosphatidylinositol-3-kinase inhibitor wortmannin, or opioid agonist morphine was administered to determine underlying mechanisms. Infarct volume, brain atrophy, and neurological outcomes after HI were evaluated. Expression of phosphorylated Akt, Bax, and phosphorylated ERK1/2 was determined by Western blotting. Results Limb ischemic postconditioning significantly reduced infarct volume at 48 hours and improved functional outcomes at 4 weeks after HI. Naloxone and wortmannin abrogated the postconditioning-mediated infarct-limiting effect. Morphine given immediately after hypoxia also decreased infarct volume. Furthermore, limb ischemic postconditioning recovered Akt activity and decreased Bax expression, whereas no differences in phosphorylated ERK1/2expression were observed. Conclusions Limb ischemic postconditioning protects against neonatal HI brain injury in rats by activating the opioid receptor/phosphatidylinositol-3-kinase/Akt signaling pathway. PMID:21183744

  4. The degradation of mixed lineage kinase domain-like protein promotes neuroprotection after ischemic brain injury

    PubMed Central

    Zhou, Yanlong; Zhou, Beiqun; Tu, Hui; Tang, Yan; Xu, Chen; Chen, Yanbo; Zhao, Zhong; Miao, Zhigang

    2017-01-01

    Mixed lineage kinase domain-like (MLKL) protein was recently found to play a critical role in necrotic cell death. To explore its role in neurological diseases, we measured MLKL protein expression after ischemia injury in a mouse model. We found that MLKL expression significantly increased 12 h after ischemia/reperfusion (I/R) injury with peak levels at 48 h. Inhibition of MLKL by intraperitoneal administration of NSA significantly reduced infarct volume and improved neurological deficits after 75 min of ischemia and 24 h of reperfusion. Further, we found NSA reduced MLKL levels via the ubiquitination proteasome pathway, but not by inhibiting RNA transcription. Interestingly, NSA administration increased cleaved PARP-1 levels, indicating the protective effects of MLKL inhibition is not related to apoptosis. These findings suggest MLKL is a new therapeutic target for neurological pathologies like stroke. Therefore, promoting degradation of MLKL may be a novel avenue to reduce necrotic cell death after ischemic brain injury. PMID:28978125

  5. The degradation of mixed lineage kinase domain-like protein promotes neuroprotection after ischemic brain injury.

    PubMed

    Zhou, Yanlong; Zhou, Beiqun; Tu, Hui; Tang, Yan; Xu, Chen; Chen, Yanbo; Zhao, Zhong; Miao, Zhigang

    2017-09-15

    Mixed lineage kinase domain-like (MLKL) protein was recently found to play a critical role in necrotic cell death. To explore its role in neurological diseases, we measured MLKL protein expression after ischemia injury in a mouse model. We found that MLKL expression significantly increased 12 h after ischemia/reperfusion (I/R) injury with peak levels at 48 h. Inhibition of MLKL by intraperitoneal administration of NSA significantly reduced infarct volume and improved neurological deficits after 75 min of ischemia and 24 h of reperfusion. Further, we found NSA reduced MLKL levels via the ubiquitination proteasome pathway, but not by inhibiting RNA transcription. Interestingly, NSA administration increased cleaved PARP-1 levels, indicating the protective effects of MLKL inhibition is not related to apoptosis. These findings suggest MLKL is a new therapeutic target for neurological pathologies like stroke. Therefore, promoting degradation of MLKL may be a novel avenue to reduce necrotic cell death after ischemic brain injury.

  6. [Preservation of kidneys with ischemic injury using hypothermic storage and mechanical prolonged perfusion].

    PubMed

    Wienand, P; Grundmann, R; Bischoff, A; Pichlmaier, H

    1978-01-01

    Dog kidneys were flushed and stored in Collins (n = 30) and Sacks (n = 32) solution under hypothermia. These results were compared with those gained by mechanical perfusion (n = 21). Before preservation, the kidneys were subjected to 15 - 60 min of warm ischemia then stored for 12 - 24 h. It was concluded that 12-h preservation time after 15-min ischemic injury was the limit of hypothermic storage preservation. Sacks' solution gave better results than Collins' solution as regards the immediate function after transplantation. In contrast, mechanical perfusion was well tolerated for 24-h preservation time after a warm ischemia of 30 min. In case of warm ischemic damage, mechanical perfusion should be preferred to hypothermic storage.

  7. Interleukin-19 Mediates Tissue Damage in Murine Ischemic Acute Kidney Injury

    PubMed Central

    Sung, Junne-Ming; Chen, Wei-Ting; Hou, Ya-Chin; Chang, Ming-Shi

    2013-01-01

    Inflammation and renal tubular injury are major features of acute kidney injury (AKI). Many cytokines and chemokines are released from injured tubular cells and acts as proinflammatory mediators. However, the role of IL-19 in the pathogenesis of AKI is not defined yet. In bilateral renal ischemia/reperfusion injury (IRI)-induced and HgCl2-induced AKI animal models, real-time quantitative (RTQ)-PCR showed that the kidneys, livers, and lungs of AKI mice expressed significantly higher IL-19 and its receptors than did sham control mice. Immunohistochemical staining showed that IL-19 and its receptors were strongly stained in the kidney, liver, and lung tissue of AKI mice. In vitro, IL-19 upregulated MCP-1, TGF-β1, and IL-19, and induced mitochondria-dependent apoptosis in murine renal tubular epithelial M-1 cells. IL-19 upregulated TNF-α and IL-10 in cultured HepG2 cells, and it increased IL-1β and TNF-α expression in cultured A549 cells. In vivo, after renal IRI or a nephrotoxic dose of HgCl2 treatment, IL-20R1-deficient mice (the deficiency blocks IL-19 signaling) showed lower levels of blood urea nitrogen (BUN) in serum and less tubular damage than did wild-type mice. Therefore, we conclude that IL-19 mediates kidney, liver, and lung tissue damage in murine AKI and that blocking IL-19 signaling may provide a potent therapeutic strategy for treating AKI. PMID:23468852

  8. 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

  9. 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.

  10. 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

  11. SDF-1 provides morphological and functional protection against renal ischaemia/reperfusion injury.

    PubMed

    Stokman, Geurt; Stroo, Ingrid; Claessen, Nike; Teske, Gwendoline J D; Florquin, Sandrine; Leemans, Jaklien C

    2010-12-01

    The chemokine stromal cell-derived factor-1 (SDF-1) is thought to be involved in mediating tissue repair by promoting migration of bone marrow stem or progenitor cells to the site of injury. Increased levels of renal SDF-1 are found after kidney injury. However, recently, we showed that SDF-1 does not play an important role in the migration of haematopoietic stem cells to the post-ischaemic kidney. The function of increased post-ischaemic renal SDF-1 expression in modulating renal ischaemia/reperfusion injury remains, therefore, unknown. We studied the role of SDF-1 in renal ischaemia/reperfusion injury by locally decreasing SDF-1 expression and subsequent SDF-1 signalling in the corticomedullary region of the kidney using antisense oligonucleotide treatment in mice. Renal SDF-1 protein increased significantly in the early phase of ischaemia/reperfusion injury. Antisense treatment resulted in a reduction of corticomedullary SDF-1 expression which was accompanied by severely increased tubular injury and decreased renal function. We did not observe any difference in mobilization or retention of CXCR4-positive haematopoietic stem or progenitor cells after induction of renal ischaemia. Rather, antisense-treated animals showed markedly increased apoptosis of the tubular epithelium accompanied by an increased renal inflammatory response. Conclusions. These data indicate a new role for SDF-1 in renal pathogenesis by mediating tubular epithelial protection against ischaemic injury and suggest that SDF-1 by itself is not crucial for the influx of haematopoietic stem or progenitor cells towards the ischaemic injured kidney.

  12. Effect of remote ischemic preconditioning on postoperative acute kidney injury among patients undergoing cardiac and vascular interventions: a meta-analysis.

    PubMed

    Li, Bingjue; Lang, Xiabing; Cao, Luxi; Wang, Yuchen; Lu, Yingying; Feng, Shi; Yang, Yi; Chen, Jianghua; Jiang, Hong

    2017-02-01

    It is currently controversial whether remote ischemic preconditioning (RIPC) reduces the incidence of acute kidney injury (AKI) in patients undergoing cardiovascular interventions. The main objective of this meta-analysis was to investigate whether RIPC provides renal protection for patients undergoing cardiac or vascular surgery. We searched the PubMed database (1966-Oct 2015), Embase database (1966-Oct 2015), Google Scholar, Cochrane Library, ClinicalTrials Database and Open Grey. Then we conducted a meta-analysis of the randomized controlled trials that met the inclusion criteria of our study. The interventions included use of an inflatable tourniquet around the limbs or cross-clamping of the iliac arteries before surgery (RIPC groups) and general cardiovascular intervention (control groups). The main outcomes examined included the incidence of AKI; changes in acute kidney injury biomarkers; and use of renal replacement therapy. Other outcomes examined included in-hospital mortality and the lengths of hospital stay and intensive care unit (ICU) stay. Finally, we screened 26 eligible studies containing 6699 patients who underwent cardiac or vascular interventions with RIPC (n = 3343) or without RIPC (n = 3356). The AKI incidence was decreased in the RIPC group as was the length of ICU stay. There were no differences in the changes in AKI biomarkers, use of renal replacement therapy or in-hospital mortality between the two groups. Remote ischemic preconditioning may decrease the occurrence of AKI in cardiovascular surgery patients. Since studies included have a significant heterogeneity, meta-analyses using a stricter inclusion criteria are needed to clarify the renoprotection effect of RIPC.

  13. Remote ischemic conditioning enhanced the early recovery of renal function in recipients after kidney transplantation: a randomized controlled trial.

    PubMed

    Wu, Jianyong; Feng, Xiaoxiao; Huang, Hongfeng; Shou, Zhangfei; Zhang, Xiaohui; Wang, Rending; Chen, Yanyan; Chen, Jianghua

    2014-05-01

    To investigate whether remote ischemic conditioning (RIC) can attenuate ischemic reperfusion injury (IRI) in recipients after kidney transplantation using donation after cardiac death. Forty-eight recipients referred for kidney transplantation were recruited. The paired recipients who received the kidneys from the same donor were randomly assigned (one received RIC and the other did not). RIC was induced by three 5-min cycles of brief repetitive ischemia and reperfusion by clamping the exposed external iliac artery. Blood samples were withdrawn at hour 2, hour 12, days 1-7, day 14, and day 30 to measure serum creatinine level and estimated glomerular filtration rate after transplantation. Urine samples were collected at hours 2, 12, 24, and 48 to measure urine neutrophil gelatinase-associated lipocalin after transplantation. Renal tissues were obtained at 30 min for histologic changes after transplantation. There were no significant differences in clinical characteristics of the recipients and donors between RIC and control groups. The serum creatinine level was lower in the RIC group compared with that of the control group (12 h, days 1-14, P < 0.05; other P > 0.05); the estimated glomerular filtration rate was higher in the RIC group compared with that of the control group (12 h, days 1-14, P < 0.05; other P > 0.05); urine neutrophil gelatinase-associated lipocalin, an early marker of IRI, was lower in the RIC group at hours 2, 12, 24, and 48 (2 h, 48 h, P > 0.05; 12 h, 24 h, P < 0.05) compared with that of the control group. The graft pathology showed no differences between RIC and control groups. RIC enhanced the early recovery of renal function in recipients after kidney transplantation. Our results provide a novel potential approach to attenuate transplantation-associated IRI. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Vascular endothelial growth factor is neuroprotective against ischemic brain injury by inhibiting scavenger receptor A expression on microglia.

    PubMed

    Xu, Zheng; Han, Kaiwei; Chen, Jigang; Wang, Chunhui; Dong, Yan; Yu, Mingkun; Bai, Rulin; Huang, Chenguang; Hou, Lijun

    2017-09-01

    Vascular endothelial growth factor (VEGF) is a secreted mitogen associated with angiogenesis. VEGF has long been thought to be a potent neurotrophic factor for the survival of spinal cord neurons. However, the role of VEGF in the regulation of ischemic brain injury remains unclear. In this study, rats were subjected to MCAO (middle cerebral artery occlusion) followed by intraperitoneal injection of VEGF165 (10 mg/kg) immediately after surgery and once daily until the day 10. The expression of target genes was assayed using qPCR, western blot and immunofluorescence to investigate the role of VEGF165 in regulating ischemic brain injury. We found that VEGF165 significantly inhibited MCAO-induced up-regulation of Scavenger receptor class A (SR-A) on microglia in a VEGFR1-dependent manner. VEGF165 inhibited lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines IL-1β, tumor necrosis factor alpha (TNF-α) and iNOS in microglia. More importantly, the role of VEGF165 in inhibiting neuroinflammation is partially abolished by SR-A over-expression. SR-A further reduced the protective effect of VEGF165 in ischemic brain injury. These data suggest that VEGF165 suppresses neuroinflammation and ischemic brain injury by inhibiting SR-A expression, thus offering a new target for prevention of ischemic brain injury. © 2017 International Society for Neurochemistry.

  15. Mining the human urine proteome for monitoring renal transplant injury

    SciTech Connect

    Sigdel, Tara K.; Gao, Yuqian; He, Jintang; Wang, Anyou; Nicora, Carrie D.; Fillmore, Thomas L.; Shi, Tujin; Webb-Robertson, Bobbie-Jo; Smith, Richard D.; Qian, Wei-Jun; Salvatierra, Oscar; Camp, David G.; Sarwal, Minnie M.

    2016-06-01

    The human urinary proteome reflects systemic and inherent renal injury perturbations and can be analyzed to harness specific biomarkers for different kidney transplant injury states. 396 unique urine samples were collected contemporaneously with an allograft biopsy from 396 unique kidney transplant recipients. Centralized, blinded histology on the graft was used to classify matched urine samples into categories of acute rejection (AR), chronic allograft nephropathy (CAN), BK virus nephritis (BKVN), and stable graft (STA). Liquid chromatography–mass spectrometry (LC-MS) based proteomics using iTRAQ based discovery (n=108) and global label-free LC-MS analyses of individual samples (n=137) for quantitative proteome assessment were used in the discovery step. Selected reaction monitoring (SRM) was applied to identify and validate minimal urine protein/peptide biomarkers to accurately segregate organ injury causation and pathology on unique urine samples (n=151). A total of 958 proteins were initially quantified by iTRAQ, 87% of which were also identified among 1574 urine proteins detected in LC-MS validation. 103 urine proteins were significantly (p<0.05) perturbed in injury and enriched for humoral immunity, complement activation, and lymphocyte trafficking. A set of 131 peptides corresponding to 78 proteins were assessed by SRM for their significance in an independent sample cohort. A minimal set of 35 peptides mapping to 33 proteins, were modeled to segregate different injury groups (AUC =93% for AR, 99% for CAN, 83% for BKVN). Urinary proteome discovery and targeted validation identified urine protein fingerprints for non-invasive differentiation of kidney transplant injuries, thus opening the door for personalized immune risk assessment and therapy.

  16. ST2/IL-33-Dependent Microglial Response Limits Acute Ischemic Brain Injury.

    PubMed

    Yang, Yuanyuan; Liu, Huan; Zhang, Haiyue; Ye, Qing; Wang, Jianyi; Yang, Boyu; Mao, Leilei; Zhu, Wen; Leak, Rehana K; Xiao, Bo; Lu, Binfeng; Chen, Jun; Hu, Xiaoming

    2017-04-07

    ST2, a member of the interleukin 1 receptor family, and its ligand interleukin 33 (IL-33) play critical roles in immune regulation and inflammatory responses. This study explores the roles of endogenous IL-33/ST2 signaling in ischemic brain injury and elucidates the underlying mechanisms of action. The expression of IL-33 rapidly increased in oligodendrocytes and astrocytes after 60 min transient middle cerebral artery occlusion (tMCAO). ST2 receptor deficiency exacerbated brain infarction 3d after tMCAO as well as distal permanent MCAO. ST2 deficiency also aggravated neurological deficits up to 7d after tMCAO. Conversely, intracerebroventricular infusions of IL-33 after tMCAO attenuated brain infarction. Flow cytometry analyses demonstrated high levels of ST2 expression on microglia, and this expression was dramatically enhanced after tMCAO. The absence of ST2 enhanced the expression of M1 polarization markers on microglia/macrophages, and impaired the expression of M2 polarization markers after tMCAO. In vitro studies on various types of cultures and co-culture systems confirmed that IL-33/ST2 signaling potentiated expression of IL-10 and other M2 genes in primary microglia. The activation of ST2 on microglia led to a protective phenotype that enhanced neuronal survival against oxygen glucose deprivation (OGD). Further in vitro studies revealed that IL-33-activated microglia released IL-10, and that this was critical for their neuroprotective effects. Similarly, intracerebroventricular infusions of IL-33 into IL-10 knockout mice failed to provide neuroprotection against tMCAO in vivo These results shed new light on the IL-33/ST2 axis as an immune regulatory mechanism that serves as a natural brake on the progression of ischemic brain injury.Significance:This is the first study to identify the function of IL-33/ST2 signaling in post-stroke microglial responses and neuroprotection against ischemia. Using two models of ischemic stroke, we demonstrate here that ST2

  17. Acute kidney injury: Renal disease in the ICU.

    PubMed

    Seller-Pérez, G; Más-Font, S; Pérez-Calvo, C; Villa-Díaz, P; Celaya-López, M; Herrera-Gutiérrez, M E

    2016-01-01

    Acute kidney injury (AKI) in the ICU frequently requires costly supportive therapies, has high morbidity, and its long-term prognosis is not as good as it has been presumed so far. Consequently, AKI generates a significant burden for the healthcare system. The problem is that AKI lacks an effective treatment and the best approach relies on early secondary prevention. Therefore, to facilitate early diagnosis, a broader definition of AKI should be established, and a marker with more sensitivity and early-detection capacity than serum creatinine - the most common marker of AKI - should be identified. Fortunately, new classification systems (RIFLE, AKIN or KDIGO) have been developed to solve these problems, and the discovery of new biomarkers for kidney injury will hopefully change the way we approach renal patients. As a first step, the concept of renal failure has changed from being a "static" disease to being a "dynamic process" that requires continuous evaluation of kidney function adapted to the reality of the ICU patient.

  18. Acute Neuronal Injury and Blood Genomic Profiles in a Nonhuman Primate Model for Ischemic Stroke

    PubMed Central

    Rodriguez-Mercado, Rafael; Ford, Gregory D; Xu, Zhenfeng; Kraiselburd, Edmundo N; Martinez, Melween I; Eterović, Vesna A; Colon, Edgar; Rodriguez, Idia V; Portilla, Peter; Ferchmin, Pedro A; Gierbolini, Lynette; Rodriguez-Carrasquillo, Maria; Powell, Michael D; Pulliam, John VK; McCraw, Casey O; Gates, Alicia; Ford, Byron D

    2012-01-01

    The goal of this study was to characterize acute neuronal injury in a novel nonhuman primate (NHP) ischemic stroke model by using multiple outcome measures. Silk sutures were inserted into the M1 segment of the middle cerebral artery of rhesus macaques to achieve permanent occlusion of the vessel. The sutures were introduced via the femoral artery by using endovascular microcatheterization techniques. Within hours after middle cerebral artery occlusion (MCAO), infarction was detectable by using diffusion-weighted MRI imaging. The infarcts expanded by 24 h after MCAO and then were detectable on T2-weighted images. The infarcts seen by MRI were consistent with neuronal injury demonstrated histologically. Neurobehavioral function after MCAO was determined by using 2 neurologic testing scales. Neurologic assessments indicated that impairment after ischemia was limited to motor function in the contralateral arm; other neurologic and behavioral parameters were largely unaffected. We also used microarrays to examine gene expression profiles in peripheral blood mononuclear cells after MCAO-induced ischemia. Several genes were altered in a time-dependent manner after MCAO, suggesting that this ischemia model may be suitable for identifying blood biomarkers associated with the presence and severity of ischemia. This NHP stroke model likely will facilitate the elucidation of mechanisms associated with acute neuronal injury after ischemia. In addition, the ability to identify candidate blood biomarkers in NHP after ischemia may prompt the development of new strategies for the diagnosis and treatment of ischemic stroke in humans. PMID:23114047

  19. Apelin-13 protects neurovascular unit against ischemic injuries through the effects of vascular endothelial growth factor.

    PubMed

    Huang, Chuyi; Dai, Chuanfu; Gong, Kai; Zuo, Huancong; Chu, Heling

    2016-12-01

    Apelin-13 has protective effects on many neurological diseases, including cerebral ischemia. Here, we aimed to test Apelin-13's effects on ischemic neurovascular unit (NVU) injuries and investigate whether the effects were dependent on vascular endothelial growth factor (VEGF). We detected the expression of VEGF and its receptors (VEGFRs) induced by Apelin-13 injection at 1d, 3d, 7d and 14d after middle cerebral artery occlusion (MCAO). Meanwhile, we examined the effects of Apelin-13 on NVU in both in vivo and in vitro experiments as well as whether the effects were VEGF dependent by using VEGF antibody. We also assessed the related signal transduction pathways via multiple inhibitors. We demonstrated Apelin-13 highly increased VEGF and VEGFR-2 expression, not VEGFR-1. Importantly, Apelin-13 led to neurological functions improvement by associating with promotion of angiogenesis as well as reduction of neuronal death and astrocyte activation, which was markedly blocked by VEGF antibody. In cell cultures, Apelin-13 protected neurons, astrocytes and endothelial cells against oxygen-glucose deprivation (OGD) injuries. Moreover, the effect of Apelin-13 to up-regulate VEGF was suppressed by extracellular signal-regulated kinase (ERK) inhibitor U0126 and phosphatidylinositol 3'-kinase (PI3K) inhibitor LY294002. Our data suggest protective effects of Apelin-13 on ischemic NVU injuries are highly associated with the increase of VEGF binding to VEGFR-2, possibly acting through activation of ERK and PI3K/Akt pathways. Copyright © 2016. Published by Elsevier Ltd.

  20. HIF-1α inhibition ameliorates neonatal brain injury in a rat pup hypoxic-ischemic model

    PubMed Central

    Chen, Wanqiu; Jadhav, Vikram; Tang, Jiping; Zhang, John H.

    2008-01-01

    Hypoxia-inducible factor-1alpha (HIF-1α) has been considered as a regulator of both prosurvival and prodeath pathways in the nervous system. The present study was designed to elucidate the role of HIF-1α in neonatal hypoxic-ischemic (HI) brain injury. Rice-Vannucci model of neonatal hypoxic-ischemic brain injury was used in seven-day-old rats, by subjecting unilateral carotid artery ligation followed by 2h of hypoxia (8% O2 at 37°C). HIF-1α activity was inhibited by 2-methoxyestradiol (2ME2) and enhanced by dimethyloxalylglycine (DMOG). Results showed that 2ME2 exhibited dose-dependent neuroprotection by decreasing infarct volume and reducing brain edema at 48 h post HI. The neuroprotection was lost when 2ME2 was administered 3 h post HI. HIF-1α upregulation by DMOG increased the permeability of the BBB and brain edema compared with HI group. 2ME2 attenuated the increase in HIF-1α and VEGF 24 h after HI. 2ME2 also had a long-term effect of protecting against the loss of brain tissue. The study showed that the early inhibition of HIF-1α acutely after injury provided neuroprotection after neonatal hypoxia-ischemia which was associated with preservation of BBB integrity, attenuation of brain edema, and neuronal death. PMID:18602008

  1. The synthetic pentasaccharide fondaparinux prevents coronary microvascular injury and myocardial dysfunction in the ischemic heart.

    PubMed

    Montaigne, David; Marechal, Xavier; Lancel, Steve; Decoster, Brigitte; Asseman, Philippe; Neviere, Remi

    2008-11-01

    Fondaparinux is a synthetic pentasaccharide with powerful anticoagulant properties, which may also reduce ischemia-reperfusion (I/R) injury in vivo. However, the relative contributions of the anticoagulant and anti-inflammatory activities of fondaparinux to the observed protection are unknown. To address this issue, a crystalloid-perfused heart model was used to assess potential effects of fondaparinux on IR-induced heart injury in the absence of blood. Fondaparinux protects the ischemic myocardium independently of its haemostasis effects. Fondaparinux improved post ischemic myocardial contractile performance and tissue damage. These beneficial effects of fondaparinux may be related to the observed reduction in IR-induced oxidative stress and endothelial activation. In addition, fondaparinux altered NADPH oxidase activity and phosphorylated extracellular signal-regulated kinase (ERK) 1/2, suggesting activation of survival signaling pathways. The present study provides novel information by demonstrating that fondaparinux can attenuate inflammatory responses and oxidative stress in connection with IR heart injury. These findings could represent a potential therapeutic strategy for the prevention of myocardial dysfunction.

  2. Effect of pre- and posttreatment of losartan in feline model of myocardial ischemic-reperfusion injury.

    PubMed

    Kumari, R; Manchanda, S C; Maulik, S K

    2004-01-01

    This study investigated the differential effect of losartan, an AT1 receptor blocker, when administered in pre- and postischemic phases, on the biochemical, hemodynamic and oxidative stress associated with regional ischemic-reperfusion injury in cat. Losartan (5 microg/kg/min) or normal saline was administered intravenously in open chest barbiturate anesthetized cats, 15 min before and 10 min after the occlusion of the left anterior descending (LAD) coronary artery. The LAD was occluded for 15 min followed by 60 min reperfusion. In the saline treated group, there was significant depression of hemodynamic functions, i.e., mean arterial pressure (MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP) and left ventricular (LV) peak (+/-) dP/dt, along with depletion of adenosine triphosphate (ATP) of the affected myocardium. Oxidative stress during reperfusion injury was evidenced by significant increase in plasma thiobarbituric acid reactive substances (TBARS) accompanied by significant reduction in myocardial superoxide dismutase (SOD) activities. In both treatment groups, losartan caused recovery of all the hemodynamic parameters and repletion of ATP along with no significant change in plasma TBARS and myocardial SOD activity. There was no effect on catalase activity. Results from the study suggest that the effects of pre- and posttreatment of losartan are comparable in functional recovery of the heart from ischemic-reperfusion injury. (c) 2004 Prous Science. All rights reserved.

  3. 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

  4. A new idea about reducing reperfusion injury in ischemic stroke: Gradual reperfusion.

    PubMed

    Shi, Jingfei; Liu, Yi; Duan, Yunxia; Sun, Zhishan; Wang, Bincheng; Meng, Ran; Ji, Xunming

    2013-02-01

    Around the world, stroke is the second most common cause of death and a major cause of disability. The main direct cause of stroke is the occlusion of intracranial artery, which leads to cell death in the core suffered region, or cell functional impairment surrounding the dead core (termed ischemic penumbra). Opening the occluded artery to save the ischemic penumbra is the aim of thrombolysis therapy. But the reperfusion induced injury counteracts the potential profit by thrombolysis. Herein, we assume that gradual reperfusion can reduce the reperfusion injury by reducing the production of free radicals during reperfusion. The reason is: free radicals are critical in the reperfusion injury; free radicals come from the penumbra during reperfusion; the respiratory chain is the main source of free radical; the enzyme activity of the respiratory chain is upgraded during ischemia; once reperfused, the activity upgraded enzymes in the respiratory chain meet normal amount of oxygen and glucose, which produces exceeding intermediates (free radicals); while gradual reperfusion reduces the production of free radicals, because it can confine the amount of oxygen and glucose.

  5. Hypoxic ischemic brain injury following in hospital cardiac arrest - lessons from autopsy.

    PubMed

    Hinduja, Archana; Gupta, Harsh; Yang, Ju Dong; Onteddu, Sanjeeva

    2014-03-01

    Hypoxic ischemic brain injury (HIBI) is the most decisive factor in determining the outcome following a cardiac arrest. After an arrest, neuronal death may be early or delayed. The aim of our study is to determine the prevalence and predictors of HIBI on autopsy following an in hospital cardiac arrest. We retrospectively reviewed the medical records of patients who sustained an in hospital cardiorespiratory arrest and underwent autopsy following in hospital mortality at our tertiary care medical center from January 2004-June 2012. These patients were identified from the autopsy registry maintained by the Department of Pathology and were classified into two groups based on the presence or absence of HIBI on autopsy. We compared the baseline demographics, risk factors, total duration of cardiopulmonary resuscitation, number of resuscitative events and survival time between both groups. Multivariate logistic regression analysis was performed to identify predictors of hypoxic ischemic injury following cardiac arrest. Out of 71 patients identified during this study period, 21% had evidence of HIBI on autopsy. On univariate analysis, predictors of HIBI were prolonged hospital stay, prolonged survival time following an arrest and a slight increased trend following multiple resuscitative events. On multivariate analysis, prolonged survival time was the only significant predictor of HIBI. Similar to other prognostication cardiac arrest studies, there were minimal predictors of early neuronal injury even on autopsy. Published by Elsevier Ltd.

  6. Multiphoton imaging for assessing renal disposition in acute kidney injury

    NASA Astrophysics Data System (ADS)

    Liu, Xin; Liang, Xiaowen; Wang, Haolu; Roberts, Darren M.; Roberts, Michael S.

    2016-11-01

    Estimation of renal function and drug renal disposition in acute kidney injury (AKI), is important for appropriate dosing of drugs and adjustment of therapeutic strategies, but is challenging due to fluctuations in kidney function. Multiphoton microscopy has been shown to be a useful tool in studying drug disposition in liver and can reflect dynamic changes of liver function. We extend this imaging technique to investigate glomerular filtration rate (GFR) and tubular transporter functional change in various animal models of AKI, which mimic a broad range of causes of AKI such as hypoxia (renal ischemia- reperfusion), therapeutic drugs (e.g. cisplatin), rhabdomyolysis (e.g. glycerol-induced) and sepsis (e.g. LPSinduced). The MPM images revealed acute injury of tubular cells as indicated by reduced autofluorescence and cellular vacuolation in AKI groups compared to control group. In control animal, systemically injected FITC-labelled inulin was rapidly cleared from glomerulus, while the clearance of FITC-inulin was significantly delayed in most of animals in AKI group, which may reflect the reduced GFR in AKI. Following intravenous injection, rhodamine 123, a fluorescent substrate of p-glycoprotein (one of tubular transporter), was excreted into urine in proximal tubule via p-glycoprotein; in response to AKI, rhodamine 123 was retained in tubular cells as revealed by slower decay of fluorescence intensity, indicating P-gp transporter dysfunction in AKI. Thus, real-time changes in GFR and transporter function can be imaged in rodent kidney with AKI using multiphoton excitation of exogenously injected fluorescent markers.

  7. Foxp3-transduced polyclonal regulatory T cells protect against chronic renal injury from adriamycin.

    PubMed

    Wang, Yuan Min; Zhang, Geoff Yu; Wang, Yiping; Hu, Min; Wu, Huiling; Watson, Debbie; Hori, Shohei; Alexander, Ian E; Harris, David C H; Alexander, Stephen I

    2006-03-01

    Chronic proteinuric renal injury is a major cause of ESRD. Adriamycin nephropathy is a murine model of chronic proteinuric renal disease whereby chemical injury is followed by immune and structural changes that mimic human disease. Foxp3 is a gene that induces a regulatory T cell (Treg) phenotype. It was hypothesized that Foxp3-transduced Treg could protect against renal injury in Adriamycin nephropathy. CD4+ T cells were transduced with either a Foxp3-containing retrovirus or a control retrovirus. Foxp3-transduced T cells had a regulatory phenotype by functional and phenotypic assays. Adoptive transfer of Foxp3-transduced T cells protected against renal injury. Urinary protein excretion and serum creatinine were reduced (P<0.05), and there was significantly less glomerulosclerosis, tubular damage, and interstitial infiltrates (P<0.01). It is concluded that Foxp3-transduced Treg cells may have a therapeutic role in protecting against immune injury and disease progression in chronic proteinuric renal disease.

  8. The alternative complement pathway propagates inflammation and injury in murine ischemic stroke

    PubMed Central

    Elvington, Andrew; Atkinson, Carl; Zhu, Hong; Yu, Jin; Takahashi, Kazue; Stahl, Gregory L.; Kindy, Mark S; Tomlinson, Stephen

    2012-01-01

    There is mounting evidence indicating an important role for complement in the pathogenesis of cerebral ischemia reperfusion injury, or ischemic stroke. The role of the alternative complement pathway in ischemic stroke has not been investigated, and there is conflicting data on the role of the terminal pathway. Here we show that compared to wild type mice, mice deficient in the alternative pathway protein factor B, or mice treated with the alternative pathway inhibitor CR2-fH, have improved outcomes after 60 minutes middle cerebral artery occlusion (MCAO) and 24 hours reperfusion. Factor B-deficient or CR2-fH treated mice were protected in terms of improved neurological function and reduced cerebral infarct, demyelination, P-selectin expression, neutrophil infiltration and microthrombi formation. Mice deficient in both the classical and lectin pathways (C1q/MBL deficient) were also protected from cerebral IRI, and there was no detectable C3d deposition in the ipsilateral brain of these mice. These data demonstrate that alternative pathway is not alone sufficient to initiate complement activation, and indicate the alternative pathway propagates cerebral injury via amplification of the cascade. Deficiency of C6, a component of the terminal cytolytic membrane attack complex (MAC), had no effect on outcome after ischemic stroke, indicating the MAC is not involved in mediating injury in this model. We additionally show that the protective effect of fB deficiency and CR2-fH treatment is sustained in the sub-acute stage of infarct development, adding to the clinical relevance of these findings. PMID:23028050

  9. 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.

  10. Acute ischemia/reperfusion injury after isogeneic kidney transplantation is mitigated in a rat model of chronic renal failure.

    PubMed

    Vercauteren, Sven R; Ysebaert, Dirk K; Van Rompay, An R; De Greef, Kathleen E; De Broe, Marc E

    2003-05-01

    The influence of chronic renal failure on renal susceptibility to an acute ischemic insult was evaluated. Recipient Lewis rats were randomly assigned to undergo 5/6 nephrectomy (chronic renal failure, CRF) or sham operation (normal renal function, NRF). After 11 weeks, normal kidneys of Lewis donor rats were transplanted in the recipients. The outcome of the isografts was assessed. Filtration capacity of the isografts in the CRF rats was preserved to approximately one-quarter of its normal capacity on the 1st day post-transplantation, whereas it fell to 0 in the NRF rats. This was reflected by a significantly higher increase in serum creatinine in the latter group. The isografts in the CRF rats had a significantly lower degree of acute tubular necrosis and no increase in the number of macrophages and T lymphocytes in the first 24 h in contrast to the NRF rats. Epithelial regeneration and repair started earlier in the CRF group. In conclusion, the present study indicated that CRF blunted ischemia/reperfusion injury of a transplanted kidney, and that its regeneration capacity was certainly not hampered by the presence of chronic uremia. These results will be the basis for studies on modulation of early leukocyte-endothelial interactions resulting from immunological disturbances inherent to the uremic environment.

  11. High-grade renal injuries are often isolated in sports-related trauma.

    PubMed

    Patel, Darshan P; Redshaw, Jeffrey D; Breyer, Benjamin N; Smith, Thomas G; Erickson, Bradley A; Majercik, Sarah D; Gaither, Thomas W; Craig, James R; Gardner, Scott; Presson, Angela P; Zhang, Chong; Hotaling, James M; Brant, William O; Myers, Jeremy B

    2015-07-01

    Most high-grade renal injuries (American Association for Surgery of Trauma (AAST) grades III-V) result from motor vehicle collisions associated with numerous concomitant injuries. Sports-related blunt renal injury tends to have a different mechanism, a solitary blow to the flank. We hypothesized that high-grade renal injury is often isolated in sports-related renal trauma. We identified patients with AAST grades III-V blunt renal injuries from four level 1 trauma centres across the United States between 1/2005 and 1/2014. Patients were divided into "Sport" or "Non-sport" related groups. Outcomes included rates of hypotension (systolic blood pressure <90mm Hg), tachycardia (>110bpm), concomitant abdominal injury, and procedural/surgical intervention between sports and non-sports related injury. 320 patients met study criteria. 18% (59) were sports-related injuries with the most common mechanisms being skiing, snowboarding and contact sports (25%, 25%, and 24%, respectively). Median age was 24 years for sports and 30 years for non-sports related renal injuries (p=0.049). Males were more commonly involved in sports related injuries (85% vs. 72%, p=0.011). Median injury severity score was lower for sports related injuries (10 vs. 27, p<0.001). There was no difference in renal abbreviated injury scale scores. Sports related trauma was more likely to be isolated without other significant injury (69% vs. 39% (p<0.001)). Haemodynamic instability was present in 40% and 51% of sports and non-sports renal injuries (p=0.30). Sports injuries had lower transfusion (7% vs. 47%, p<0.001) and lower mortality rates (0% vs. 6%, p=0.004). There was no difference in renal-specific procedural interventions between the two groups (17% sports vs. 18% non-sports, p=0.95). High-grade sports-related blunt renal trauma is more likely to occur in isolation without other abdominal or thoracic injuries and clinicians must have a high suspicion of renal injury with significant blows to the flank

  12. High-grade renal injuries are often isolated in sports-related trauma

    PubMed Central

    Patel, Darshan P.; Redshaw, Jeffrey D.; Breyer, Benjamin N.; Smith, Thomas G.; Erickson, Bradley A.; Majercik, Sarah D.; Gaither, Thomas W.; Craig, James R.; Gardner, Scott; Presson, Angela P.; Zhang, Chong; Hotaling, James M.; Brant, William O.; Myers, Jeremy B.

    2016-01-01

    Introduction Most high-grade renal injuries (American Association for Surgery of Trauma (AAST) grades III–V) result from motor vehicle collisions associated with numerous concomitant injuries. Sports-related blunt renal injury tends to have a different mechanism, a solitary blow to the flank. We hypothesized that high-grade renal injury is often isolated in sports-related renal trauma. Material and methods We identified patients with AAST grades III–V blunt renal injuries from four level 1 trauma centres across the United States between 1/2005 and 1/2014. Patients were divided into “Sport” or “Non-sport” related groups. Outcomes included rates of hypotension (systolic blood pressure <90 mm Hg), tachycardia (>110 bpm), concomitant abdominal injury, and procedural/surgical intervention between sports and non-sports related injury. Results 320 patients met study criteria. 18% (59) were sports-related injuries with the most common mechanisms being skiing, snowboarding and contact sports (25%, 25%, and 24%, respectively). Median age was 24 years for sports and 30 years for non-sports related renal injuries (p = 0.049). Males were more commonly involved in sports related injuries (85% vs. 72%, p = 0.011). Median injury severity score was lower for sports related injuries (10 vs. 27, p < 0.001). There was no difference in renal abbreviated injury scale scores. Sports related trauma was more likely to be isolated without other significant injury (69% vs. 39% (p < 0.001)). Haemodynamic instability was present in 40% and 51% of sports and non-sports renal injuries (p = 0.30). Sports injuries had lower transfusion (7% vs. 47%, p < 0.001) and lower mortality rates (0% vs. 6%, p = 0.004). There was no difference in renal-specific procedural interventions between the two groups (17% sports vs. 18% non-sports, p = 0.95). Conclusions High-grade sports-related blunt renal trauma is more likely to occur in isolation without other abdominal or thoracic injuries and

  13. Interleukin-17A Regulates Renal Sodium Transporters and Renal Injury in Angiotensin II-Induced Hypertension.

    PubMed

    Norlander, Allison E; Saleh, Mohamed A; Kamat, Nikhil V; Ko, Benjamin; Gnecco, Juan; Zhu, Linjue; Dale, Bethany L; Iwakura, Yoichiro; Hoover, Robert S; McDonough, Alicia A; Madhur, Meena S

    2016-07-01

    Angiotensin II-induced hypertension is associated with an increase in T-cell production of interleukin-17A (IL-17A). Recently, we reported that IL-17A(-/-) mice exhibit blunted hypertension, preserved natriuresis in response to a saline challenge, and decreased renal sodium hydrogen exchanger 3 expression after 2 weeks of angiotensin II infusion compared with wild-type mice. In the current study, we performed renal transporter profiling in mice deficient in IL-17A or the related isoform, IL-17F, after 4 weeks of Ang II infusion, the time when the blood pressure reduction in IL-17A(-/-) mice is most prominent. Deficiency of IL-17A abolished the activation of distal tubule transporters, specifically the sodium-chloride cotransporter and the epithelial sodium channel and protected mice from glomerular and tubular injury. In human proximal tubule (HK-2) cells, IL-17A increased sodium hydrogen exchanger 3 expression through a serum and glucocorticoid-regulated kinase 1-dependent pathway. In mouse distal convoluted tubule cells, IL-17A increased sodium-chloride cotransporter activity in a serum and glucocorticoid-regulated kinase 1/Nedd4-2-dependent pathway. In both cell types, acute treatment with IL-17A induced phosphorylation of serum and glucocorticoid-regulated kinase 1 at serine 78, and treatment with a serum and glucocorticoid-regulated kinase 1 inhibitor blocked the effects of IL-17A on sodium hydrogen exchanger 3 and sodium-chloride cotransporter. Interestingly, both HK-2 and mouse distal convoluted tubule 15 cells produce endogenous IL-17A. IL17F had little or no effect on blood pressure or renal sodium transporter abundance. These studies provide a mechanistic link by which IL-17A modulates renal sodium transport and suggest that IL-17A inhibition may improve renal function in hypertension and other autoimmune disorders. © 2016 American Heart Association, Inc.

  14. Remote ischemic preconditioning for prevention of acute kidney injury: a meta-analysis of randomized controlled trials.

    PubMed

    Yang, Yi; Lang, Xia-Bing; Zhang, Ping; Lv, Rong; Wang, Yong-Fei; Chen, Jiang-Hua

    2014-10-01

    Remote ischemic preconditioning (RIPC) to prevent acute kidney injury (AKI) following cardiac and vascular interventions is a controversial practice. We conducted a systematic review and meta-analysis using the MEDLINE database (1966 through November 2013), EMBASE (1988 through November 2013), and Cochrane Library database. Patients undergoing cardiac and vascular interventions. Randomized controlled trials comparing patient outcome with or without RIPC for prevention of AKI following cardiac and vascular interventions. RIPC using an inflatable tourniquet around the limb or cross-clamping the iliac arteries versus non-RIPC. AKI, need for renal replacement therapy, postoperative kidney biomarkers, in-hospital mortality, and length of intensive care unit and hospital stay. 13 trials (1,334 participants) were included. RIPC decreased the risk of AKI for patients undergoing cardiac and vascular interventions compared with the control group (11 trials; 1,216 participants; risk ratio [RR], 0.70; 95% CI, 0.48-1.02; P = 0.06; I(2) = 45%) with marginal statistical significance. There were no differences in levels of postoperative kidney biomarkers (serum creatinine and glomerular filtration rate), incidence of renal replacement therapy, in-hospital mortality, hospital stay, or intensive care unit stay between the 2 groups. Metaregression analysis indicated that contrast intervention was not a covariate contributing significantly to heterogeneity on the risk estimate for AKI incidence; also, there was no dose effect of RIPC using tourniquet cuff around the limb on AKI prevention based on different ischemia duration. Different AKI definitions adopted in the trials included. RIPC might be beneficial for the prevention of AKI following cardiac and vascular interventions, but the current evidence is not robust enough to make a recommendation. Adequately powered trials are needed to provide more evidence in the future. Copyright © 2014 National Kidney Foundation, Inc. Published

  15. 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

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

    PubMed

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

    2015-07-01

    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. 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. 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. 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 reduces hypertrophy, thereby limiting

  17. Effects of activated protein C on neonatal hypoxic ischemic brain injury.

    PubMed

    Yesilirmak, Didem Cemile; Kumral, Abdullah; Tugyan, Kazim; Cilaker, Serap; Baskin, Huseyin; Yilmaz, Osman; Duman, Nuray; Ozkan, Hasan

    2008-05-19

    Perinatal hypoxia-ischemia remains the single most important cause of brain injury in the newborn, leading to death or lifelong sequelae. White matter injuries in newborn infants have long-term effects on physical, visual, motor, sensory, cognitive and social development in human infants. There is no known cure for neonatal hypoxic ischemic encephalopathy (NHIE). Activated protein C has potent anticoagulant activity due to its ability to inactivate factor Va and VIIIa. APC is the first effective biological therapy approved for the treatment of severe sepsis. Although APC is well defined as a physiological anticoagulant, emerging data suggest that it also has cytoprotective, anti-inflammatory and antiapoptotic properties. APC has been shown to provide neuroprotection in ischemic brain and spinal cord injury. Here, we propose that APC, which modulates many of these processes, may represent a promising therapeutic agent for NHIE. Seven days old Wistar Albino rat pups have been used in the study (n=42). Experimental groups in the study were: sham-operated group, APC treated group, and vehicle treated group. In hypoxia-ischemia groups, the left common carotid artery was ligated permanently on the seventh postnatal day. Two hours after the procedure, hypoxia (92% nitrogen and 8% oxygen) was applied for 2.5 h. APC were injected (intraperitoneally; i.p.) as a single dose immediately after the hypoxia period. Brain nitrite levels, neuronal cell death, and apoptosis were evaluated in both hemispheres 72 h after the hypoxic-ischemic insult. Histopathological evaluation demonstrated that APC significantly diminished the number of "apoptotic cells" in the hippocampal CA1, CA2, CA3 and gyrus dentatus regions in both hemispheres. APC treatment significantly reduced "apoptotic cell death" in both hemispheres, when compared with vehicle treated group. APC significantly preserved the number of neurons CA1, CA3 regions of the hippocampus, when compared with vehicle treated group. Our

  18. The protective effects of dexmedetomidine on ischemic brain injury: A meta-analysis.

    PubMed

    Jiang, Lianxiang; Hu, Meizhu; Lu, Yan; Cao, Ya; Chang, Yan; Dai, Zeping

    2017-08-01

    Intracranial lesions, trauma or surgery-related damage activate immune inflammation and neuroendocrine responses, causing ischemic brain injury. Studies have shown that inflammatory cascade mediated by neuroendocrine hormones and proinflammatory mediators is implicated in the pathophysiology of ischemic brain injury. Alpha2-adrenoceptor agonists, dexmedetomidine, is widely used as neuroprotectants in anesthesia practice. However, it is still lack of a comprehensive meta-analysis to evaluate the neuroprotection of dexmedetomidine against ischemic brain injury via suppressing these two physiological responses. Searched the Cochrane Library, Pub-Med, EMBASE, EBSCO, Ovid, Chinese biological and medical database (CBM). Related literatures published in English or Chinese before January 2017 were enrolled. We assessed the quality of eligible studies and synthesized predefined outcomes with a random-effects model or fixed-effects model. Nineteen Randomized Controlled Trials including 879 patients were included. Findings for meta-analysis of various outcomes were summarised. Primary results shown that compared with placebo, dexmedetomidine reduced a surge of TNF-α [SMD=-2.34, 95%CI (-3.25, -1.44)], IL-6 [SMD=-2.44, 95%CI (-3.40, -1.47)], S100-β [SMD=-2.73, 95%CI (-3.65, -1.82)], NSE [SMD=-1.69, 95%CI (-2.77, -0.61)], cortisol [SMD=-2.48, 95%CI (-3.38, -1.58)] and glucose [SMD=-1.44, 95%CI (-1.85, -1.04)]; maintained the level of SOD [SMD=1.36, 95%CI (0.62, 2.10)]; decreased the rise in CRP level at postoperative one day. In response to stress reaction, dexmedetomidine attenuated the stress-related increasing of MAP, HR and intracranial pressure without significant effects on cerebral oxygen metabolism. Alpha2-adrenoceptor agonists, dexmedetomidine, could reduce the release of inflammatory mediators and neuroendocrine hormones as well as maintain intracranial homoeostasis, alleviating ischemic brain injury and exerting an effect on brain protection. Copyright © 2017

  19. 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

  20. Biomarkers of hepatic injury and function in neonatal hypoxic ischemic encephalopathy and with therapeutic hypothermia.

    PubMed

    Muniraman, Hemananda; Gardner, Danielle; Skinner, Jane; Paweletz, Anna; Vayalakkad, Anitha; Chee, Ying Hui; Clifford, Clare; Sanka, Sunil; Venkatesh, Vidheya; Curley, Anna; Victor, Suresh; Turner, Mark A; Clarke, Paul

    2017-07-24

    Therapeutic hypothermia (TH) is now provided as standard care to infants with moderate-severe hypoxic ischemic encephalopathy (HIE). The role of TH in limiting neuronal injury is well recognized, but its effect on hepatic injury which occurs frequently in neonatal HIE is not known. Our objective was to characterize biomarkers of liver injury and function in the setting of neonatal HIE and to describe whether HIE severity and provision of TH influence these hepatic biomarkers. We performed a multicenter retrospective study and compared hepatic biomarkers obtained during the first postnatal week, according to the severity of HIE and whether treated with TH. Of a total of 361 infants with HIE, 223 (62%) received TH and 138 (38%) were managed at normal temperature. Most hepatic biomarkers and C-reactive protein (CRP) were significantly associated with the severity of HIE (p < 0.001). Infants treated with TH had lower peak alanine aminotransferase (ALT) concentrations (p = 0.025) and a delay in reaching peak CRP concentration (p < 0.001). We observed a significant association between the clinical grade of HIE and biomarkers of liver metabolism and function. Therapeutic hypothermia was associated with delayed CRP responses and with lower ALT concentrations and so may have the potential to modulate hepatic injury. What is Known: • Ischemic hepatic injury occurs frequently as a part of multiorgan dysfunction in infants with hypoxic ischemic encephalopathy (HIE). • The neuroprotective role of therapeutic hypothermia in management of infants with HIE is well recognized, but the potential hepato-protective effects of hypothermia are unclear. What is New/What this study adds: • Therapeutic hypothermia was associated with lower alanine aminotransferase and albumin concentrations and a delayed C-reactive protein (CRP) response and so may have the potential to modulate hepatic injury. • An elevated CRP concentration during the first postnatal week may be regarded as

  1. Protective effect of artemisia asiatica extract against renal ischemia-reperfusion injury in mice.

    PubMed

    Jang, Hyuk Jai; Jeong, Eui Kyun; Kim, Seong Su; Lee, Ji Hwan; Oh, Mi Young; Kang, Ki Sung; Kwan, Hak Cheol; Song, Kyung Il; Eom, Dae Woon; Han, Duck Jong

    2015-04-01

    An extract of Artemisia asiatica was reported to possess antioxidative and cytoprotective actions in various experiments. Ischemia-reperfusion injury remains a major problem in kidney transplant, and the inflammatory response to ischemia-reperfusion injury exacerbates the resultant renal injury. In the present study, we investigated whether an extract of Artemisia asiatica exhibits renoprotective effects against ischemia-reperfusion-induced acute kidney injury in mice. Renal ischemia-reperfusion injury was induced in male C57BL/6 mice by bilateral renal pedicle occlusion for 30 minutes followed by reperfusion for 48 hours. An extract of Artemisia asiatica (100 mg/kg oral) was administered 4 days before ischemia-reperfusion injury. Sham operation and phosphate-buffered saline were used as controls. Blood and renal tissues were evaluated at 48 hours after ischemiareperfusion injury. Treatment with an extract of Artemisia asiatica significantly decreased blood urea nitrogen, serum creatinine levels, and kidney tubular injury (P ≤ .05). Western blot showed that an extract of Artemisia asiatica significantly increased the level of heme oxygenase-1 and B-cell lymphoma 2 at 48 hours after ischemia-reperfusion injury and attenuated the level of inducible nitric oxide synthase. An extract of Artemisia asiatica improves acute renal ischemia-reperfusion injury by reducing inflammation and apoptosis. These findings suggest that an extract of Artemisia asiatica is a potential therapeutic agent against acute ischemia-induced renal damage.

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

    PubMed

    Kazama, Itsuro

    2016-02-01

    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.

  3. Lung injury pathways: Adenosine receptor 2B signaling limits development of ischemic bronchiolitis obliterans organizing pneumonia.

    PubMed

    Densmore, John C; Schaid, Terry R; Jeziorczak, Paul M; Medhora, Meetha; Audi, Said; Nayak, Shraddha; Auchampach, John; Dwinell, Melinda R; Geurts, Aron M; Jacobs, Elizabeth R

    2017-02-01

    Purpose/Aim of the Study: Adenosine signaling was studied in bronchiolitis obliterans organizing pneumonia (BOOP) resulting from unilateral lung ischemia. Ischemia was achieved by either left main pulmonary artery or complete hilar ligation. Sprague-Dawley (SD) rats, Dahl salt sensitive (SS) rats and SS mutant rat strains containing a mutation in the A2B adenosine receptor gene (Adora2b) were studied. Adenosine concentrations were measured in bronchoalveolar lavage (BAL) by HPLC. A2A (A2AAR) and A2B adenosine receptor (A2BAR) mRNA and protein were quantified. Twenty-four hours after unilateral PA ligation, BAL adenosine concentrations from ischemic lungs were increased relative to contralateral lungs in SD rats. A2BAR mRNA and protein concentrations were increased after PA ligation while miR27a, a negatively regulating microRNA, was decreased in ischemic lungs. A2AAR mRNA and protein concentrations remained unchanged following ischemia. A2BAR protein was increased in PA ligated lungs of SS rats after 7 days, and 4 h after complete hilar ligation in SD rats. SS-Adora2b mutants showed a greater extent of BOOP relative to SS rats, and greater inflammatory changes. Increased A2BAR and adenosine following unilateral lung ischemia as well as more BOOP in A2BAR mutant rats implicate a protective role for A2BAR signaling in countering ischemic lung injury.

  4. Sodium Pyruvate Reduced Hypoxic-Ischemic Injury to Neonatal Rat Brain

    PubMed Central

    Pan, Rui; Rong, Zhihui; She, Yun; Cao, Yuan; Chang, Li-Wen; Lee, Wei-Hua

    2013-01-01

    Background Neonatal hypoxia-ischemia (HI) remains a major cause of severe brain damage and is often associated with high mortality and lifelong disability. Immature brains are extremely sensitive to hypoxia-ischemia, shown as prolonged mitochondrial neuronal death. Sodium pyruvate (SP), a substrate of the tricarboxylic acid cycle and an extracellular antioxidant, has been considered as a potential treatment for hypoxic-ischemic encephalopathy (HIE), but its effects have not been evaluated in appropriate animal models for hypoxic-ischemic encephalopathy (HIE). Methods This investigation employed primary cortical neuron cultures derived from neonatal rats subjected to oxygen and glucose deprivation (OGD) and a well-established neonatal rat hypoxia-ischemia model. Results HI caused brain tissue loss and impaired sensorimotor function and spatial memory while SP significantly reduced brain damage and improved neurological performance. These neuroprotective effects of SP are likely the result of improved cerebral metabolism as demonstrated by maintaining ATP levels and preventing an increase in intracellular reactive oxygen species (ROS) levels. SP treatment also decreased levels of Bax, a death signal for immature neurons, blocked caspases-3 activation, and activated a key survival signaling kinase, Akt, both in vitro and in vivo. Conclusion SP protected neonatal brain from hypoxic-ischemic injury through maintaining cerebral metabolism and mitochondrial function. PMID:22885415

  5. Periostin Promotes Neural Stem Cell Proliferation and Differentiation following Hypoxic-Ischemic Injury.

    PubMed

    Ma, Si-Min; Chen, Long-Xia; Lin, Yi-Feng; Yan, Hu; Lv, Jing-Wen; Xiong, Man; Li, Jin; Cheng, Guo-Qiang; Yang, Yi; Qiu, Zi-Long; Zhou, Wen-Hao

    2015-01-01

    Neural stem cell (NSC) proliferation and differentiation are required to replace neurons damaged or lost after hypoxic-ischemic events and recover brain function. Periostin (POSTN), a novel matricellular protein, plays pivotal roles in the survival, migration, and regeneration of various cell types, but its function in NSCs of neonatal rodent brain is still unknown. The purpose of this study was to investigate the role of POSTN in NSCs following hypoxia-ischemia (HI). We found that POSTN mRNA levels significantly increased in differentiating NSCs. The proliferation and differentiation of NSCs in the hippocampus is compromised in POSTN knockout mice. Moreover, NSC proliferation and differentiation into neurons and astrocytes significantly increased in cultured NSCs treated with recombinant POSTN. Consistently, injection of POSTN into neonatal hypoxic-ischemic rat brains stimulated NSC proliferation and differentiation in the subventricular and subgranular zones after 7 and 14 days of brain injury. Lastly, POSTN treatment significantly improved the spatial learning deficits of rats subjected to HI. These results suggest that POSTN significantly enhances NSC proliferation and differentiation after HI, and provides new insights into therapeutic strategies for the treatment of hypoxic-ischemic encephalopathy.

  6. Electrophysiological studies of upregulated P2X7 receptors in rat superior cervical ganglia after myocardial ischemic injury.

    PubMed

    Kong, Fanjun; Liu, Shuangmei; Xu, Changshui; Liu, Jun; Li, Guodong; Li, Guilin; Gao, Yun; Lin, Hong; Tu, Guihua; Peng, Haiying; Qiu, Shuyi; Fan, Bo; Zhu, Qicheng; Yu, Shicheng; Zheng, Chaoran; Liang, Shangdong

    2013-09-01

    Myocardial ischemic injury activates cardiac sympathetic afferent fibers and elicits a sympathoexcitatory reflex by exciting sympathetic efferent action, with resultant augmentation of myocardial oxygen consumption, leading to a vicious cycle of exaggerating myocardial ischemia. P2X7 receptor participates in the neuronal functions and the neurological disorders. This study examined the role of P2X7 receptor of superior cervical ganglia (SCG) in sympathoexcitatory reflex. Our results showed that the expression of P2X7 receptor at both mRNA and protein in SCG was increased after myocardial ischemic injury. P2X7 receptor agonists at the same concentration activated much larger amplitudes of the currents in the SCG neurons of myocardial ischemic rats than those in control rats. P2X7 receptor antagonist (brilliant blue G, BBG) significantly inhibited P2X7 receptor agonist-activated currents in the SCG neurons. Excessive phosphorylation of MAPK ERK1/2 upon the activation of P2X7 receptor might be a mechanism mediating the signal transduction after myocardial ischemic injury. Therefore, the sensitized P2X7 receptor in SCG was involved in the nociceptive transmission of sympathoexcitatory reflex induced by myocardial ischemic injury.

  7. MicroRNA-15a/16-1 Antagomir Ameliorates Ischemic Brain Injury in Experimental Stroke.

    PubMed

    Yang, Xinxin; Tang, Xuelian; Sun, Ping; Shi, Yejie; Liu, Kai; Hassan, Sulaiman H; Stetler, R Anne; Chen, Jun; Yin, Ke-Jie

    2017-07-01

    Dysregulation of the miR-15a/16-1 cluster in plasma has been reported in patients with stroke as a potential biomarker for diagnostic and prognostic use. However, the essential role and therapeutic potential of the miR-15a/16-1 cluster in ischemic stroke are poorly understood. This study is aimed at investigating the regulatory role of the miR-15a/16-1 cluster in ischemic brain injury and insight mechanisms. Adult male miR-15a/16-1 knockout and wild-type mice, or adult male C57 BL/6J mice injected via tail vein with the miR-15a/16-1-specific inhibitor (antagomir, 30 pmol/g), were subjected to 1 hour of middle cerebral artery occlusion and 72 hours of reperfusion. The neurological scores, brain infarct volume, brain water content, and neurobehavioral tests were then evaluated and analyzed. To explore underlying signaling pathways associated with alteration of miR-15a/16-1 activity, major proinflammatory cytokines were measured by quantitative polymerase chain reaction or ELISA and antiapoptotic proteins were examined by Western blotting. Genetic deletion of the miR-15a/16-1 cluster or intravenous delivery of miR-15a/16-1 antagomir significantly reduced cerebral infarct size, decreased brain water content, and improved neurological outcomes in stroke mice. Inhibition of miR-15a/16-1 significantly decreased the expression of the proinflammatory cytokines interleukin-6, monocyte chemoattractant protein-1, vascular cell adhesion molecule 1, tumor necrosis factor alpha, and increased Bcl-2 and Bcl-w levels in the ischemic brain regions. Our data indicate that pharmacological inhibition of the miR-15a/16-1 cluster reduces ischemic brain injury via both upregulation of antiapoptotic proteins and suppression of proinflammatory molecules. These results suggest that the miR-15a/16-1 cluster is a novel therapeutic target for ischemic stroke. © 2017 American Heart Association, Inc.

  8. Nicotinamide attenuates the decrease of astrocytic phosphoprotein PEA-15 in focal cerebral ischemic injury.

    PubMed

    Koh, Phil-Ok

    2012-03-01

    Nicotinamide exerts neuroprotective effects against focal cerebral ischemic injury. Phosphoprotein enriched in astrocytes 15 (PEA-15) is prominently expressed in astrocytes that exert broad anti-apoptotic functions. This study investigated whether nicotinamide modulates PEA-15 and levels of two phosphorylated PEA-15 (Serine 104 and 116) in an animal model of middle cerebral artery occlusion (MCAO)-induced injury. Adult male rats were treated with vehicle or nicotinamide (500 mg/kg) 2 hr after the onset of MCAO and cerebral cortices were collected at 24 hr after MCAO. In a proteomic approach, MCAO induced decreases of PEA-15 levels, while nicotinamide treatment attenuated the injury-induced decrease in PEA-15. The results of Western blot analysis suggest that nicotinamide prevented injury-induced reduction in phospho-PEA-15 (Serine 104) and phospho-PEA-15 (Serine 116) levels. The phosphorylation of PEA-15 exerts anti-apoptotic functions, and reduction of PEA-15 phosphorylation leads to apoptotic cell death. These results suggest that nicotinamide exerts a neuroprotective effect by attenuating the injury-induced decreases of PEA-15 and phospho-PEA-15 (Ser 104 and Ser 116) proteins.

  9. Hypoxic-ischemic brain injury: imaging findings from birth to adulthood.

    PubMed

    Huang, Benjamin Y; Castillo, Mauricio

    2008-01-01

    Global hypoxic-ischemic injury (HII) to the brain is a significant cause of mortality and severe neurologic disability. Imaging plays an important role in the diagnosis and treatment of HII, helping guide case management in the acute setting and providing valuable information about long-term prognosis. Appropriate radiologic diagnosis of HII requires familiarity with the many imaging manifestations of this injury. Factors such as brain maturity, duration and severity of insult, and type and timing of imaging studies all influence findings in HII. Severe hypoxia-ischemia in both preterm and term neonates preferentially damages the deep gray matter, with perirolandic involvement more frequently observed in the latter age group. Less profound insults result in intraventricular hemorrhages and periventricular white matter injury in preterm neonates and parasagittal watershed territory infarcts in term neonates. In the postnatal period, severe insults result in diffuse gray matter injury, with relative sparing of the perirolandic cortex and the structures supplied by the posterior circulation. Profound hypoxia-ischemia in older children and adults affects the deep gray matter nuclei, cortices, hippocampi, and cerebellum. Because findings at conventional imaging may be subtle or even absent in the acute setting, particularly in neonates, magnetic resonance spectroscopy can help establish the diagnosis of HII. Promising new neuroprotective strategies designed to limit the extent of brain injury caused by hypoxia-ischemia are currently under investigation. (c) RSNA, 2008

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

    USDA-ARS?s Scientific Manuscript database

    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, ...

  11. Failure of remote ischemic preconditioning to reduce the risk of postoperative acute kidney injury in children undergoing operation for complex congenital heart disease: a randomized single-center study.

    PubMed

    Pedersen, Kirsten Rønholt; Ravn, Hanne Berg; Povlsen, Johan Vestergaard; Schmidt, Michael Rahbek; Erlandsen, Erland Jørn; Hjortdal, Vibeke Elisabeth

    2012-03-01

    The objective of this study was to evaluate whether remote ischemic preconditioning can protect kidney function in children undergoing operation for complex congenital heart disease. Children (n = 113) aged 0 to 15 years admitted for complex congenital heart disease were randomly allocated according to age to remote ischemic preconditioning and control groups. After exclusion of 8 patients, we conducted the analysis on 105 patients (remote ischemic preconditioning group, n = 54; control group, n = 51). Before surgery, remote ischemic preconditioning was performed as 4 cycles of 5 minutes of ischemia by inflating a cuff around a leg to 40 mm Hg above the systolic pressure. End points were development of acute kidney injury, initiation of dialysis, plasma creatinine, estimated glomerular filtration rate, plasma cystatin C, plasma and urinary neutrophil gelatinase-associated lipocalin, and urinary output. Secondary end points included postoperative blood pressure, inotropic score, and mortality, as well as morbidity reflected by reoperation and stays in the intensive care unit and hospital. Overall, 57 of the children (54%) had acute kidney injury develop, with 27 (50%) in the remote ischemic preconditioning group and 30 (59%) in the control group (P > .2). Remote ischemic preconditioning was not associated with improvement in either any of the renal biomarkers or any of the secondary end points. We found no evidence that remote ischemic preconditioning provided protection of kidney function in children undergoing operation for complex congenital heart disease. Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

  12. Growth factors for the treatment of ischemic brain injury (growth factor treatment).

    PubMed

    Larpthaveesarp, Amara; Ferriero, Donna M; Gonzalez, Fernando F

    2015-04-30

    In recent years, growth factor therapy has emerged as a potential treatment for ischemic brain injury. The efficacy of therapies that either directly introduce or stimulate local production of growth factors and their receptors in damaged brain tissue has been tested in a multitude of models for different Central Nervous System (CNS) diseases. These growth factors include erythropoietin (EPO), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor (IGF-1), among others. Despite the promise shown in animal models, the particular growth factors that should be used to maximize both brain protection and repair, and the therapeutic critical period, are not well defined. We will review current pre-clinical and clinical evidence for growth factor therapies in treating different causes of brain injury, as well as issues to be addressed prior to application in humans.

  13. A pathophysiological role of TRPV1 in ischemic injury after transient focal cerebral ischemia in mice

    SciTech Connect

    Miyanohara, Jun; Shirakawa, Hisashi; Sanpei, Kazuaki; Nakagawa, Takayuki; Kaneko, Shuji

    2015-11-20

    Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel with high Ca{sup 2+} permeability, which functions as a polymodal nociceptor activated by heat, protons and several vanilloids, including capsaicin and anandamide. Although TRPV1 channels are widely distributed in the mammalian brain, their pathophysiological roles in the brain remain to be elucidated. In this study, we investigated whether TRPV1 is involved in cerebral ischemic injury using a middle cerebral artery (MCA) occlusion model in wild-type (WT) and TRPV1-knockout (KO) mice. For transient ischemia, the left MCA of C57BL/6 mice was occluded for 60 min and reperfused at 1 and 2 days after ischemia. We found that neurological and motor deficits, and infarct volumes in TRPV1-KO mice were lower than those of WT mice. Consistent with these results, intracerebroventricular injection of a TRPV1 antagonist, capsazepine (20 nmol), 30 min before the onset of ischemia attenuated neurological and motor deficits and improved infarct size without influencing cerebral blood flow in the occluded MCA territory. The protective effect of capsazepine on ischemic brain damage was not observed in TRPV1-KO mice. WT and TRPV1-KO mice did not show any differences with respect to the increased number of Iba1-positive microglia/macrophages, GFAP-positive astrocytes, and Gr1-positive neutrophils at 1 and 2 days after cerebral ischemia. Taken together, we conclude that brain TRPV1 channels are activated by ischemic stroke and cause neurological and motor deficits and infarction after brain ischemia. - Highlights: • We investigated whether TRPV1 is involved in transient ischemic brain damage in mice. • Neurological deficits and infarct volumes were lower in TRPV1-KO mice than in WT mice. • Injection of a TRPV1 antagonist, capsazepine, attenuated neurological deficits and improved infarct size. • No differences in astrocytic or microglial activation were observed between WT and TRPV1-KO mice.

  14. Nature of the renal injury following total renal ischemia in man.

    PubMed Central

    Myers, B D; Miller, D C; Mehigan, J T; Olcott, C O; Golbetz, H; Robertson, C R; Derby, G; Spencer, R; Friedman, S

    1984-01-01

    The effects of total renal ischemia (TRI) of 15-87 min duration due to suprarenal clamping of the aorta were studied in 15 mannitol-treated patients undergoing abdominal aortic surgery. 15 patients undergoing similar surgery but requiring only infrarenal clamping served as controls. 1-2 h following TRI, GFR was reduced to only 39% of that in controls, 23 +/- 5 vs. 59 +/- 7 ml/min (P less than 0.001). This could not be ascribed to impaired renal plasma flow (RPF), which was mildly reduced to 331 +/- 71 and was not different from the value in controls, 407 +/- 66 ml/min. However, impaired PAH extraction (43 +/- 7%) and isosthenuria, not present in controls, suggest a primary role for tubular injury in lowering GFR at this time. 24 h following TRI, the GFR remained depressed below controls, 45 +/- 8 vs. 84 +/- 8 ml/min (P less than 0.005), while the transglomerular sieving of neutral dextrans was significantly enhanced (radius interval, 24-40 A). A theoretical analysis of transcapillary solute exchange revealed that these findings could be largely explained by a selective reduction of either RPF (-61%) or of transmembrane hydraulic pressure difference (-18%) below control values. Alternately, a combination of these two factors with changes of smaller magnitude could explain the findings. In contrast, a selective increase in oncotic pressure or decrease of the glomerular ultrafiltration coefficient could be excluded as a cause of hypofiltration 24 h after TRI. These observations lead us to suggest that the transient azotemia observed following TRI is due to a self-limited injury to the nephron that is identical to that seen in overt and sustained forms of acute renal failure. PMID:6421876

  15. Selective renal blood perfusion induces renal tubules injury in a porcine model.

    PubMed

    Kalder, Johannes; Kokozidou, Maria; Keschenau, Paula; Tamm, Miriam; Greiner, Andreas; Koeppel, Thomas A; Tolba, Rene; Jacobs, Michael J

    2016-03-01

    Extracorporeal circulation is routinely used in thoracoabdominal aortic aneurysm repair to preserve blood perfusion. Despite this protective measure, acute and chronic kidney disorders can develop. Therefore, the aim of this study was to establish a new large-animal model to assess the efficacy of selective renal perfusion (SRP) with extracorporeal circulation in a setting of thoracoabdominal aortic aneurysm repair. Eighteen pigs underwent a thoracolaparotomy, during with the aorta and renal arteries were exposed. The animals were divided into three cohorts of six pigs each: cohort I--control; cohort II--thoracic aortic clamping with distal aortic perfusion (DAP) using a roller pump; and cohort III--thoracic aortic clamping with DAP plus SRP. Kidney metabolism, kidney injury, and red blood cell damage were measured by oxygen extraction ratio (O2ER), neutrophil gelatinase-associated lipocalin, a marker for acute kidney damage, and serum free hemoglobin. With normal mean arterial blood pressures, flow rates in the renal arteries during perfusion decreased to 75% (group II) with DAP and to 50% (group III) with SRP compared with the control animals (group I; P = .0279 for I vs II; P = .0002 for I vs III). Microcirculation, measured by microspheres, did not differ significantly among the groups. In contrast, O2ER (P = .0021 for I vs III) and neutrophil gelatinase-associated lipocalin (P = .0083 for I vs III) levels were significantly increased in group III, whereas free hemoglobin was increased in groups II and III (P = .0406 for I vs II; P = .0018 for I vs III). SRP with a roller pump induces kidney tubule injury. Thus, distal aortic and SRP in our model does not provide adequate kidney protection. Furthermore, the perfusion system provokes red blood cell damage with increased free hemoglobin. Hence, the SRP perfusion technique should be revised and tested. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

  16. 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.

  17. Ischemic preconditioning protects the brain against injury via inhibiting CaMKII-nNOS signaling pathway.

    PubMed

    Wang, Mei; Qi, Da-Shi; Zhou, Cui; Han, Dong; Li, Pei-Pei; Zhang, Fang; Zhou, Xiao-Yan; Han, Meng; Di, Jie-Hui; Ye, Jun-Song; Yu, Hong-Min; Song, Yuan-Jian; Zhang, Guang-Yi

    2016-03-01

    Although studies have shown that cerebral ischemic preconditioning (IPC) can ameliorate ischemia/reperfusion (I/R) induced brain damage, but its precise mechanisms remain unknown. Therefore, the aim of this study was to investigate the neuroprotective mechanisms of IPC against ischemic brain damage induced by cerebral I/R and to explore whether the Calcium/calmodulin-dependent protein kinase II (CaMKII)-mediated up-regulation of nNOS ser847-phosphorylation signaling pathway contributed to the protection provided by IPC. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The rats were pretreated with 3 min of IPC alone or KN62 (selective antagonist of CaMKII) treatment before IPC, after reperfusion for 3 days, 6 min ischemia was induced. Cresyl violet staining was used to examine the survival of hippocampal CA1 pyramidal neurons. Immunoblotting was performed to measure the phosphorylation of CaMKII, nNOS, c-Jun and the expression of FasL. Immunoprecipitation was used to examine the binding between PSD95 and nNOS. The results showed that IPC could significantly protect neurons against cerebral I/R injury, furthermore, the combination of PSD95 and nNOS was increased, coinstantaneously the phosphorylation of CaMKII and nNOS (ser847) were up-regulated, however the activation of c-Jun and FasL were reduced. Conversely, KN62 treatment before IPC reversed all these effects of IPC. Taken together, the results suggest that IPC could diminish ischemic brain injury through CaMKII-mediated up-regulation of nNOS ser847-phosphorylation signaling pathway.

  18. 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.

  19. Glycyrrhizin attenuates rat ischemic spinal cord injury by suppressing inflammatory cytokines and HMGB1

    PubMed Central

    Gong, Gu; Yuan, Li-bang; Hu, Ling; Wu, Wei; Yin, Liang; Hou, Jing-li; Liu, Ying-hai; Zhou, Le-shun

    2012-01-01

    Aim: To investigate the neuroprotective effect of glycyrrhizin (Gly) against the ischemic injury of rat spinal cord and the possible role of the nuclear protein high-mobility group box 1 (HMGB1) in the process. Methods: Male Sprague-Dawley rats were subjected to 45 min aortic occlusion to induce transient lumbar spinal cord ischemia. The motor functions of the animals were assessed according to the modified Tarlov scale. The animals were sacrificed 72 h after reperfusion and the lumbar spinal cord segment (L2–L4) was taken out for histopathological examination and Western blotting analysis. Serum inflammatory cytokine and HMGB1 levels were analyzed using ELISA. Results: Gly (6 mg/kg) administered intravenously 30 min before inducing the transient lumbar spinal cord ischemia significantly improved the hind-limb motor function scores, and reduced the number of apoptotic neurons, which was accompanied by reduced levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in the plasma and injured spinal cord. Moreover, the serum HMGB1 level correlated well with the serum TNF-α, IL-1β and IL-6 levels during the time period of reperfusion. Conclusion: The results suggest that Gly can attenuate the transient spinal cord ischemic injury in rats via reducing inflammatory cytokines and inhibiting the release of HMGB1. PMID:22158106

  20. Optimal hemoglobin concentration in patients with subarachnoid hemorrhage, acute ischemic stroke and traumatic brain injury.

    PubMed

    Leal-Noval, Santiago R; Múñoz-Gómez, Manuel; Murillo-Cabezas, Francisco

    2008-04-01

    The review outlines recent clinical and experimental studies regarding the effects of red blood-cell transfusion on clinical outcome in neurocritical patients, including patients with subarachnoid hemorrhage, acute ischemic stroke and traumatic brain injury. Optimal hemoglobin transfusion trigger and the role of other transfusion indicators for neurocritical patients are discussed. Acute anemia (hemoglobin levels near 7 g/dl) is well tolerated by healthy subjects, but extreme anemia might negatively affect clinical outcome of neurocritical patients. Conversely, high hemoglobin levels, attained by means other than red blood-cell transfusion, improve clinical outcome, whereas red blood-cell transfusion is associated with poorer clinical outcome (mortality, length of stay and disability) in patients presenting subarachnoid hemorrhage, acute ischemic stroke and traumatic brain injury. Studies defining the optimal hemoglobin concentration in neurocritical patients are lacking, but a restrictive transfusion policy seems to be safe and is often recommended. In the near future, signals coming from the brain, such as brain tissue oxygen tension and regional cerebral oxygen saturation, might potentially be developed into transfusion triggers. Both severe anemia and red blood-cell transfusion may negatively influence clinical outcome in neurocritical patients. Acceptance of low hemoglobin concentrations may be justified by avoiding negative transfusion effects. No evidence-based transfusion trigger in neurocritical patients can be recommended.

  1. Hypoxic-ischemic brain damage induces distant inflammatory lung injury in newborn piglets.

    PubMed

    Arruza, Luis; Pazos, M Ruth; Mohammed, Nagat; Escribano, Natalia; Lafuente, Hector; Santos, Martín; Alvarez-Díaz, Francisco J; Martínez-Orgado, Jose

    2016-03-01

    We aimed to investigate whether neonatal hypoxic-ischemic (HI) brain injury induces inflammatory lung damage. Thus, hypoxic (HYP, FiO2 10% for 30 min), ischemic (ISC, bilateral carotid flow interruption for 30 min), or HI event was performed in 1-2-d-old piglets. Dynamic compliance (Cdyn), oxygenation index (OI), and extravascular lung water (EVLW) were monitored for 6 h. Then, histologic damage was assessed in brain and lung (lung injury severity score). Total protein content (TPC) was determined in broncoalveolar lavage fluid (BALF), and IL-1β concentration was measured in lung and brain tissues and blood. Piglets without hypoxia or ischemia served as controls (SHM). HI-induced brain damage was associated with decreased Cdyn, increased OI and EVLW, and histologic lung damage (interstitial leukocyte infiltration, congestive hyperemia, and interstitial edema). BALF TPC was increased, suggesting inflammatory damage. In agreement, tissue IL-1β concentration increased in the brain and lung, in correspondence with increased IL-1β serum concentration. Neither HYP nor ISC alone led to brain or lung damage. HI brain damage in newborn piglets led to inflammatory lung damage, suggesting an additional mechanism accounting for the development of lung dysfunction after neonatal HI encephalopathy.

  2. 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

  3. 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. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. The role of Toll-like receptor 2 in inflammation and fibrosis during progressive renal injury.

    PubMed

    Leemans, Jaklien C; Butter, Loes M; Pulskens, Wilco P C; Teske, Gwendoline J D; Claessen, Nike; van der Poll, Tom; Florquin, Sandrine

    2009-05-27

    Tissue fibrosis and chronic inflammation are common causes of progressive organ damage, including progressive renal disease, leading to loss of physiological functions. Recently, it was shown that Toll-like receptor 2 (TLR2) is expressed in the kidney and activated by endogenous danger signals. The expression and function of TLR2 during renal fibrosis and chronic inflammation has however not yet been elucidated. Therefore, we studied TLR2 expression in human and murine progressive renal diseases and explored its role by inducing obstructive nephropathy in TLR2(-/-) or TLR2(+/+) mice. We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury. In mice with obstructive nephropathy, renal injury was associated with a marked upregulation and change in distribution of TLR2 and upregulation of murine TLR2 danger ligands Gp96, biglycan, and HMGB1. Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-beta in kidneys of TLR2(-/-) mice compared with TLR2(+/+) animals. Although, the obstructed kidneys of TLR2(-/-) mice had less interstitial myofibroblasts in the later phase of obstructive nephropathy, tubular injury and renal matrix accumulation was similar in both mouse strains. Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis.

  5. The Role of Toll-Like Receptor 2 in Inflammation and Fibrosis during Progressive Renal Injury

    PubMed Central

    Leemans, Jaklien C.; Butter, Loes M.; Pulskens, Wilco P. C.; Teske, Gwendoline J. D.; Claessen, Nike; van der Poll, Tom; Florquin, Sandrine

    2009-01-01

    Tissue fibrosis and chronic inflammation are common causes of progressive organ damage, including progressive renal disease, leading to loss of physiological functions. Recently, it was shown that Toll-like receptor 2 (TLR2) is expressed in the kidney and activated by endogenous danger signals. The expression and function of TLR2 during renal fibrosis and chronic inflammation has however not yet been elucidated. Therefore, we studied TLR2 expression in human and murine progressive renal diseases and explored its role by inducing obstructive nephropathy in TLR2−/− or TLR2+/+ mice. We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury. In mice with obstructive nephropathy, renal injury was associated with a marked upregulation and change in distribution of TLR2 and upregulation of murine TLR2 danger ligands Gp96, biglycan, and HMGB1. Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-β in kidneys of TLR2−/− mice compared with TLR2+/+ animals. Although, the obstructed kidneys of TLR2−/− mice had less interstitial myofibroblasts in the later phase of obstructive nephropathy, tubular injury and renal matrix accumulation was similar in both mouse strains. Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis. PMID:19479087

  6. 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

  7. Maternal Cigarette Smoke Exposure Worsens Neurological Outcomes in Adolescent Offspring with Hypoxic-Ischemic Injury.

    PubMed

    Chan, Yik L; Saad, Sonia; Machaalani, Rita; Oliver, Brian G; Vissel, Bryce; Pollock, Carol; Jones, Nicole M; Chen, Hui

    2017-01-01

    Hypoxic-ischemic (HI) encephalopathy occurs in approximately 6 per 1000 term newborns leading to devastating neurological consequences, such as cerebral palsy and seizures. Maternal smoking is one of the prominent risk factors contributing to HI injury. Mitochondrial integrity plays a critical role in neural injury and repair during HI. We previously showed that maternal cigarette smoke exposure (SE) can reduce brain mitochondrial fission and autophagosome markers in male offspring. This was accompanied by increased brain cell apoptosis (active caspase-3) and DNA fragmentation (TUNEL staining). Here, we aimed to investigate whether maternal SE leads to more severe neurological damage after HI brain injury in male offspring. Female BALB/c mice (8 weeks) were exposed to cigarette smoke prior to mating, during gestation, and lactation. At postnatal day 10, half of the pups from each litter underwent left carotid artery occlusion, followed by exposure to 8% oxygen (92% nitrogen). At postnatal day 40-44, maternal SE reduced grip strength in grip traction and foot fault tests, which were also reduced by HI injury to similar levels regardless of the maternal group. Limb coordination was impaired by maternal SE which was not worsened by HI injury. Maternal SE increased anxiety level in the offspring, which was normalized by HI injury. Apoptosis markers were increased in different brain regions by maternal SE, with the cortex having further increased TUNEL by HI injury, along with increased markers of inflammation and mitophagy. We conclude that maternal SE can worsen HI-induced cellular damage in male offspring well into adolescence.

  8. Rap1 Ameliorates Renal Tubular Injury in Diabetic Nephropathy

    PubMed Central

    Xiao, Li; Zhu, Xuejing; Yang, Shikun; Liu, Fuyou; Zhou, Zhiguang; Zhan, Ming; Xie, Ping; Zhang, Dongshan; Li, Jun; Song, Panai; Kanwar, Yashpal S.; Sun, Lin

    2014-01-01

    Rap1b ameliorates high glucose (HG)-induced mitochondrial dysfunction in tubular cells. However, its role and precise mechanism in diabetic nephropathy (DN) in vivo remain unclear. We hypothesize that Rap1 plays a protective role in tubular damage of DN by modulating primarily the mitochondria-derived oxidative stress. The role and precise mechanisms of Rap1b on mitochondrial dysfunction and of tubular cells in DN were examined in rats with streptozotocin (STZ)-induced diabetes that have Rap1b gene transfer using an ultrasound microbubble-mediated technique as well as in renal proximal epithelial tubular cell line (HK-2) exposed to HG ambiance. The results showed that Rap1b expression decreased significantly in tubules of renal biopsies from patients with DN. Overexpression of a constitutively active Rap1b G12V notably ameliorated renal tubular mitochondrial dysfunction, oxidative stress, and apoptosis in the kidneys of STZ-induced rats, which was accompanied with increased expression of transcription factor C/EBP-β and PGC-1α. Furthermore, Rap1b G12V also decreased phosphorylation of Drp-1, a key mitochondrial fission protein, while boosting the expression of genes related to mitochondrial biogenesis and antioxidants in HK-2 cells induced by HG. These effects were imitated by transfection with C/EBP-β or PGC-1α short interfering RNA. In addition, Rap1b could modulate C/EBP-β binding to the endogenous PGC-1α promoter and the interaction between PGC-1α and catalase or mitochondrial superoxide dismutase, indicating that Rap1b ameliorates tubular injury and slows the progression of DN by modulation of mitochondrial dysfunction via C/EBP-β–PGC-1α signaling. PMID:24353183

  9. 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

  10. Toll-like Receptor 2: A Novel Therapeutic Target for Ischemic White Matter Injury and Oligodendrocyte Death.

    PubMed

    Choi, Jun Young; Kim, Byung Gon

    2017-08-01

    Despite paramount clinical significance of white matter stroke, there is a paucity of researches on the pathomechanism of ischemic white matter damage and accompanying oligodendrocyte (OL) death. Therefore, a large gap exists between clinical needs and laboratory researches in this disease entity. Recent works have started to elucidate cellular and molecular basis of white matter injury under ischemic stress. In this paper, we briefly introduce white matter stroke from a clinical point of view and review pathophysiology of ischemic white matter injury characterized by OL death and demyelination. We present a series of evidence that Toll-like receptor 2 (TLR2), one of the membranous pattern recognition receptors, plays a cell-autonomous protective role in ischemic OL death and ensuing demyelination. Moreover, we also discuss our recent findings that its endogenous ligand, high-mobility group box 1 (HMGB1), is released from dying OLs and exerts autocrine trophic effects on OLs and myelin sheath under ischemic condition. We propose that modulation of TLR2 and its endogenous ligand HMGB1 can be a novel therapeutic target for ischemic white matter disease.

  11. 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

  12. Rat umbilical cord blood cells attenuate hypoxic–ischemic brain injury in neonatal rats

    PubMed Central

    Nakanishi, Keiko; Sato, Yoshiaki; Mizutani, Yuka; Ito, Miharu; Hirakawa, Akihiro; Higashi, Yujiro

    2017-01-01

    Increasing evidence has suggested that human umbilical cord blood cells (hUCBC) have a favorable effect on hypoxic–ischemic (HI) brain injury. However, the efficacy of using hUCBCs to treat this injury has been variable and the underlying mechanism remains elusive. Here, we investigated its effectiveness using stereological analysis in an allogeneic system to examine whether intraperitoneal injection of cells derived from UCBCs of green fluorescent protein (GFP)-transgenic rats could ameliorate brain injury in neonatal rats. Three weeks after the HI event, the estimated residual brain volume was larger and motor function improved more in the cell-injected rats than in the control (PBS-treated) rats. The GFP-positive cells were hardly detectable in the brain (0.0057% of injected cells) 9 days after injection. Although 60% of GFP-positive cells in the brain were Iba1-positive, none of these were positive for NeuroD or DCX. While the number of proliferating cells increased in the hippocampus, that of activated microglia/macrophages decreased and a proportion of M2 microglia/macrophages increased in the ipsilateral hemisphere of cell-injected rats. These results suggest that intraperitoneal injection of cells derived from UCBCs could ameliorate HI injury, possibly through an endogenous response and not by supplying differentiated neurons derived from the injected stem cells. PMID:28281676

  13. Electroacupuncture preconditioning attenuates ischemic brain injury by activation of the adenosine monophosphate-activated protein kinase signaling pathway

    PubMed Central

    Ran, Qiang-qiang; Chen, Huai-long; Liu, Yan-li; Yu, Hai-xia; Shi, Fei; Wang, Ming-shan

    2015-01-01

    Electroacupuncture has therapeutic effects on ischemic brain injury, but its mechanism is still poorly understood. In this study, mice were stimulated by electroacupuncture at the Baihui (GV20) acupoint for 30 minutes at 1 mA and 2/15 Hz for 5 consecutive days. A cerebral ischemia model was established by ligating the bilateral common carotid artery for 15 minutes. At 72 hours after injury, neuronal injury in the mouse hippocampus had lessened, and the number of terminal deoxynucleotide transferase-mediated dUTP nick-end labeling-positive cells reduced after electroacupuncture treatment. Moreover, expression of adenosine monophosphate-activated protein kinase α (AMPKα) and phosphorylated AMPKα was up-regulated. Intraperitoneal injection of the AMPK antagonist, compound C, suppressed this phenomenon. Our findings suggest that electroacupuncture preconditioning alleviates ischemic brain injury via AMPK activation. PMID:26330828

  14. Focal Brain Injury Associated with a Model of Severe Hypoxic-Ischemic Encephalopathy in Nonhuman Primates.

    PubMed

    McAdams, Ryan M; McPherson, Ronald J; Kapur, Raj P; Juul, Sandra E

    2017-03-25

    Worldwide, hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal mortality and morbidity. To better understand the mechanisms contributing to brain injury and improve outcomes in neonates with HIE, better preclinical animal models that mimic the clinical situation following birth asphyxia in term newborns are needed. In an effort to achieve this goal, we modified our nonhuman primate model of HIE induced by in utero umbilical cord occlusion (UCO) to include postnatal hypoxic episodes, in order to simulate apneic events in human neonates with HIE. We describe a cohort of 4 near-term fetal Macaca nemestrina that underwent 18 min of in utero UCO, followed by cesarean section delivery, resuscitation, and subsequent postnatal mechanical ventilation, with exposure to intermittent daily hypoxia (3 min, 8% O2 3-8 times daily for 3 days). After delivery, all animals demonstrated severe metabolic acidosis (pH 7 ± 0.12; mean ± SD) and low APGAR scores (<5 at 10 min of age). Three of 4 animals had both electrographic and clinical seizures. Serial blood samples were collected and plasma metabolites were determined by 2-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC × GC-TOFMS). The 4 UCO animals and a single nonasphyxiated animal (delivered by cesarean section but without exposure to UCO or prolonged sedation) underwent brain magnetic resonance imaging (MRI) on day 8 of life. Thalamic injury was present on MRI in 3 UCO animals, but not in the control animal. Following necropsy on day 8, brain histopathology revealed neuronal injury/loss and gliosis in portions of the ventrolateral thalamus in all 4 UCO, with 2 animals also demonstrating putamen/globus pallidus involvement. In addition, all 4 UCO animals demonstrated brain stem gliosis, with neuronal loss present in the midbrain, pons, and lateral medulla in 3 of 4 animals. Transmission electron microscopy imaging of the brain tissues was performed, which demonstrated

  15. Cell Adhesion Molecules in Chemically-Induced Renal Injury

    PubMed Central

    Prozialeck, Walter C.; Edwards, Joshua R.

    2007-01-01

    Cell adhesion molecules are integral cell-membrane proteins that maintain cell-cell and cell-substrate adhesion, and in some cases, act as regulators of intracellular signaling cascades. In the kidney, cell adhesion molecules such as the cadherins, the catenins, ZO-1, occludin and the claudins are essential for maintaining the epithelial polarity and barrier integrity that are necessary for the normal absorption/excretion of fluid and solutes. A growing volume of evidence indicates that these cell adhesion molecules are important early targets for a variety of nephrotoxic substances including metals, drugs, and venom components. In addition, it is now widely appreciated that molecules such as ICAM-1, the integrins and selectins play important roles in the recruitment of leukocytes and inflammatory responses that are associated with nephrotoxic injury. This review summarizes the results of recent in vitro and in vivo studies indicating that these cell adhesion molecules may be primary molecular targets in many types of chemically-induced renal injury. Some of the specific agents that are discussed include Cd, Hg, Bi, cisplatin, aminoglycoside antibiotics, S-(1,2-dichlorovinyl-L-cysteine) (DCVC) and various venom toxins. This review also includes a discussion of the various mechanisms by which these substances can affect cell adhesion molecules in the kidney. PMID:17316817

  16. Heme oxygenase-1 mediated memorial and revivable protective effect of ischemic preconditioning on brain injury.

    PubMed

    Le, Li-Li; Li, Xue-Yi; Meng, Dan; Liang, Qiu-Jun; Wang, Xin-Hong; Li, Ning; Quan, Jing; Xiang, Meng; Jiang, Mei; Sun, Jian; Chen, Si-Feng

    2013-12-01

    Ischemic preconditioning (IPC) has short-term benefits for stroke patients. However, if IPC protective effect is memorial and the role of the intracellular protective protein heme oxygenase-1 (HO-1) is not known. Ischemic preconditioning and the corresponding sham control were achieved by blocking the blood flow of the left internal carotid artery for 20 min and 2 second, respectively, in rats. Both IPC and sham-operated animals were divided into three groups and treated with PBS, the HO-1 inducer hemin, and the HO-1 inhibitor Znpp. Three weeks after IPC, brain ischemia-reperfusion injury was achieved by left middle cerebral artery obstruction for 45 min followed by 24-h reperfusion. 2,3,5-triphenyltetrazolium chloride staining and neurological dysfunction scoring showed IPC significantly reduced brain infarct area and improved neurological function occurred 3 weeks after IPC. Hemin treatment promoted whereas ZnPP blocked the benefits of IPC. Immunohistochemical analysis and Western blotting showed that the expression of HO-1 was higher in the border zone than in the necrotic core zone. The memorial IPC protection is independent of adenosine receptor A1R and A2aR expressions. We found for the first time that the protective effect of IPC can be remembered to protect brain injury occurred after acute response disappear. The results indicate that interventional treatment can achieve protective effect for future cerebral injury not only through interventional treatment itself but also through the memorial and revivable IPC, eliminating the concern that temporary ischemia caused by interventional treatment may leave harmful effect in the brain. © 2013 John Wiley & Sons Ltd.

  17. 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.

  18. 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

  19. Acute Ischemic Stroke After Moderate to Severe Traumatic Brain Injury: Incidence and Impact on Outcome.

    PubMed

    Kowalski, Robert G; Haarbauer-Krupa, Juliet K; Bell, Jeneita M; Corrigan, John D; Hammond, Flora M; Torbey, Michel T; Hofmann, Melissa C; Dams-O'Connor, Kristen; Miller, A Cate; Whiteneck, Gale G

    2017-07-01

    Traumatic brain injury (TBI) leads to nearly 300 000 annual US hospitalizations and increased lifetime risk of acute ischemic stroke (AIS). Occurrence of AIS immediately after TBI has not been well characterized. We evaluated AIS acutely after TBI and its impact on outcome. A prospective database of moderate to severe TBI survivors, admitted to inpatient rehabilitation at 22 Traumatic Brain Injury Model Systems centers and their referring acute-care hospitals, was analyzed. Outcome measures were AIS incidence, duration of posttraumatic amnesia, Functional Independence Measure, and Disability Rating Scale, at rehabilitation discharge. Between October 1, 2007, and March 31, 2015, 6488 patients with TBI were enrolled in the Traumatic Brain Injury Model Systems National Database. One hundred and fifty-nine (2.5%) patients had a concurrent AIS, and among these, median age was 40 years. AIS was associated with intracranial mass effect and carotid or vertebral artery dissection. High-velocity events more commonly caused TBI with dissection. AIS predicted poorer outcome by all measures, accounting for a 13.3-point reduction in Functional Independence Measure total score (95% confidence interval, -16.8 to -9.7; P<0.001), a 1.9-point increase in Disability Rating Scale (95% confidence interval, 1.3-2.5; P<0.001), and an 18.3-day increase in posttraumatic amnesia duration (95% confidence interval, 13.1-23.4; P<0.001). Ischemic stroke is observed acutely in 2.5% of moderate to severe TBI survivors and predicts worse functional and cognitive outcome. Half of TBI patients with AIS were aged ≤40 years, and AIS patients more often had cervical dissection. Vigilance for AIS is warranted acutely after TBI, particularly after high-velocity events. © 2017 American Heart Association, Inc.

  20. Ischemic postconditioning may not influence early brain injury induced by focal cerebral ischemia/reperfusion in rats

    PubMed Central

    Kim, Yoo Kyung; Shin, Jin Woo; Joung, Kyoung Woon

    2010-01-01

    Background Experimental studies have shown that ischemic postconditioning can reduce neuronal injury in the setting of cerebral ischemia, but the mechanisms are not yet clearly elucidated. This study was conducted to determine whether ischemic postconditioning can alter expression of heat shock protein 70 and reduce acute phase neuronal injury in rats subjected to transient focal cerebral ischemia/reperfusion. Methods Focal cerebral ischemia was induced by intraluminal middle cerebral artery occlusion for 60 min in twenty male Sprague-Dawley rats (250-300 g). Rats were randomized into control group and an ischemic postconditioning group (10 rats per group). The animals of control group had no intervention either before or after MCA occlusion. Ischemic postconditioning was elicited by 3 cycles of 30 s reperfusion interspersed by 10 s ischemia immediately after onset of reperfusion. The infarct ratios, brain edema ratios and motor behavior deficits were analyzed 24 hrs after ischemic insult. Caspase-3 reactive cells and cells showing heat shock protein 70 activity were counted in the caudoputamen and frontoparietal cortex. Results Ischemic postconditiong did not reduce infarct size and brain edema ratios compared to control group. Neurologic scores were not significantly different between groups. The number of caspase-3 reactive cells in the ischemic postconditioning group was not significantly different than the value of the control group in the caudoputamen and frontoparietal cortex. The number of cells showing heat shock protein 70 activity was not significantly different than the control group, as well. Conclusions These results suggest that ischemic postconditioning may not influence the early brain damage induced by focal cerebral ischemia in rats. PMID:20498797

  1. Injury of the Hypothalamus in Patients With Hypoxic-Ischemic Brain Injury: A Diffusion Tensor Imaging Study.

    PubMed

    Jang, Sung Ho; Kwon, Hyeok Gyu

    2017-08-18

    The survival rate for hypoxic-ischemic brain injury (HI-BI) is less than 20%. Several brain regions, including the caudate, hippocampus, and hypothalamus, are vulnerable to HI-BI. Hypothalamus is involved in regulation of temperature, sleep-wakefulness cycle, emotional behavior, and memory function. Using diffusion tensor imaging, we examined injury of the hypothalamus in patients with HI-BI. Twelve patients with HI-BI and 27 healthy control subjects were recruited. The region of interest was defined for the hypothalamus and the fractional anisotropy and apparent diffusion coefficient were measured. The fractional anisotropy value was significantly lower in the patient group compared with the control group (P < 0.05), whereas the apparent diffusion coefficient value was significantly higher compared with that of the control group (P < 0.05). In the individual analysis, 7 (58.3%) of 12 patients and 14 (58.3%) of 24 hemispheres showed a decrement or increment of more than two SDs in either fractional anisotropy or apparent diffusion coefficient values compared with the control group. Using diffusion tensor imaging, injury of the hypothalamus was demonstrated in patients with HI-BI. Our methodology and results of this study would be helpful in research on the hypothalamus in patients with HI-BI.

  2. Spectroscopic imaging for detection of ischemic injury in rat kidneys by use of changes in intrinsic optical properties

    NASA Astrophysics Data System (ADS)

    Michalopoulou, Andromachi P.; Fitzgerald, Jason T.; Troppmann, Christoph; Demos, Stavros G.

    2005-04-01

    It is currently impossible to consistently predict kidney graft viability and function before and after transplantation. We explored optical spectroscopy to assess the degree of ischemic damage in kidney tissue. Tunable UV laser excitation was used to record autofluorescence images, at different spectral ranges, of injured and contralateral control rat kidneys to reveal the excitation conditions that offered optimal contrast. Autofluorescence and near-infrared cross-polarized light-scattering imaging were both used to monitor changes in intensity and spectral characteristics, as a function of exposure time to ischemic injury. These two modalities provided different temporal behaviors, arguably arising from two different mechanisms providing direct correlation of intrinsic optical signatures to ischemic injury time.

  3. Induction of renal growth and injury in the intact rat kidney by dietary deficiency of antioxidants.

    PubMed Central

    Nath, K A; Salahudeen, A K

    1990-01-01

    We report induction of renal growth and injury in the intact rat kidney using a diet deficient in vitamin E and selenium. This diet was imposed in 3-wk-old male weanling rats, and after 9 wk, enhancement of growth, characterized by increased wet weight, dry weight, protein content, and DNA content appeared. Morphometric analyses revealed increased kidney volume, tubular epithelial volume, and mean glomerular volume. There were no differences in nephron number. The animals on the deficient diet displayed increased urinary protein excretion at 9 wk. Renal injury was also characterized by an interstitial cellular infiltrate and diminutions in glomerular filtration rate. Enhanced growth and injury were antedated by increased renal ammoniagenesis. The deficient diet did not induce metabolic acidosis, potassium depletion, glucose intolerance, or elevated plasma amino acid concentration. Enhancement of renal growth and ammoniagenesis by the deficient diet was not suppressible by chronic alkali therapy. Stimulation of renal growth could not be ascribed to increased intrarenal iron, induction of ornithine decarboxylase, or alterations in glomerular hemodynamics. Stimulation of renal ammoniagenesis by dietary deficiency of antioxidants is a novel finding, as is induction of growth and injury. We suggest that increased renal ammoniagenesis contributes to induction of renal growth and injury. Images PMID:2212007

  4. Protective effect of Urtica dioica L. on renal ischemia/reperfusion injury in rat.

    PubMed

    Sayhan, Mustafa Burak; Kanter, Mehmet; Oguz, Serhat; Erboga, Mustafa

    2012-12-01

    Renal ischemia-reperfusion (I/R) injury may occur after renal transplantation, thoracoabdominal aortic surgery, and renal artery interventions. This study was designed to investigate the effect of Urtica dioica L. (UD), in I/R induced renal injury. A total of 32 male Sprague-Dawley rats were divided into four groups: control, UD alone, I/R and I/R + UD; each group contain 8 animals. A rat model of renal I/R injury was induced by 45-min occlusion of the bilateral renal pedicles and 24-h reperfusion. In the UD group, 3 days before I/R, UD (2 ml/kg/day intraperitoneal) was administered by gastric gavage. All animals were sacrificed at the end of reperfusion and kidney tissues samples were obtained for histopathological investigation in all groups. To date, no more histopathological changes on intestinal I/R injury in rats by UD treatment have been reported. Renal I/R caused severe histopathological injury including tubular damage, atrophy dilatation, loss of brush border and hydropic epithelial cell degenerations, renal corpuscle atrophy, glomerular shrinkage,