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Sample records for induces renal morphopathology

  1. Morphopathological aspects of healthy nails and nails affected by onychomycosis.

    PubMed

    Zaikovska, Olga; Pilmane, Mara; Kisis, Janis

    2014-09-01

    Patients of onychomycosis are common in the dermatology practice. Contemporary morphology creates opportunities to study the functional units of the nail when such infections occur from morphopathological point of view. There were 22 nails biopsies from onychomycosis patients taken for the research of morphopathological changes in the thickened nail plate affected by onychomycosis. Samples of cadaverous' nails were used as a control material. The material was stained with haematoxylin and eosin and immunohistochemical methods. Terminal deoxynucleotidyl transferase dUTP nick end labelling reaction and periodic acid-Schiff reaction were also performed. We found patchy hypertrophy in the granulose layer of the epidermis, with focal acanthosis. In the horn layer, we identified nests of parakeratosis of various sizes, with incorporations of homogenous and eosinophil masses. We found high levels of interleukin 6 and interleukin 10 positive cells in the nail bed and in the bloodstream. Interleukin 1, however, was not a part of any of the functional units of any of the nails. Significant amount of fibres containing human beta defensin-2 were found in the bed and plate of the nail. Therefore one can conclude that as regards the nails affected by onychomycosis, the most effective morphopathogenical processes include cytokine and defensin excretion occurrence in the nail bed.

  2. Ifosfamide induced renal rickets.

    PubMed

    Lionel, Arul P; Chinnaswamy, Girish; John, Rikki R; Mathai, Sarah

    2014-09-01

    Ifosfamide is commonly used as a chemotherapeutic agent in children. The authors report a 4-y-old boy who developed proximal renal tubulopathy with florid rickets a year after completion of ifosfamide therapy for Ewing's sarcoma. After initiation of treatment, there was complete healing of rickets and he did not need supplements beyond 18 mo. Growth monitoring and musculoskeletal system examination is important in all children who have received ifosfamide therapy. Routine monitoring for nephrotoxicity during and after ifosfamide therapy helps in early identification and intervention.

  3. [Morphopathological changes in glaucoma-induced trabecular meshwork].

    PubMed

    Petraru, D; Indrei, Anca; Costin, D; Mihalache, G

    2011-01-01

    Glaucoma causes trabecular meshwork and Schlemm canal changes, resulting in the obstruction of the aqueous flow at this level. To show the histological changes in the surgically removed trabecular meshwork tissues. Trabecular meshwork fragments were histologically processed for histological diagnosis. 29.87% of all patients had ordered structure with high eosinophilia, 20.12% a rare structure with high eosinophilia, 21.34% a voluminous trabecular meshwork with fusiform cells, 21.03% tissue fibrosis and 7.62% had tissue necrosis. Aqueous flow obstruction in trabecular meshwork is produced by the histological changes at this level, found in all tissue specimens removed during surgery.

  4. Radiocontrast-Induced Renal Failure

    PubMed Central

    Misson, Robert T.; Cutler, Ralph E.

    1985-01-01

    Review of the literature concerning contrast-induced renal dysfunction shows that the currently used agents are remarkably safe with careful patient selection. Clinically apparent kidney failure after their use is essentially nonexistent in those without preexistent renal insufficiency. The incidence rises rapidly in those with azotemia from any cause, however, and diabetic persons with nephropathy are perhaps at special risk. Vigorous volume expansion is possibly effective as a preventive measure and may attenuate adverse effects in those in whom postcontrast dysfunction occurs. New agents are becoming available. It is not yet known if these will prove safer or cost-effective. They have some experimentally demonstrated and theoretic advantages over the presently used agents. PMID:4013281

  5. Local anesthetics induce human renal cell apoptosis.

    PubMed

    Lee, H Thomas; Xu, Hua; Siegel, Cory D; Krichevsky, Igor E

    2003-01-01

    Renal cell apoptosis contributes significantly to the pathogenesis of acute renal failure. Local anesthetics induce apoptosis in neuronal and lymphocytic cell lines. We examined the effects of chronic (48 h) local anesthetic treatment (lidocaine, bupivacaine and tetracaine) on human proximal tubular (HK-2) cells. Apoptosis induction was assessed by detecting poly(ADP)-ribose polymerase fragmentation, caspase activation, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining, DNA laddering and by cellular morphology. Cell death was quantified by measuring neutral red dye uptake and lactate dehydrogenase released into the cell culture medium. All 3 local anesthetics caused concentration-dependent cell death, induced HK-2 cell apoptosis and potentiated TNF-alpha induced apoptosis. Local anesthetics induced HK-2 cell apoptosis by activation of caspases 3, 6, 7, 8 and 9. ZVAD-fmk, a pan-caspase inhibitor, blocked the local anesthetic induced HK-2 cell apoptosis. Local anesthetics also inhibited the activities of anti-apoptotic kinases protein kinase B (Akt) and extracellular signal regulated mitrogen-activated protein kinase. Local anesthetic's pro-apoptotic effects are independent of sodium channel inhibition as tetrodotoxin, a selective voltage-gated sodium channel blocker, failed to mimic local anesthetic-mediated induction or potentiation of HK-2 cell apoptosis. We conclude that local anesthetics induce human renal cell apoptotic signaling by caspase activation and via inhibition of pro-survival signaling pathways.

  6. Cyclosporine A-Induced Renal Fibrosis

    PubMed Central

    Slattery, Craig; Campbell, Eric; McMorrow, Tara; Ryan, Michael P.

    2005-01-01

    Cyclosporine A, which has been the foremost immunosuppressive agent since the early 1980’s, significantly improves the success of organ transplantation. However, common complications of cyclosporine A therapy, such as severe renal tubulointerstitial fibrosis, limit the drug’s clinical use. Although the exact mechanisms driving cyclosporine A-induced tubulointerstitial fibrosis remain elusive, we hypothesized that epithelial-mesenchymal transition (EMT) may play a major role. We investigated this in vitro by treating human proximal tubular cells with cyclosporine A. Morphological changes were observed after cyclosporine A treatment, including cell elongation (with a large degree of detachment), cytoskeletal rearrangement, and junctional disruption. In addition, expression of the myofibroblast-specific marker α-smooth muscle actin was detected in treated cells. These observations are consistent with events described during EMT. Using Affymetrix gene microarrays, we identified 128 genes that were differentially regulated in renal tubular cells after cyclosporine A treatment, including known profibrotic factors, oncogenes, and transcriptional regulators. Cyclosporine A induced a dose-dependent increase in transforming growth factor-β secretion from proximal tubular cells. Subsequent functional studies revealed that protein kinase C-β isoforms play a key role in cyclosporine A-induced effects. These findings provide novel insights into cyclosporine A-induced renal fibrosis and the molecular mechanisms underlying EMT, events that may be relevant in other disease states. PMID:16049326

  7. Nuclear magnetic resonance imaging of induced renal lesions

    SciTech Connect

    London, D.A.; Davis, P.L.; Williams, R.D.; Crooks, L.E.; Sheldon, P.E.; Gooding, C.A.

    1983-07-01

    Nuclear magnetic resonance (NMR) images obtained after unilateral ligation of the ureter, renal artery, or renal vein in the rat were analyzed and compared with NMR images of the normal rat kidney. Anatomic and functional correlation of the induced renal lesions was made by concurrent CT and by gross examination of the excised kidneys. Many normal anatomic structures at the level of the renal hilum can be identified by high resolution NMR imaging. Differentiation of urine from renal parenchyma permits detection of gross changes both in renal function and in the mass of the renal parenchyma. NMR imaging is capable of diagnosing hydronephrosis, acute renal ischemia, and acute venous congestion in this rat model. In addition, a trend toward prolongation of the relaxation times T1 and T2 for abnormal renal parenchyma is demonstrated.

  8. Erdosteine against acetaminophen induced renal toxicity.

    PubMed

    Isik, Bunyamin; Bayrak, Reyhan; Akcay, Ali; Sogut, Sadik

    2006-07-01

    Acetaminophen (APAP) induced toxicities have been a major problem in clinical practice. The aim of the present study was to demonstrate a possible protective role of erdosteine, a mucolytic agent having antioxidant properties via its active metabolites, on APAP induced renal damage in rats. Female Wistar Albino rats were divided into groups including control, erdosteine (150 mg/kg, oral), APAP (1 g/kg, oral) APAP+erdosteine (150 mg/kg, oral) and APAP+erdosteine (300 mg/kg, oral). APAP treatment caused lipid peroxidation as well as high NO level in renal tissue. Also, APAP treated rats had decreased activities of CAT and GSH-Px, but not SOD. In addition, tubular epithelial degeneration, vacuolization and cell desquamation were clearly observed in the APAP treated rats. The cellular debris in the proximal tubules and cortical interstitial congestions were prominent in the kidneys of APAP treated rats. BUN and creatinine levels were increased after APAP administration. All these pathological changes were reversed after erdosteine treatments. Erdosteine treated APAP groups showed milder tubular degeneration, epithelial vacuolization in the proximal tubules, lesser cellular desquamation and better morphology when compared with APAP groups. In conclusion, erdosteine may be a choice of preventive treatment against APAP induced nephrotoxicity.

  9. Fluoride-induced chronic renal failure.

    PubMed

    Lantz, O; Jouvin, M H; De Vernejoul, M C; Druet, P

    1987-08-01

    Renal fluoride toxicity in human beings is difficult to assess in the literature. Although experimental studies and research on methoxyflurane toxicity have shown frank renal damage, observations of renal insufficiency related to chronic fluoride exposure are scarce. We report a case of fluoride intoxication related to potomania of Vichy water, a highly mineralized water containing 8.5 mg/L of fluoride. Features of fluoride osteosclerosis were prominent and end-stage renal failure was present. The young age of the patient, the long duration of high fluoride intake, and the absence of other cause of renal insufficiency suggest a causal relationship between fluoride intoxication and renal failure.

  10. Honey induces apoptosis in renal cell carcinoma

    PubMed Central

    Samarghandian, Saeed; Afshari, Jalil Tavakkol; Davoodi, Saiedeh

    2011-01-01

    Background: The fact that antioxidants have several preventative effects against different diseases, such as coronary diseases, inflammatory disorders, neurologic degeneration, aging, and cancer, has led to the search for food rich in antioxidants. Honey has been used as a traditional food and medical source since ancient times. However, recently many scientists have been concentrating on the antioxidant property of honey. By use of human renal cancer cell lines (ACHN), we investigated the antiproliferative activity, apoptosis, and the antitumor activity of honey. Materials and Methods: The cells were cultured in Dulbecco’s modified Eagle’s medium with 10% fetal bovine serum treated with different concentrations of honey for 3 consecutive days. Cell viability was quantitated by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptotic cells were determined using Annexin-V-fluorescein isothiocyanate (FITC) by flow cytometry. Results: Honey decreased the cell viability in the malignant cells in a concentration- and time-dependent manner. The IC 50 values against the ACHN cell lines were determined as 1.7 ± 0.04% and 2.1 ± 0.03% μg/mL after 48 and 72 h, respectively. Honey induced apoptosis of the ACHN cells in a concentration-dependent manner, as determined by flow cytometry histogram of treated cells. Conclusion: It might be concluded that honey may cause cell death in the ACHN cells, in which apoptosis plays an important role. Most of the drugs used in the cancer treatment are apoptotic inducers, hence apoptotic nature of honey is considered vital. Therefore, it prompted us to investigate honey as a potential candidate for renal cancer treatment. PMID:21472079

  11. Renal Osteodystrophy or Kidney-Induced Osteoporosis?

    PubMed

    Moe, Sharon M

    2017-06-01

    Chronic kidney disease (CKD) affects nearly 10% of the population. The incidence of fractures in population studies demonstrate an increase with worsening stages of kidney disease suggesting specific CKD related causes of fracture. The increase in fractures with CKD most likely represents disordered bone quality due to the abnormal bone remodeling from renal osteodystrophy. There is also an increase in fractures with age in patients with CKD, suggesting that patients with CKD also have many fracture risk factors common to patients without known CKD. Osteoporosis is defined by the National Institutes of Health as "A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Bone strength reflects the integration of two main features: bone quantity and bone quality." Thus, CKD-related fractures can be considered a type of osteoporosis-where the bone quality is additionally impaired above that of age/hormonal-related osteoporosis. Perhaps using the term CKD-induced osteoporosis, similar to steroid-induced osteoporosis, will allow patients with CKD to be studied in trials investigating therapeutic agents. In this series, we will examine how CKD-induced osteoporosis may be diagnosed and treated.

  12. Tweak induces proliferation in renal tubular epithelium: a role in uninephrectomy induced renal hyperplasia

    PubMed Central

    Sanz, Ana B; Sanchez-Niño, Maria Dolores; Izquierdo, Maria Concepcion; Jakubowski, Aniela; Justo, Pilar; Blanco-Colio, Luis M; Ruiz-Ortega, Marta; Egido, Jesús; Ortiz, Alberto

    2009-01-01

    The tumour necrosis factor (TNF) family member TWEAK activates the Fn14 receptor and has pro-apoptotic, proliferative and pro-inflammatory actions that depend on the cell type and the microenvironment. We explored the proliferative actions of TWEAK on cultured tubular cells and in vivo on renal tubules. Additionally, we studied the role of TWEAK in compensatory proliferation following unilateral nephrectomy and in an inflammatory model of acute kidney injury (AKI) induced by a folic acid overdose. TWEAK increased the proliferation, cell number and cyclin D1 expression of cultured tubular cells, in vitro. Exposure to serum increased TWEAK and Fn14 expression and the proliferative response to TWEAK. TWEAK activated the mitogen-activated protein kinases ERK and p38, the phosphatidyl-inositol 3-kinase (PI3K)/Akt pathway and NF-κB. TWEAK-induced proliferation was prevented by inhibitors of these protein kinases and by the NF-κB inhibitor parthenolide. TWEAK-induced tubular cell proliferation as assessed by PCNA and cyclin D1 expression in the kidneys of adult healthy mice in vivo. By contrast, TWEAK knock-out mice displayed lower tubular cell proliferation in the remnant kidney following unilateral nephrectomy, a non-inflammatory model. This is consistent with TWEAK-induced proliferation on cultured tubular cells in the absence of inflammatory cytokines. Consistent with our previously published data, in the presence of inflammatory cytokines TWEAK promoted apoptosis, not proliferation, of cultured tubular cells. In this regard, TWEAK knock-out mice with AKI displayed less tubular apoptosis and proliferation, as well as improved renal function. In conclusion, TWEAK actions in tubular cells are context dependent. In a non-inflammatory milieu TWEAK induces proliferation of tubular epithelium. This may be relevant for compensatory renal hyperplasia following nephrectomy. PMID:19426154

  13. 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.

  14. Effect of Cuscuta chinensis on renal function in ischemia/reperfusion-induced acute renal failure rats.

    PubMed

    Shin, Sun; Lee, Yun Jung; Kim, Eun Ju; Lee, An Sook; Kang, Dae Gill; Lee, Ho Sub

    2011-01-01

    The kidneys play a central role in regulating water, ion composition and excretion of metabolic waste products in the urine. Cuscuta chinensis has been known as an important traditional Oriental medicine for the treatment of liver and kidney disorders. Thus, we studied whether an aqueous extract of Cuscuta chinensis (ACC) seeds has an effect on renal function parameters in ischemia/reperfusion-induced acute renal failure (ARF) rats. Administration of 250 mg/kg/day ACC showed that renal functional parameters including urinary excretion rate, osmolality, Na(+), K(+), Cl(-), creatinine clearance, solute-free water reabsorption were significantly recovered in ischemia/reperfusion-induced ARF. Periodic acid Schiff staining showed that administration of ACC improved tubular damage in ischemia/reperfusion-induced ARF. In immunoblot and immunohistological examinations, ischemia/reperfusion-induced ARF decreased the expressions of water channel AQP 2, 3 and sodium potassium pump Na,K-ATPase in the renal medulla. However, administration of ACC markedly incremented AQP 2, 3 and Na,K-ATPase expressions. Therefore, these data indicate that administration of ACC ameliorates regulation of the urine concentration and renal functions in rats with ischemia/reperfusion-induced ARF.

  15. Rifampicin-Induced Concomitant Renal Injury and Hepatitis

    PubMed Central

    Chogtu, Bharti; Surendra, Vyshak Uddur; Acharya, Preetam Rajgopal; Yerrapragada, Devesh Bhaskar

    2016-01-01

    Adverse drug reactions are not unusual during Anti-Tubercular Therapy (ATT). One of the common complications of anti-tubercular treatment is drug induced hepatitis and renal insufficiency has also been reported. Renal failure and/or hepatitis encountered during treatment of tuberculosis can have varied aetiologies: drug induced, concomitant viral infection, pre-existing co-morbidities or a combination of these. Since, hepatitis and/or renal insufficiency can be life threatening a prompt diagnosis is warranted, where drugs should be kept as one of the important cause. Identifying the drug helps in treating hepatitis and/or renal insufficiency along with helping the physician to change the combination of ATT regimen. Rifampicin is one of the most important first line drugs in the treatment of tuberculosis. Hepatitis, epigastric distress, anaemia, thrombocytopenia, and interstitial nephritis are reported adverse drug reactions to rifampicin. As per literature rifampicin induced renal toxicity is usually seen on rifampicin re-exposure, or rifampicin administration on alternate days, both being present in this case. Here we are reporting a case of ATT induced renal failure with concomitant hepatitis where rifampicin was suspected to be the cause. PMID:27790502

  16. Fetal kidney stem cells ameliorate cisplatin induced acute renal failure and promote renal angiogenesis

    PubMed Central

    Gupta, Ashwani Kumar; Jadhav, Sachin H; Tripathy, Naresh Kumar; Nityanand, Soniya

    2015-01-01

    AIM: To investigate whether fetal kidney stem cells (fKSC) ameliorate cisplatin induced acute renal failure (ARF) in rats and promote renal angiogenesis. METHODS: The fKSC were isolated from rat fetuses of gestation day 16 and expanded in vitro up to 3rd passage. They were characterized for the expression of mesenchymal and renal progenitor markers by flow cytometry and immunocytochemistry, respectively. The in vitro differentiation of fKSC towards epithelial lineage was evaluated by the treatment with specific induction medium and their angiogenic potential by matrigel induced tube formation assay. To study the effect of fKSC in ARF, fKSC labeled with PKH26 were infused in rats with cisplatin induced ARF and, the blood and renal tissues of the rats were collected at different time points. Blood biochemical parameters were studied to evaluate renal function. Renal tissues were evaluated for renal architecture, renal cell proliferation and angiogenesis by immunohistochemistry, renal cell apoptosis by terminal deoxynucleotidyl transferase nick-end labeling assay and early expression of angiogenic molecules viz. vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1α and endothelial nitric oxide synthase (eNOS) by western blot. RESULTS: The fKSC expressed mesenchymal markers viz. CD29, CD44, CD73, CD90 and CD105 as well as renal progenitor markers viz. Wt1, Pax2 and Six2. They exhibited a potential to form CD31 and Von Willebrand factor expressing capillary-like structures and could be differentiated into cytokeratin (CK)18 and CK19 positive epithelial cells. Administration of fKSC in rats with ARF as compared to administration of saline alone, resulted in a significant improvement in renal function and histology on day 3 (2.33 ± 0.33 vs 3.50 ± 0.34, P < 0.05) and on day 7 (0.83 ± 0.16 vs 2.00 ± 0.25, P < 0.05). The infused PKH26 labeled fKSC were observed to engraft in damaged renal tubules and showed increased proliferation and reduced

  17. Cross-Reactive Myelin Antibody Induces Renal Disease

    PubMed Central

    Peterson, Lisa K.; Masaki, Takahisa; Wheelwright, Steven R.; Tsunoda, Ikuo; Fujinami, Robert S.

    2011-01-01

    Experimental autoimmune encephalomyelitis (EAE) is an autoimmune model for multiple sclerosis (MS). Previously, we reported renal immunoglobulin (Ig) deposition in mice with myelin oligodendrocyte glycoprotein (MOG92-106) induced progressive-EAE and naïve mice injected with MOG92-106 hybridoma cells producing antibody that cross-reacts with various autoantigens including double-stranded DNA. To assess whether MOG92-106 antibodies actually induce kidney changes, the extent of renal Ig deposition and changes in glomerular histology and filtration were investigated. Mice with progressive-EAE exhibited Ig deposition, glomerular hypercellularity and proteinuria indicating kidney dysfunction. MOG92-106 hybridoma cell injected mice also had Ig in the kidneys and proteinuria. Therefore, sensitization with MOG92-106 and transfer of MOG92-106 antibodies can induce both central nervous system and renal pathology. The renal involvement reported in MS is believed to occur as a side effect of nephrotoxic drugs or neurogenic bladder. Our results demonstrate that an autoimmune response against myelin could induce pathologic changes in the kidney and may help explain renal changes reported in patients with progressive MS. PMID:18608179

  18. Nephrolithiasis-induced end stage renal disease

    PubMed Central

    Ounissi, M; Gargueh, T; Mahfoudhi, M; Boubaker, K; Hedri, H; Goucha, R; Abderrahim, E; Ben Hamida, F; Ben Abdallah, T; El Younsi, F; Ben Maiz, H; Kheder, A

    2010-01-01

    Introduction: Nephrolithiasis still remains a too frequent and underappreciated cause of end stage renal disease (ESRD). Methods and patients: Of the entire cohort of 7128 consecutive patients who started maintenance dialysis in our nephrology department between January 1992 and December 2006, a total of 45 patients (26 women, 19 men) had renal stone disease as the cause of ESRD. The type of nephrolithiasis was determined in 45 cases and etiology in 42. The treatment and evolution of stone disease and patient’s survival were studied. Results: The overall proportion of nephrolithiasis related ESRD was 0.63%. The mean age was 48.4 years. Infection stones (struvite) accounted for 40%, calcium stones, 26.67% (primary hyperparathyroidism:15.56%; familial hypercalciuria: 4.44%, unknown etiology: 6.66%), primary hyperoxaluria type 1, 17.78% and uric acid lithiasis in 15.56% of cases. The mean delay of the evolution of the stone renal disease to chronic renal failure was 85.8 months. The feminine gender, obesity and elevated alkaline phosphatases >128 IU/L were significantly correlated with fast evolution of ESRD. The median evolution to ESRD was 12 months. The normal body mass index (BMI), medical treatment of stone and primary hyperoxaluria type 1 were correlated with fast evolution to ESRD. All patients were treated by hemodialysis during a mean evolution of 60 months. Sixteen patients died. The patient's survival rate at 1, 3 and 5 years was 97.6, 92.8 and 69% respectively. Hypocalcemia, cardiopathy and normal calcium-phosphate product were significantly correlated with lower survival rate. Conclusion: Severe forms of nephrolithiasis remain an underestimated cause of ESRD. These findings highlight the crucial importance of accurate stone analysis and metabolic evaluation to provide early diagnosis and efficient treatment for conditions leading to ESRD. PMID:21694924

  19. 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.

  20. Renal Denervation Findings on Cardiac and Renal Fibrosis in Rats with Isoproterenol Induced Cardiomyopathy

    PubMed Central

    Liu, Qian; Zhang, Qi; Wang, Kai; Wang, Shengchan; Lu, Dasheng; Li, Zhenzhen; Geng, Jie; Fang, Ping; Wang, Ying; Shan, Qijun

    2015-01-01

    Cardio-renal fibrosis plays key roles in heart failure and chronic kidney disease. We sought to determine the effects of renal denervation (RDN) on cardiac and renal fibrosis in rats with isoproterenol induced cardiomyopathy. Sixty male Sprague Dawley rats were randomly assigned to Control (n = 10) and isoproterenol (ISO)-induced cardiomyopathy group (n = 50). At week 5, 31 survival ISO-induced cardiomyopathy rats were randomized to RDN (n = 15) and Sham group (n = 16). Compared with Control group, ejection fraction was decreased, diastolic interventricular septal thickness and left atrial dimension were increased in ISO-induced cardiomyopathy group at 5 week. After 10 weeks, cardio-renal pathophysiologic results demonstrated that the collagen volume fraction of left atrio-ventricular and kidney tissues reduced significantly in RDN group compared with Sham group. Moreover the pro-fibrosis factors (TGF-β1, MMP2 and Collagen I), inflammatory cytokines (CRP and TNF-α), and collagen synthesis biomarkers (PICP, PINP and PIIINP) concentration significantly decreased in RDN group. Compared with Sham group, RDN group showed that release of noradrenaline and aldosterone were reduced, angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/angiotensin II type-1 receptor (AT1R) axis was downregulated. Meanwhile, angiotensin-converting enzyme 2 (ACE2)/angiotensin-1-7 (Ang-(1-7))/mas receptor (Mas-R) axis was upregulated. RDN inhibits cardio-renal fibrogenesis through multiple pathways, including reducing SNS over-activity, rebalancing RAAS axis. PMID:26689945

  1. Renal Denervation Findings on Cardiac and Renal Fibrosis in Rats with Isoproterenol Induced Cardiomyopathy

    NASA Astrophysics Data System (ADS)

    Liu, Qian; Zhang, Qi; Wang, Kai; Wang, Shengchan; Lu, Dasheng; Li, Zhenzhen; Geng, Jie; Fang, Ping; Wang, Ying; Shan, Qijun

    2015-12-01

    Cardio-renal fibrosis plays key roles in heart failure and chronic kidney disease. We sought to determine the effects of renal denervation (RDN) on cardiac and renal fibrosis in rats with isoproterenol induced cardiomyopathy. Sixty male Sprague Dawley rats were randomly assigned to Control (n = 10) and isoproterenol (ISO)-induced cardiomyopathy group (n = 50). At week 5, 31 survival ISO-induced cardiomyopathy rats were randomized to RDN (n = 15) and Sham group (n = 16). Compared with Control group, ejection fraction was decreased, diastolic interventricular septal thickness and left atrial dimension were increased in ISO-induced cardiomyopathy group at 5 week. After 10 weeks, cardio-renal pathophysiologic results demonstrated that the collagen volume fraction of left atrio-ventricular and kidney tissues reduced significantly in RDN group compared with Sham group. Moreover the pro-fibrosis factors (TGF-β1, MMP2 and Collagen I), inflammatory cytokines (CRP and TNF-α), and collagen synthesis biomarkers (PICP, PINP and PIIINP) concentration significantly decreased in RDN group. Compared with Sham group, RDN group showed that release of noradrenaline and aldosterone were reduced, angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/angiotensin II type-1 receptor (AT1R) axis was downregulated. Meanwhile, angiotensin-converting enzyme 2 (ACE2)/angiotensin-1-7 (Ang-(1-7))/mas receptor (Mas-R) axis was upregulated. RDN inhibits cardio-renal fibrogenesis through multiple pathways, including reducing SNS over-activity, rebalancing RAAS axis.

  2. Combination of tadalafil and diltiazem attenuates renal ischemia reperfusion-induced acute renal failure in rats.

    PubMed

    El-Sisi, Alaa E; Sokar, Samia S; Abu-Risha, Sally E; Ibrahim, Hanaa A

    2016-12-01

    Life threatening conditions characterized by renal ischemia/reperfusion (RIR) such as kidney transplantation, partial nephrectomy, renal artery angioplasty, cardiopulmonary bypass and aortic bypass surgery, continue to be among the most frequent causes of acute renal failure. The current study investigated the possible protective effects of tadalafil alone and in combination with diltiazem in experimentally-induced renal ischemia/reperfusion injury in rats. Possible underlying mechanisms were also investigated such as oxidative stress and inflammation. Rats were divided into sham-operated and I/R-operated groups. Anesthetized rats (urethane 1.3g/kg) were subjected to bilateral ischemia for 30min by occlusion of renal pedicles, then reperfused for 6h. Rats in the vehicle I/R group showed a significant (p˂0.05) increase in kidney malondialdehyde (MDA) content; myeloperoxidase (MPO) activity; TNF-α and IL-1β contents. In addition significant (p˂0.05) increase in intercellular adhesion molecule-1(ICAM-1) content, BUN and creatinine levels, along with significant decrease in kidney superoxide dismutase (SOD) activity. In addition, marked diffuse histopathological damage and severe cytoplasmic staining of caspase-3 were detected. Pretreatment with combination of tadalafil (5mg/kg bdwt) and diltiazem (5mg/kg bdwt) resulted in reversal of the increased biochemical parameters investigated. Also, histopathological examination revealed partial return to normal cellular architecture. In conclusion, pretreatment with tadalafil and diltiazem combination protected against RIR injury.

  3. Heparin-based hydrogels induce human renal tubulogenesis in vitro.

    PubMed

    Weber, Heather M; Tsurkan, Mikhail V; Magno, Valentina; Freudenberg, Uwe; Werner, Carsten

    2017-07-15

    Dialysis or kidney transplantation is the only therapeutic option for end stage renal disease. Accordingly, there is a large unmet clinical need for new causative therapeutic treatments. Obtaining robust models that mimic the complex nature of the human kidney is a critical step in the development of new therapeutic strategies. Here we establish a synthetic in vitro human renal tubulogenesis model based on a tunable glycosaminoglycan-hydrogel platform. In this system, renal tubulogenesis can be modulated by the adjustment of hydrogel mechanics and degradability, growth factor signaling, and the presence of insoluble adhesion cues, potentially providing new insights for regenerative therapy. Different hydrogel properties were systematically investigated for their ability to regulate renal tubulogenesis. Hydrogels based on heparin and matrix metalloproteinase cleavable peptide linker units were found to induce the morphogenesis of single human proximal tubule epithelial cells into physiologically sized tubule structures. The generated tubules display polarization markers, extracellular matrix components, and organic anion transport functions of the in vivo renal proximal tubule and respond to nephrotoxins comparable to the human clinical response. The established hydrogel-based human renal tubulogenesis model is thus considered highly valuable for renal regenerative medicine and personalized nephrotoxicity studies. The only cure for end stage kidney disease is kidney transplantation. Hence, there is a huge need for reliable human kidney models to study renal regeneration and establish alternative treatments. Here we show the development and application of an in vitro human renal tubulogenesis model using heparin-based hydrogels. To the best of our knowledge, this is the first system where human renal tubulogenesis can be monitored from single cells to physiologically sized tubule structures in a tunable hydrogel system. To validate the efficacy of our model as a drug

  4. Renal simplicity denervation reduces blood pressure and renal injuries in an obesity-induced hypertension dog model.

    PubMed

    Zhang, Zhihui; Yang, Kan; Zeng, Lixiong; Wang, Xiaoyan; Jiang, Fenglin; Tu, Shan; Liang, Qishun; Shen, Zhijie

    2016-08-25

    This study aimed to investigate the effects of renal sympathetic denervation (RDN) on blood pressure, renal function, and renal tissue pathological changes in obesity-induced hypertensive dogs. Thirty-two beagle dogs (10-12 months) were randomized to the control (n=10) and model groups (n=22). High-fat diet (HFD) was used to establish the obesity-induced hypertensive model. After 3 months of HFD, 20 animals with successfully induced hypertension were randomized to the RDN (n=10) and sham groups (n=10). Renal artery angiography, body weight, blood pressure, heart rate, and blood and urine biochemistry were determined 1, 3, and 6 months after surgery. Models were sacrificed 6 months after surgery. Pathological changes in the renal artery and renal tissue were assessed. The HFD group had significantly (P<0.05) increased body weight, heart rate, and blood pressure, and higher levels of urine albumin, serum norepinephrine, and angiotensin II compared with controls. After RDN, blood pressure was decreased compared with baseline and the sham group (P<0.05). In the RDN group, examination of the renal artery and renal tissue showed intact intima of renal artery in the surgical area, renal sympathetic nerve degeneration, necrosis, and dissolution, and widened space between nerve fibers. Hypertension-induced renal pathological changes were mild to moderate in the RDN group, but severe in the sham group. The control group had normal glomerular structure. In conclusion, RDN can effectively lower blood pressure in obesity-induced hypertensive dogs, as well as hypertension-induced renal pathological changes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  5. Drug-induced impairment of renal function

    PubMed Central

    Pazhayattil, George Sunny; Shirali, Anushree C

    2014-01-01

    Pharmaceutical agents provide diagnostic and therapeutic utility that are central to patient care. However, all agents also carry adverse drug effect profiles. While most of these are clinically insignificant, some drugs may cause unacceptable toxicity that impacts negatively on patient morbidity and mortality. Recognizing adverse effects is important for administering appropriate drug doses, instituting preventive strategies, and withdrawing the offending agent due to toxicity. In the present article, we will review those drugs that are associated with impaired renal function. By focusing on pharmaceutical agents that are currently in clinical practice, we will provide an overview of nephrotoxic drugs that a treating physician is most likely to encounter. In doing so, we will summarize risk factors for nephrotoxicity, describe clinical manifestations, and address preventive and treatment strategies. PMID:25540591

  6. Renal

    MedlinePlus

    ... term "renal" refers to the kidney. For example, renal failure means kidney failure. Related topics: Kidney disease Kidney disease - diet Kidney failure Kidney function tests Renal scan Kidney transplant

  7. 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.

  8. Malaria-induced renal damage: facts and myths.

    PubMed

    Ehrich, Jochen H H; Eke, Felicia U

    2007-05-01

    Malaria infections repeatedly have been reported to induce nephrotic syndrome and acute renal failure. Questions have been raised whether the association of a nephrotic syndrome with quartan malaria was only coincidental, and whether the acute renal failure was a specific or unspecific consequence of Plasmodium falciparum infection. This review attempts to answer questions about "chronic quartan malaria nephropathy" and "acute falciparum malaria nephropathy". The literature review was performed on all publications on kidney involvement in human and experimental malarial infections accessible in PubMed or available at the library of the London School of Hygiene and Tropical Medicine. The association of a nephrotic syndrome with quartan malaria was mostly described before 1975 in children and rarely in adult patients living in areas endemic for Plasmodium malariae. The pooled data on malaria-induced acute renal failure included children and adults acquiring falciparum malaria in endemic areas either as natives or as travellers from non-tropical countries. Non-immunes (not living in endemic areas) had a higher risk of developing acute renal failure than semi-immunes (living in endemic areas). Children with cerebral malaria had a higher rate and more severe course of acute renal failure than children with mild malaria. Today, there is no evidence of a dominant role of steroid-resistant and chronic "malarial glomerulopathies" in children with a nephrotic syndrome in Africa. Acute renal failure was a frequent and serious complication of falciparum malaria in non-immune adults. However, recently it has been reported more often in semi-immune African children with associated morbidity and mortality.

  9. Diphenylamine-induced renal lesions in the chicken.

    PubMed

    Sorrentino, F; Fella, A; Pota, A

    1978-01-01

    Chronic intoxication with diphenylamine (DPA), which causes a cystic kidney disease in the rat and the guinea-pig, caused degeneration of the renal tubular epithelium in the chicken. This was similar to but much more serious than that preceding the formation of cysts in the rodents, but did not actually result in cyst formation, probably because of the high mortality rate observed in the birds even at this early stage. In the chicken until now it had been possible to obtain a pattern of renal cysts only with polychlorinated biphenyls (PCB) which also induce the "chick oedema" syndrome. The renal lesions due to DPA in the chicken were similar to those produced by PCB, but were not accompanied by oedema, which suggests that "chick oedema" caused by PCB is not due to renal insufficiency. The differences in the renal lesions noted in the various animal species give credit to the hypothesis that DPA may have two effects on the tubular epitelium, one stimulating cell proliferation and one leading to degeneration. Cysts may be formed only in those species in which there is cell proliferation.

  10. Contribution of renal purinergic receptors to renal vasoconstriction in angiotensin II-induced hypertensive rats.

    PubMed

    Franco, Martha; Bautista, Rocio; Tapia, Edilia; Soto, Virgilia; Santamaría, José; Osorio, Horacio; Pacheco, Ursino; Sánchez-Lozada, L Gabriela; Kobori, Hiroyuki; Navar, L Gabriel

    2011-06-01

    To investigate the participation of purinergic P2 receptors in the regulation of renal function in ANG II-dependent hypertension, renal and glomerular hemodynamics were evaluated in chronic ANG II-infused (14 days) and Sham rats during acute blockade of P2 receptors with PPADS. In addition, P2X1 and P2Y1 protein and mRNA expression were compared in ANG II-infused and Sham rats. Chronic ANG II-infused rats exhibited increased afferent and efferent arteriolar resistances and reductions in glomerular blood flow, glomerular filtration rate (GFR), single-nephron GFR (SNGFR), and glomerular ultrafiltration coefficient. PPADS restored afferent and efferent resistances as well as glomerular blood flow and SNGFR, but did not ameliorate the elevated arterial blood pressure. In Sham rats, PPADS increased afferent and efferent arteriolar resistances and reduced GFR and SNGFR. Since purinergic blockade may influence nitric oxide (NO) release, we evaluated the role of NO in the response to PPADS. Acute blockade with N(ω)-nitro-l-arginine methyl ester (l-NAME) reversed the vasodilatory effects of PPADS and reduced urinary nitrate excretion (NO(2)(-)/NO(3)(-)) in ANG II-infused rats, indicating a NO-mediated vasodilation during PPADS treatment. In Sham rats, PPADS induced renal vasoconstriction which was not modified by l-NAME, suggesting blockade of a P2X receptor subtype linked to the NO pathway; the response was similar to that obtained with l-NAME alone. P2X1 receptor expression in the renal cortex was increased by chronic ANG II infusion, but there were no changes in P2Y1 receptor abundance. These findings indicate that there is an enhanced P2 receptor-mediated vasoconstriction of afferent and efferent arterioles in chronic ANG II-infused rats, which contributes to the increased renal vascular resistance observed in ANG II-dependent hypertension.

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. Tubular cell apoptosis and cidofovir-induced acute renal failure.

    PubMed

    Ortiz, Alberto; Justo, Pilar; Sanz, Ana; Melero, Rosa; Caramelo, Carlos; Guerrero, Manuel Fernández; Strutz, Frank; Müller, Gerhard; Barat, Antonio; Egido, Jesus

    2005-01-01

    Cidofovir is an antiviral drug with activity against a wide array of DNA viruses including poxvirus. The therapeutic use of cidofovir is marred by a dose-limiting side effect, nephrotoxicity, leading to proximal tubular cell injury and acute renal failure. Treatment with cidofovir requires the routine use of prophylactic measures. A correct knowledge of the cellular and molecular mechanisms of cidofovir toxicity may lead to the development of alternative prophylactic strategies. We recently cared for a patient with irreversible acute renal failure due to cidofovir. Renal biopsy showed tubular cell apoptosis. Cidofovir induced apoptosis in primary cultures of human proximal tubular cells in a temporal (peak apoptosis at 7 days) and concentration (10-40 microg/ml) pattern consistent with that of clinical toxicity. Apoptosis was identified by the presence of hypodiploid cells, by the exposure of annexin V binding sites and by morphological features and was associated with the appearance of active caspase-3 fragments. Cell death was specific as it was also present in a human proximal tubular epithelial cell line (HK-2), but not in a human kidney fibroblast cell line, and was prevented by probenecid. An inhibitor of caspase-3 (DEVD) prevented cidofovir apoptosis. The survival factors present in serum, insulin-like growth factor-1 and hepatocyte growth factor, were also protective. The present data suggest that apoptosis induction is a mechanism contributing to cidofovir nephrotoxicity. The prophylactic administration of factors with survival activity for tubular epithelium should be further explored in cidofovir renal injury.

  16. Leukocyte involvement in renal reperfusion-induced liver damage.

    PubMed

    Khastar, Hossein; Kadkhodaee, Mehri; Sadeghipour, Hamid Reza; Seifi, Behjat; Hadjati, Jamshid; Delavari, Fatemeh; Soleimani, Manoocher

    2011-01-01

    Renal ischemia-reperfusion (IR) induces organ damage in remote organs. The aim of this study was to assess the role of leukocytes in the induction of liver damage after renal IR injury. Inbred mice were subjected to either sham operation or bilateral renal IR injury (60 min ischemia followed by 3 h reperfusion). Mice were then anesthetized for collection of leukocytes by heart puncture. Isolated leukocytes were transferred to two other groups: intact recipient mice that received leukocytes from IR mice and intact recipient mice that received leukocytes from sham-operated control mice. After 24 h, recipient mice were anesthetized and samples were collected. Alanine aminotransferase, aspartate aminotransferase, and hepatic malondialdehyde increased significantly, and hepatic glutathione decreased significantly in intact recipient mice that received leukocytes from IR mice in comparison with intact recipient mice that received leukocytes from sham-operated control mice. Loss of normal liver architecture, cytoplasmic vacuolization, and focal infiltration of leukocytes were seen. These results suggest that leukocytes are one of the possible factors that contribute to liver damage after renal IR injury and this damage is partly due to the induction of oxidative stress.

  17. Renal tissue damage induced by focused shock waves

    NASA Astrophysics Data System (ADS)

    Ioritani, N.; Kuwahara, M.; Kambe, K.; Taguchi, K.; Saitoh, T.; Shirai, S.; Orikasa, S.; Takayama, K.; Lush, P. A.

    1990-07-01

    Biological evidence of renal arterial wall damage induced by the microjet due to shock wave-cavitation bubble interaction was demonstrated in living dog kidneys. We also intended to clarify the mechanism of renal tissue damage and the effects of different conditions of shock wave exposure (peak pressure of focused area, number of shots, exposure rate) on the renal tissue damage in comparison to stone disintegration. Disruption of arterial wall was the most remarkable histological change in the focused area of the kidneys. This lesion appeared as if the wall had been punctured by a needle. Large hematoma formation in the renal parenchym, and interstitial hemorrhage seemed to be the results of the arterial lesion. This arterial disorder also led to ischemic necrosis of the tubules surrounding the hematoma. Micro-angiographic examination of extracted kidneys also proved such arterial puncture lesions and ischemic lesions. The number of shots required for model stone disintegration was not inversely proportional to peak pressure. It decreased markedly when peak pressure was above 700 bar. Similarly thenumber of shots for hematoma formation was not inversely proportional to peak pressure, however, this decreased markedly above 500 bar. These results suggested that a hematoma could be formed under a lower peak pressure than that required for stone disintegration.

  18. Review of vancomycin-induced renal toxicity: an update

    PubMed Central

    Bamgbola, Oluwatoyin

    2016-01-01

    In recent times the use of larger doses of vancomycin aimed at curbing the increasing incidence of resistant strains of Staphylococcus aureus has led to a wider report of acute kidney injury (AKI). Apart from biological plausibility, causality is implied by the predictive association of AKI with larger doses, longer duration, and graded plasma concentrations of vancomycin. AKI is more likely to occur with the concurrent use of nephrotoxic agents, and in critically ill patients who are susceptible to poor renal perfusion. Although most vancomycin-induced AKI cases are mild and therefore reversible, their occurrence may be associated with greater incidence of end-stage kidney disease and higher mortality rate. The strategy for its prevention includes adequate renal perfusion and therapeutic drug monitoring in high-risk individuals. In the near future, there is feasibility of renoprotective use of antioxidative substances in the delivery of vancomycin. PMID:27293542

  19. 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

  20. 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

  1. MUTATIONS IN THE VHL GENE FRIOM POTASSIUM BROMATE-INDUCED RAT CLEAR CELL RENAL TUMORS

    EPA Science Inventory

    Potassium bromate (KBrO3) is a rat renal carcinogen and a major drinking water disinfection by-product in water disinfected with ozone. Clear cell renal tumors, the most common form of human renal epithelial neoplasm, are rare in animals but are inducible by KBrO3 in F344 rats. ...

  2. MUTATIONS IN THE VHL GENE FRIOM POTASSIUM BROMATE-INDUCED RAT CLEAR CELL RENAL TUMORS

    EPA Science Inventory

    Potassium bromate (KBrO3) is a rat renal carcinogen and a major drinking water disinfection by-product in water disinfected with ozone. Clear cell renal tumors, the most common form of human renal epithelial neoplasm, are rare in animals but are inducible by KBrO3 in F344 rats. ...

  3. Lansoprazole-induced acute allergic interstitial nephritis in a renal transplant recipient: a case report.

    PubMed

    Yildirim, Tolga; Yilmaz, Rahmi; Baydar, Dilek Ertoy; Kutlugun, Aysun Aybal; Aki, Tuncay; Turgan, Cetin

    2012-12-01

    Drug-induced interstitial nephritis is one of the causes of graft dysfunction in renal transplant recipients. Although commonly implicated as a cause of drug-induced interstitial nephritis in the general population, proton pump inhibitor-induced interstitial nephritis has not yet been reported in renal transplant recipients. Trimethoprim-sulfamethoxazole is responsible for most cases of interstitial nephritis in this population. Here, we describe the first case of proton pump inhibitor-related interstitial nephritis in a renal transplant recipient.

  4. AUTOLOGOUS IMMUNE COMPLEX NEPHRITIS INDUCED WITH RENAL TUBULAR ANTIGEN

    PubMed Central

    Glassock, Richard J.; Edgington, Thomas S.; Watson, J. Ian; Dixon, Frank J.

    1968-01-01

    The pathogenetic mechanism involved in a form of experimental allergic glomerulonephritis induced by immunization of rats with renal tubular antigen has been investigated. A single immunization with less than a milligram of a crude renal tubular preparation, probably containing less than 25 µg of the specific nephritogenic antigen, is effective in the induction of this form of chronic membranous glomerulonephritis. In the nephritic kidney autologous nephritogenic tubular antigen is found in the glomerular deposits along with γ-globulin and complement. When large amounts of antigen are injected during induction of the disease the exogenous immunizing antigen can also be detected in the glomerular deposits. It appears that this disease results from the formation of circulating antibodies capable of reacting with autologous renal tubular antigen(s) and the deposition of these antibodies and antigen(s) plus complement apparently as immune complexes in the glomeruli. This pathogenetic system has been termed an autologous immune complex disease and the resultant glomerulonephritis has been similarly designated. PMID:4169966

  5. 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.

  6. Normalizing renal reducing ability prevents adriamycin-induced proteinuria

    SciTech Connect

    Oteki, Takaaki; Nagase, Sohji . E-mail: sohji-n@md.tsukuba.ac.jp; Yokoyama, Hidekatsu; Ohya, Hiroaki; Akatsuka, Takao; Tada, Mika; Ueda, Atsushi; Hirayama, Aki; Koyama, Akio

    2005-11-11

    Reactive oxygen species play an important role in adriamycin (ADR) nephropathy. We showed by in vivo electron paramagnetic resonance (EPR) that renal reducing ability (RRA) declined on the 7th day after ADR administration. Proteinuria appeared after the decline in RRA. The aim of this study was to prove by in vivo EPR whether the decline in RRA is altered by scavengers such as dimethyl sulfoxide (DMSO) and dimethylthiourea (DMTU) and that it is this change which is responsible for the proteinuria in ADR nephropathy. By showing that DMSO and DMTU ameliorate the RRA, we demonstrate that the decline in RRA is related to ADR-induced proteinuria.

  7. Efferent pathways in sodium overload-induced renal vasodilation in rats.

    PubMed

    Amaral, Nathalia O; de Oliveira, Thiago S; Naves, Lara M; Filgueira, Fernando P; Ferreira-Neto, Marcos L; Schoorlemmer, Gerard H M; de Castro, Carlos H; Freiria-Oliveira, André H; Xavier, Carlos H; Colugnati, Diego B; Rosa, Daniel A; Blanch, Graziela T; Borges, Clayton L; Soares, Célia M A; Reis, Angela A S; Cravo, Sergio L; Pedrino, Gustavo R

    2014-01-01

    Hypernatremia stimulates the secretion of oxytocin (OT), but the physiological role of OT remains unclear. The present study sought to determine the involvement of OT and renal nerves in the renal responses to an intravenous infusion of hypertonic saline. Male Wistar rats (280-350 g) were anesthetized with sodium thiopental (40 mg. kg(-1), i.v.). A bladder cannula was implanted for collection of urine. Animals were also instrumented for measurement of mean arterial pressure (MAP) and renal blood flow (RBF). Renal vascular conductance (RVC) was calculated as the ratio of RBF by MAP. In anesthetized rats (n = 6), OT infusion (0.03 µg • kg(-1), i.v.) induced renal vasodilation. Consistent with this result, ex vivo experiments demonstrated that OT caused renal artery relaxation. Blockade of OT receptors (OXTR) reduced these responses to OT, indicating a direct effect of this peptide on OXTR on this artery. Hypertonic saline (3 M NaCl, 1.8 ml • kg(-1) b.wt., i.v.) was infused over 60 s. In sham rats (n = 6), hypertonic saline induced renal vasodilation. The OXTR antagonist (AT; atosiban, 40 µg • kg(-1) • h(-1), i.v.; n = 7) and renal denervation (RX) reduced the renal vasodilation induced by hypernatremia. The combination of atosiban and renal denervation (RX+AT; n = 7) completely abolished the renal vasodilation induced by sodium overload. Intact rats excreted 51% of the injected sodium within 90 min. Natriuresis was slightly blunted by atosiban and renal denervation (42% and 39% of load, respectively), whereas atosiban with renal denervation reduced sodium excretion to 16% of the load. These results suggest that OT and renal nerves are involved in renal vasodilation and natriuresis induced by acute plasma hypernatremia.

  8. 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.

  9. Renal hemodynamics in radiocontrast medium-induced renal dysfunction: A role for dopamine-1 receptors.

    PubMed

    Bakris, G L; Lass, N A; Glock, D

    1999-07-01

    Radiocontrast medium (RCM) administration induces a transient increase in renal blood flow (RBF), followed by a prolonged vasoconstriction. This vasoconstrictor phase in RBF is accompanied by a decrement in glomerular filtration rate (GFR). Nonselective dopamine (DA) receptor stimulation is known to increase RBF and GFR. Clinical studies, however, fail to demonstrate a renoprotective effect of DA following RCM administration. This lack of renoprotection may relate to nonspecific adrenergic stimulation by DA. The effect of select DA-1 receptor stimulation on renal hemodynamics following RCM administration has not been evaluated. This study tests the hypothesis that selective DA-1 receptor stimulation blunts the declines in RBF and GFR that follow RCM injections, independent of changes in baseline RBF and GFR. Experiments were performed in six anesthetized, volume-depleted dogs. RBF was measured by an electromagnetic flow probe around the renal artery and GFR by inulin clearance. After a 60-minute equilibration period, baseline values of RBF, GFR, and arterial pressure were determined. Two separate intrarenal bolus injections of the ionic RCM Renograffin were then given in the presence of saline infusion. After a 60-minute recovery period, intra-arterial infusions of either the selective DA-1 receptor agonist fenoldopam or the selective DA-1 receptor antagonist Schering 23390 were started in random order, and experiments were repeated. Neither agent significantly altered baseline values of arterial pressure, RBF, or GFR rate. Fenoldopam prevented reductions in GFR (-17 +/- 2 Deltaml/min, control vs. 2 +/- 1 Deltaml/min, fenoldopam, P < 0.001). Conversely, GFR was further reduced in the presence of Schering 23390 (-15 +/- 2 Deltaml/min, control vs. -23 +/- 1 Deltaml/min, Schering 23390, P < 0.05). Similarly, the maximal reduction in RBF was blunted with fenoldopam (-71 +/- 12 Deltaml/min, control vs. -3 +/- 2 Deltaml/min, fenoldopam, P < 0. 01), whereas Schering 23390

  10. Mechanisms of portal hypertension-induced alterations in renal hemodynamics, renal water excretion, and renin secretion.

    PubMed Central

    Anderson, R J; Cronin, R E; McDonald, K M; Schrier, R W

    1976-01-01

    Clinical states with portal venous hypertension are frequently associated with impairment in renal hemodynamics and water excretion, as well as increased renin secretion. In the present investigation, portal venous pressure (PVP) was increased in anesthetized dogs undergoing a water diuresis. Renal arterial pressure was maintained constant in all studies. As PVP was increased from 6 to 20 mm Hg, decreases in cardiac output (2.5-2.0 liter/min, P less than 0.05) and mean arterial pressure (140-131 mm Hg, P less than 0.05) were observed. Increases in PVP were also associated with decreases in glomerular filtration rate (GFR, 40-31 ml/min, P less than 0.001), renal blood flow (RBF, 276-193 ml/min, P less than 0.001), and increases in renin secretion (232-939 U/min, P less than 0.025) in innervated kidneys. No significant change in either GFR or RBF and a decrease in renin secretion occurred with increases in PVP in denervated kidneys. To dissociate the changes in cardiac output and mean arterial pressure induced by increase PVP from the observed decreases in GFR and RBF, studies were performed on animals undergoing constriction of the thoracic inferior vena cava. In these studies, similar decreases in cardiac output and mean arterial pressure were not associated with significant changes in GFR or RBF. Increases in PVP also were associated with an antidiuresis as urine osmolality increased from 101 to 446 mosmol/kg H2O (P less than 0.001). This antidiuresis was significantly blunted but not abolished by acute hypophysectomy. In hypophysectomized animals, changes in free water clearance and urine flow were linearly correlated as PVP was increased. These studies indicate that increases in PVP result in decreases in GFR and RBF and increases in renin secretion mediated by increased renal adrenergic tone. Increased PVP is also associated with antidiuresis; this antidiuresis is mediated both by vasopressin release and by diminished tubular fluid delivery to the distal

  11. Dietary zinc modifies diabetic-induced renal pathology in rats.

    PubMed

    Elsaed, Wael M; Mohamed, Hazem Abdelhamid

    2017-11-01

    This study was conducted to investigate how far dietary zinc (Zn) modifies the histomorphological alterations induced by diabetes in rat kidneys. The animals were divided into negative control group (10 rats). Diabetes was induced in thirty animals by streptozotocin. After confirming diabetes, the animals were divided into three groups (n = 10). Group II served as the positive control group (fed on standard diet), group III was fed on Zn deficient diet, and group IV was fed on Zn supplemented diet. Caspase-3 immune staining was used to estimate the caspase activity. Stereological procedures were used to measure the quantity of the immune stain and the surface area of the Bowman's space. The renal cortices of group II rats revealed apparent widening of Bowman's spaces with few apoptotic figures. The filtration barrier showed thickening of the basement membrane. The proximal convoluted tubules showed patchy loss of the apical microvilli with swollen mitochondria. The distal convoluted tubules revealed area of irregular basal enfolding. The picture was aggravated by Zn deficiency in group III besides areas of cortical interstitial fibrosis. The histopathological alterations were minimal in the cortices of group IV. A significant increase of the Bowman's space surface area in group II and IV while decrease in group III compared with group I. The expression of Caspase-3 density was significantly increased in group II and III compared with group I while in group IV was non significant. In conclusion, dietary Zn modulated renal cortical changes caused by diabetes in rats.

  12. Two cases of cisplatin-induced permanent renal failure following neoadjuvant chemotherapy for esophageal cancer

    PubMed Central

    Sasaki, Tomohiko; Motoyama, Satoru; Komatsuda, Atsushi; Shibata, Hiroyuki; Sato, Yusuke; Yoshino, Kei; Wakita, Akiyuki; Saito, Hajime; Anbai, Akira; Jin, Mario; Minamiya, Yoshihiro

    2016-01-01

    Introduction We experienced two esophageal cancer patients who developed severe acute renal failure after neoadjuvant chemotherapy with cisplatin and 5-fluorourasil. Presentation of case After administration of cisplatin, their serum creatinine increased gradually until they required hemodialysis and their renal failure was permanent. In both cases, renal biopsy examination indicated partial recovery of the proximal tubule, but renal function did not recover. After these events, one patient underwent definitive radiotherapy and the other underwent esophagectomy for their esophageal cancers, while continuing dialysis. Both patients are alive without cancer recurrence. Discussion In these two cases of cisplatin-induced renal failure, renal biopsy examination showed only slight disorder of proximal tubules and tendency to recover. Conclusion Although cisplatin-related nephrotoxicity is a well-recognized complication, there have been few reports of renal failure requiring hemodialysis in cancer patients. In this report, we present their clinical courses and the pathological findings of cisplatin-related renal failure. PMID:26851395

  13. Angiotensin II induces apoptosis in renal proximal tubular cells.

    PubMed

    Bhaskaran, Madhu; Reddy, Krishna; Radhakrishanan, Neetu; Franki, Nicholas; Ding, Guohua; Singhal, Pravin C

    2003-05-01

    ANG II has been demonstrated to play a role in the progression of tubulointerstial injury. We studied the direct effect of ANG II on apoptosis of cultured rat renal proximal tubular epithelial cells (RPTECs). ANG II promoted RPTEC apoptosis in a dose- and time-dependent manner. This effect of ANG II was attenuated by anti-transforming growth factor (TGF)-beta antibody. Moreover, TGF-beta triggered RPTEC apoptosis in a dose-dependent manner. ANG II also enhanced RPTEC expression of Fas and Fas ligand (FasL); furthermore, anti-FasL antibody attenuated ANG II-induced RPTEC apoptosis. In addition, ANG II increased RPTEC expression of Bax, a cell death protein. Both ANG II type 1 (AT(1)) and type 2 (AT(2)) receptor blockers inhibited ANG II-induced RPTEC apoptosis. SB-202190, an inhibitor of p38 MAPK phosphorylation, and caspase-3 inhibitor also attenuated ANG II-induced RPTEC apoptosis. ANG II enhanced RPTEC heme oxygenase (HO)-1 expression. Interestingly, pretreatment with hemin as well as curcumin (inducers of HO-1) inhibited the ANG II-induced tubular cell apoptosis; conversely, pretreatment with zinc protoporphyrin, an inhibitor of HO-1 expression, promoted the effect of ANG II. These results suggest that ANG II-induced apoptosis is mediated via both AT(1) and AT(2) receptors through the generation of TGF-beta, followed by the transcription of cell death genes such as Fas, FasL, and Bax. Modulation of tubular cell expression of HO-1 has an inverse relationship with the ANG II-induced tubular cell apoptosis.

  14. Renal 20-HETE inhibition attenuates changes in renal hemodynamics induced by L-NAME treatment in pregnant rats.

    PubMed

    Huang, Hui; Zhou, Yiqiang; Raju, Venugopal T; Du, Juan; Chang, Hsin-Hsin; Wang, Cong-Yi; Brands, Michael W; Falck, John R; Wang, Mong-Heng

    2005-11-01

    We previously reported that inhibition of nitric oxide (NO) synthesis by N-nitro-L-arginine methyl ester (L-NAME) during late pregnancy leads to increased production of renal vascular 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P-450 (CYP) 4A-derived vasoconstrictor, in pregnant rats. However, the effect of upregulation of vascular 20-HETE production on renal function after NO inhibition is not known. To test the hypothesis that increased gestational vascular 20-HETE synthesis after NO inhibition is involved in mediating blood pressure and renal functional changes, we first determined the IC(50) value of the effect of nitroprusside (SNP), a NO donor, on renal 20-HETE production in cortical microsomes. We then divided pregnant rats and age-matched virgin rats into a vehicle control group, an L-NAME treatment group (0.25 mg/ml in drinking water), and a group treated with L-NAME plus N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; CYP4A-selective inhibitor, 10 mg.kg(-1).day(-1) iv). After 4 days of treatment, we measured blood pressure, renal blood flow (RBF), renal vascular resistance (RVR), and glomerular filtration rate (GFR) in each group. The addition of SNP (IC(50) = 22 microM) decreased renal cortical 20-HETE production. In pregnant rats, L-NAME treatment led to significantly higher mean arterial pressure (MAP) and RVR, and lower RBF and GFR. Combined treatment with DDMS and L-NAME significantly attenuated the increases in MAP and RVR and the decrease in GFR, but not the reduction in RBF induced by L-NAME treatment. L-NAME and L-NAME plus DDMS had no significant impact on renal hemodynamics in virgin rats. In addition, chronic treatment with DDMS selectively inhibited cortical 20-HETE production without a significant effect on CYP4A expression in L-NAME-treated pregnant rats. In conclusion, NO effectively inhibits renal cortical microsomal 20-HETE production in female rats. In pregnant rats, the augmentation of renal 20-HETE production after

  15. Vitamin D3 pretreatment alleviates renal oxidative stress in lipopolysaccharide-induced acute kidney injury.

    PubMed

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

    2015-08-01

    Increasing evidence demonstrates that reactive oxygen species plays important roles in sepsis-induced acute kidney injury. This study investigated the effects of VitD3 pretreatment on renal oxidative stress in sepsis-induced acute kidney injury. Mice were intraperitoneally injected with lipopolysaccharide (LPS, 2.0mg/kg) to establish an animal model of sepsis-induced acute kidney injury. In VitD3+LPS group, mice were orally pretreated with three doses of VitD3 (25 μg/kg) at 1, 24 and 48 h before LPS injection. As expected, oral pretreatment with three daily recommended doses of VitD3 markedly elevated serum 25(OH)D concentration and efficiently activated renal VDR signaling. Interestingly, LPS-induced renal GSH depletion and lipid peroxidation were markedly alleviated in VitD3-pretreated mice. LPS-induced serum and renal nitric oxide (NO) production was obviously suppressed by VitD3 pretreatment. In addition, LPS-induced renal protein nitration, as determined by 3-nitrotyrosine residue, was obviously attenuated by VitD3 pretreatment. Further analysis showed that LPS-induced up-regulation of renal inducible nitric oxide synthase (inos) was repressed in VitD3-pretreated mice. LPS-induced up-regulation of renal p47phox and gp91phox, two NADPH oxidase subunits, were normalized by VitD3 pretreatment. In addition, LPS-induced down-regulation of renal superoxide dismutase (sod) 1 and sod2, two antioxidant enzyme genes, was reversed in VitD3-pretreated mice. Finally, LPS-induced tubular epithelial cell apoptosis, as determined by TUNEL, was alleviated by VitD3 pretreatment. Taken together, these results suggest that VitD3 pretreatment alleviates LPS-induced renal oxidative stress through regulating oxidant and antioxidant enzyme genes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. D-ribose ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in mice.

    PubMed

    Ueki, Masaaki; Ueno, Masaki; Morishita, Jun; Maekawa, Nobuhiro

    2013-01-01

    Cisplatin is one of the most potent chemotherapeutic anticancer drugs, but it can produce side effects such as nephrotoxicity. Inflammatory cytokines, chemokines and adhesion molecules have important roles in the pathogenesis of cisplatin-induced nephrotoxicity. D-Ribose is a naturally occurring five-carbon monosaccharide that is found in all living cells, and has anti-inflammatory effects in renal ischemia/reperfusion injury. The purpose of this study was to determine the protective effects of D-ribose on cisplatin-induced nephrotoxicity. Forty-eight mice were randomly divided into four groups: control, cisplatin, cisplatin + ribose, and ribose. Mice were given cisplatin (20 mg/kg body weight, intraperitoneally) with or without D-ribose (400 mg/kg body weight, intraperitoneally, immediately after cisplatin injection). At 72 h after cisplatin injection, we measured serum and renal tumor necrosis factor (TNF)-α and renal monocyte chemoattractant protein (MCP)-1 concentrations by enzyme-linked immunosorbent assay; renal expression of intercellular adhesion molecule (ICAM)-1 mRNA by real-time polymerase chain reaction; serum blood urea nitrogen and creatinine; and histological changes. Cisplatin increased serum and renal TNF-α concentrations, renal MCP-1 concentration, and renal ICAM-1 mRNA expression. Treatment with D-ribose attenuated the increase in serum and renal TNF-α concentrations, renal MCP-1 concentration, and renal ICAM-1 mRNA expression. Consequently, cisplatin-induced renal dysfunction and renal tubular necrosis were attenuated by D-ribose treatment. This is believed to be the first time that protective effects of D-ribose on cisplatin-induced nephrotoxicity via inhibition of inflammatory reactions have been investigated. Thus, D-ribose may become a new therapeutic candidate for the treatment of cisplatin-induced nephrotoxicity.

  17. Isoniazid-induced seizures with secondary rhabdomyolysis and associated acute renal failure in a dog.

    PubMed

    Haburjak, J J; Spangler, W L

    2002-04-01

    Isoniazid-induced seizures resulted in rhabdomyolysis and associated acute renal tubular necrosis in a dog. Rhabdomyolysis and myoglobinuric renal failure, although recognised in the dog, are reported infrequently as a consequence of seizures. The clinical presentation of isoniazid toxicity in a dog is described.

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

    PubMed

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

    2015-12-22

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

  19. The metabolic syndrome induces early changes in the swine renal medullary mitochondria.

    PubMed

    Eirin, Alfonso; Woollard, John R; Ferguson, Christopher M; Jordan, Kyra L; Tang, Hui; Textor, Stephen C; Lerman, Amir; Lerman, Lilach O

    2017-03-11

    The metabolic syndrome (MetS) is associated with nutrient surplus and kidney hyperfiltration, accelerating chronic renal failure. Mitochondria can be overwhelmed by substrate excess, leading to inefficient energy production and thereby tissue hypoxia. Mitochondrial dysfunction is emerging as an important determinant of renal damage, but whether it contributes to MetS-induced renal injury remains unknown. We hypothesized that early MetS induces kidney mitochondrial abnormalities and dysfunction, which would be notable in the vulnerable renal medulla. Pigs were studied after 16 weeks of diet-induced MetS, MetS treated for the last 4 weeks with the mitochondria-targeted peptide elamipretide (0.1 mg/kg SC q.d), and Lean controls (n = 7 each). Single-kidney renal blood flow, glomerular filtration rate, and oxygenation were measured in-vivo, whereas cortical and medullary mitochondrial structure and function and renal injurious pathways were studied ex-vivo. Blood pressure was slightly elevated in MetS pigs, and their renal blood flow and glomerular filtration rate were elevated. Blood oxygen level-dependent magnetic resonance imaging demonstrated that this was associated with medullary hypoxia, whereas cortical oxygenation remained intact. MetS decreased renal content of the inner mitochondrial membrane cardiolipin, particularly the tetra-linoleoyl (C18:2) cardiolipin species, and altered mitochondrial morphology and function, particularly in the medullary thick ascending limb. MetS also increased renal cytochrome-c-induced apoptosis, oxidative stress, and tubular injury. Chronic mitoprotection restored mitochondrial structure, ATP synthesis, and antioxidant defenses and decreased mitochondrial oxidative stress, medullary hypoxia, and renal injury. These findings implicate medullary mitochondrial damage in renal injury in experimental MetS, and position the mitochondria as a therapeutic target.

  20. [Fluoroquinolone induced acute renal failure. General review about a case report with crystalluria due to ciprofloxacin].

    PubMed

    Montagnac, Richard; Briat, Claude; Schillinger, Francis; Sartelet, Hervé; Birembaut, Philippe; Daudon, Michel

    2005-03-01

    A 58 year-old woman developed an acute renal failure very quickly after ingestion of two 500 mg tablets of ciprofloxacin, without any other identifiable risk factor. Renal biopsy was performed. No sign of acute interstitial nephritis was observed but tubular lesions were found, accompanied by deposits of a brown-yellowish substance identified by infrared microscopy as a ciprofloxacin salt. The outcome was favourable. This observation gives the opportunity to remind the different forms of quinolone-induced renal injury and to discuss the possible ways for preventing renal side-effects related to the quinolone use.

  1. Plasma renin activity during the development of paracetamol (acetaminophen) induced acute renal failure in man.

    PubMed

    Wilkinson, R; James, O F; Roberts, S H; Morley, A R; Robson, V

    1979-04-01

    Plasma renin activity has been measured daily in 36 patients suffering from self poisoning with acetaminophen. In 3 developing porto-systemic encephalopathy terminal renal failure developed with high plasma renin activity. In 2 who developed acute renal failure without porto-systemic encephalopathy, plasma renin activity was noted to rise before serum creatinine and to return to initial levels after 3 or 4 days while renal failure persisted. Six other patients with similar hepatic damage showed comparable rises in renin without developing renal failure. Our findings are consistent with but do not establish a pathogenetic role for renin in acetaminophen-induced acute renal failure. It is suggested that other factors may act with renin to bring about renal failure.

  2. [Comparison of pharmacological renal preconditioning with dalargin and lithium ions in the model of gentamycin-induced acute renal failure].

    PubMed

    Cherpakov, R A; Grebenchikov, O A; Plotnikov, E Ju; Likhvantsev, V V

    2015-01-01

    To examine the efficacy of renal preconditioning effect of dalargin and lithium ions by observing the model of gentamycin-induced acute renalfailure. The experiments were performed on white rats, male. The influence of dalargin and lithium ions on the development of gentamycin-induced acute renalfailure was studied in vivo. On the first 24 hours after dalargin injections were terminated, the rats were euthanized humanly. After this we took the blood for a biochemistry study and a renal culture for biochemical test and also for the test of gsk-3β activity. Concentrations of creatinine and urea were studied in serum. The culture samples of renal tubular epithelium before insertion of gentamycin were incubated in dalargin or lithium ions in different concentrations. After that the substratum was immediately changed to gentamycin in different concentrations also and the incubated for 24 hours. After all the standards MTT-test was performed (based on the ability of living cells to reduce the unpainted form by 3-4,5-dimethylthiazol-2-yl-2,5-difenilterarazola to blue crystalline farmazan). Lithium precondition leads to the 250% increase of gsk-3β concentration (p = 0.035). The same results were observed after injection of dalargin in 50 mcg/kg concentration. Concentration of creatinine was 44% lower in the dalargin group than in the control group (p = 0.022). Concentration of creatinine was 32% lower in the lithium group than in the control group (p = 0.030). Concentration of urea was 27% lower in the lithium group than in the control group (p = 0.049). Morphological inflammatory changes in the control group were more significant also. In vitro studies showed the maximum efficacy in the lithium group. The most effective dalargin concentration was 5 mg/ml. Lithium and dalargine preconditioning lowers the signs of gentamycine induced acute renal failure and damage rate of renal parenchyma in vivo and in vitro.

  3. Lisinopril attenuates renal oxidative injury in L-NAME-induced hypertensive rats.

    PubMed

    Oktem, Faruk; Kirbas, Aynur; Armagan, Abdullah; Kuybulu, Ayca Esra; Yilmaz, H Ramazan; Ozguner, Fehmi; Uz, Efkan

    2011-06-01

    Hypertension and related oxidative stress are involved in the pathogenesis of any renal diseases. Angiotensin-converting enzyme inhibitors have multi-directional renoprotective effects. In this study, we aimed to investigate whether lisinopril treatment has any biochemical alterations on renal tissue in L-NAME (Nε-nitro-L-arginine methyl ester) induced hypertension model. Twenty-eight Sprague-Dawley rats were included in this study and divided into four equal groups (n = 7): control group, L-NAME treated group (75 mg/kg/day), L-NAME plus lisinopril treated group and only lisinopril treated group (10 mg/kg/day). L-NAME and lisinopril were continued for 6 weeks. Systolic blood pressures were measured by using tail cuff method. In biochemical analysis, malondialdehyde (MDA, an index of lipid peroxidation) levels, the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in renal tissues were used as markers of oxidative stress-induced renal impairment. Microalbumin and N-acetyl-β-D-glucosaminidase (NAG) in urine were determined as markers of renal tubular damage related to hypertension. Chronic L-NAME administration resulted in a significant depletion of serum nitric oxide (NO). When compared with control group, serum creatinine, microalbumin, urine NAG, renal tissue MDA level, and CAT activities were significantly high, while renal tissue SOD and GSH-Px activities low in L-NAME group. In the L-NAME plus lisinopril treated group, serum creatinine, microalbumin and urine NAG, renal MDA level and CAT activity decreased, whereas SOD, GSH-Px activities in renal tissue and serum NO levels were increased. Thus, lisinopril treatment reversed these effects. There were not any significant difference between L-NAME plus lisinopril treated group and control group concerning serum creatinine, renal tissue MDA level and SOD, GSH-Px, CAT activities. These results suggest that lisinopril could diminish biochemical alterations in L: -NAME

  4. Prognostic factors of renal dysfunction induced by environmental cadmium pollution

    SciTech Connect

    Nishijo, Muneko; Nakagawa, Hideaki; Morikawa, Yuko; Tabata, Masaji; Senma, Masami; Kitagawa, Yumiko; Kawano, Shunichi; Ishizaki, Masao ); Sugita, Naomichi; Nishi, Masami )

    1994-02-01

    To assess the influence of environmental cadmium (Cd) exposure on long-term outcome, a follow-up study was conducted from 1981-1982 to March 1991 on 3178 inhabitants living in the Cd-polluted Kakehashi River basin. The standardized mortality ratios of the urinary [beta][sub 2]-microglobulin ([beta]2-MG)-, protein-, and amino acid-positive subjects of both sexes and the urinary glucose-positive female subjects were higher than those of the subjects with urinary-negative findings or the general Japanese population during the observation period. After adjusting for age using Cox's proportional hazards model, significant associations were found between mortality and urinary indices. In multiple comparisons using all of the indices, urinary protein and [beta]2-MG in the women and urinary protein in the men were the factors most contributing to the mortality rates. In the urinary protein-negative female group as well, as significant association was found between urinary [beta]2-MG and mortality. These results suggest that the prognosis of subjects with Cd-induced renal dysfunction is unfavorable, with the mortality rate increasing even in the early stage of proximal tubular dysfunction. Urinary protein and urinary [beta]2-MG are important prognostic factors, with the latter, in particular, considered to be useful as an early index predictive of premature mortality. 30 refs., 6 tabs.

  5. Perinatal radiation-induced renal damage in the beagle

    SciTech Connect

    Jaenke, R.S.; Angleton, G.M. )

    1990-04-01

    The developing perinatal kidney is particularly sensitive to radiation. The pathogenesis of the radiation-induced lesion is related to the destruction of outer cortical developing nephrons and direct radiation injury with secondary hemodynamic alterations in remnant nephrons. In this study, which is part of a life span investigation of the effects of whole-body gamma radiation during prenatal and early postnatal life, dogs were given 0, 0.16, 0.83, or 1.25 Gy irradiation at either 55 days postcoitus or 2 days postpartum and were examined morphometrically and histopathologically at 70 days of age. Although irradiated dogs showed no reduction in the total number of nephrons per kidney, there was a significant increase in the total number and relative percentage of immature, dysplastic glomeruli. In addition, deeper cortical glomeruli of irradiated kidneys exhibited mesangial sclerosis similar to that associated with progressive renal failure in our previous studies. These findings are in accord with those reported at doses of 2.24 to 3.57 Gy and demonstrate that the perinatal kidney is affected by radiation doses much lower than previously demonstrated.

  6. 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

  7. Effects of lysine-induced acute renal failure in dogs.

    PubMed

    Asanuma, Kentaro; Adachi, Kenji; Sugimoto, Tetsuro; Chiba, Shuichi

    2006-05-01

    This study investigates the effects of lysine-induced acute renal failure. Female dogs received a lysine hydrochloride (lysine) of 4500 mg/kg/day (3.75 ml/kg/hr) for 3 consecutive days. The dogs were observed for clinical signs. Body weights were recorded, food consumption and water consumption calculated, and urinalysis and blood biochemistry were performed daily. Plasma samples for amino acid determinations were obtained from all dogs, which were necropsied on Day 3. Histopathological examinations were done on all test animals. Compound-related findings include the following. Blood biochemistry results showed increases in ammonia, blood urea nitrogen, blood urea nitrogen/creatinine ratio, and creatinine. Urinary changes consisted of increases in urine volume, total protein, albumin, gamma-glutamyl transpeptidase, and N-acetyl-beta-D-glucosaminidase. In addition, macroscopic findings consisted of pale, congested capsule; microscopic findings consisted of hypertrophy of proximal convoluted tubule (mainly S1 segment), and degeneration/desquamation of urinary tubule (mainly S3 segment with hyaline casts) in the kidney. From these findings, it can be concluded that lysine is nephrotoxic in dogs. Nephrotoxicity of lysine may relate to direct tubular toxicity and to tubular obstruction.

  8. 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

  9. Tonic postganglionic sympathetic inhibition induced by afferent renal nerves?

    PubMed

    Ditting, Tilmann; Freisinger, Wolfgang; Siegel, Kirsten; Fiedler, Christian; Small, Lisa; Neuhuber, Winfried; Heinlein, Sonja; Reeh, Peter W; Schmieder, Roland E; Veelken, Roland

    2012-02-01

    Other than efferent sympathetic innervation, the kidney has peptidergic afferent fibers expressing TRPV1 receptors and releasing substance P. We tested the hypothesis that stimulation of afferent renal nerve activity with the TRPV1 agonist capsaicin inhibits efferent renal sympathetic nerve activity tonically by a neurokinin 1 receptor-dependant mechanism. Anesthetized Sprague-Dawley rats were instrumented as follows: (1) arterial and venous catheters for recording of blood pressure and heart rate and drug administration; (2) left-sided renal arterial catheter for selective intrarenal administration of the TRPV1 agonist capsaicin (3.3, 6.6, 10, 33*10(-7) m; 10 μL; after 15, 30, 45, and 60 minutes, respectively) to stimulate afferent renal nerve activity; (3) right-sided bipolar electrode for continuous renal sympathetic nerve recording; and (4) specialized renal pelvic and renal artery catheters to separate pelvic from intrarenal afferent activity. Before and after intrarenal capsaicin application, increasing intravenous doses of the neurokinin 1 receptor blocker RP67580 were given. Intrarenal capsaicin decreased integrated renal sympathetic activity from 65.4±13.0 mV*s (baseline) to 12.8±3.2 mV*s (minimum; P<0.01). This sustained renal sympathetic inhibition reached its minimum within 70 minutes and was not directly linked to the transient electric afferent response to be expected with intrarenal capsaicin. Suppressed renal sympathetic activity transiently but completely recovered after intravenous administration of the neurokinin 1 blocker (maximum: 120.3±19.4 mV*s; P<0.01). Intrarenal afferent activity could be unequivocally separated from pelvic afferent activity. For the first time we provide direct evidence that afferent intrarenal nerves provide a tonically acting sympathoinhibitory system, which seems to be rather mediated by neurokinin release acting via neurokinin 1 receptor pathways rather than by electric afferent effects on central sympathetic

  10. Tubular Overexpression of Gremlin Induces Renal Damage Susceptibility in Mice

    PubMed Central

    Droguett, Alejandra; Krall, Paola; Burgos, M. Eugenia; Valderrama, Graciela; Carpio, Daniel; Ardiles, Leopoldo; Rodriguez-Diez, Raquel; Kerr, Bredford; Walz, Katherina; Ruiz-Ortega, Marta; Egido, Jesus; Mezzano, Sergio

    2014-01-01

    A growing number of patients are recognized worldwide to have chronic kidney disease. Glomerular and interstitial fibrosis are hallmarks of renal progression. However, fibrosis of the kidney remains an unresolved challenge, and its molecular mechanisms are still not fully understood. Gremlin is an embryogenic gene that has been shown to play a key role in nephrogenesis, and its expression is generally low in the normal adult kidney. However, gremlin expression is elevated in many human renal diseases, including diabetic nephropathy, pauci-immune glomerulonephritis and chronic allograft nephropathy. Several studies have proposed that gremlin may be involved in renal damage by acting as a downstream mediator of TGF-β. To examine the in vivo role of gremlin in kidney pathophysiology, we generated seven viable transgenic mouse lines expressing human gremlin (GREM1) specifically in renal proximal tubular epithelial cells under the control of an androgen-regulated promoter. These lines demonstrated 1.2- to 200-fold increased GREM1 expression. GREM1 transgenic mice presented a normal phenotype and were without proteinuria and renal function involvement. In response to the acute renal damage cause by folic acid nephrotoxicity, tubule-specific GREM1 transgenic mice developed increased proteinuria after 7 and 14 days compared with wild-type treated mice. At 14 days tubular lesions, such as dilatation, epithelium flattening and hyaline casts, with interstitial cell infiltration and mild fibrosis were significantly more prominent in transgenic mice than wild-type mice. Tubular GREM1 overexpression was correlated with the renal upregulation of profibrotic factors, such as TGF-β and αSMA, and with increased numbers of monocytes/macrophages and lymphocytes compared to wild-type mice. Taken together, our results suggest that GREM1-overexpressing mice have an increased susceptibility to renal damage, supporting the involvement of gremlin in renal damage progression. This

  11. Tubular overexpression of gremlin induces renal damage susceptibility in mice.

    PubMed

    Droguett, Alejandra; Krall, Paola; Burgos, M Eugenia; Valderrama, Graciela; Carpio, Daniel; Ardiles, Leopoldo; Rodriguez-Diez, Raquel; Kerr, Bredford; Walz, Katherina; Ruiz-Ortega, Marta; Egido, Jesus; Mezzano, Sergio

    2014-01-01

    A growing number of patients are recognized worldwide to have chronic kidney disease. Glomerular and interstitial fibrosis are hallmarks of renal progression. However, fibrosis of the kidney remains an unresolved challenge, and its molecular mechanisms are still not fully understood. Gremlin is an embryogenic gene that has been shown to play a key role in nephrogenesis, and its expression is generally low in the normal adult kidney. However, gremlin expression is elevated in many human renal diseases, including diabetic nephropathy, pauci-immune glomerulonephritis and chronic allograft nephropathy. Several studies have proposed that gremlin may be involved in renal damage by acting as a downstream mediator of TGF-β. To examine the in vivo role of gremlin in kidney pathophysiology, we generated seven viable transgenic mouse lines expressing human gremlin (GREM1) specifically in renal proximal tubular epithelial cells under the control of an androgen-regulated promoter. These lines demonstrated 1.2- to 200-fold increased GREM1 expression. GREM1 transgenic mice presented a normal phenotype and were without proteinuria and renal function involvement. In response to the acute renal damage cause by folic acid nephrotoxicity, tubule-specific GREM1 transgenic mice developed increased proteinuria after 7 and 14 days compared with wild-type treated mice. At 14 days tubular lesions, such as dilatation, epithelium flattening and hyaline casts, with interstitial cell infiltration and mild fibrosis were significantly more prominent in transgenic mice than wild-type mice. Tubular GREM1 overexpression was correlated with the renal upregulation of profibrotic factors, such as TGF-β and αSMA, and with increased numbers of monocytes/macrophages and lymphocytes compared to wild-type mice. Taken together, our results suggest that GREM1-overexpressing mice have an increased susceptibility to renal damage, supporting the involvement of gremlin in renal damage progression. This

  12. 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

  13. Sida rhomboidea.Roxb leaf extract ameliorates gentamicin induced nephrotoxicity and renal dysfunction in rats.

    PubMed

    Thounaojam, Menaka C; Jadeja, Ravirajsinh N; Devkar, Ranjitsinh V; Ramachandran, A V

    2010-10-28

    Sida rhomboidea.Roxb (SR) known as "Mahabala" in Ayurveda and marketed as "Shahadeyi" is used in ethnomedicine to treat ailments such as dysuria and urinary disorders. To evaluate nephroprotective potential of SR against gentamicin (GM) induced nephrotoxicity and renal dysfunction. Nephrotoxicity was induced in rats with GM (100 mg/kg bodyweight (i.p.) for 8 days) and were treated with SR extract (200 and 400 mg/kg bodyweight (p.o.) for 8 days) or 0.5% carboxymethyl cellulose (vehicle). Plasma and urine urea and creatinine, renal enzymatic and non-enzymatic antioxidants along with lipid peroxidation were evaluated in various experimental groups. GM treatment induced significant elevation (p<0.05) in plasma and urine urea, creatinine, renal lipid peroxidation along with significant decrement (p<0.05) in renal enzymatic and non-enzymatic antioxidants. SR treatment to GM treated rats (GM+SR) recorded significant decrement (p<0.05) in plasma and urine urea and creatinine, renal lipid peroxidation along with significant increment (p<0.05) in renal enzymatic and non-enzymatic antioxidants. SR leaf extract ameliorates GM induced nephrotoxicity and renal dysfunction and thus validates its ethnomedicinal use. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  14. Nlrp3 is a key modulator of diet-induced nephropathy and renal cholesterol accumulation.

    PubMed

    Bakker, Pieter J; Butter, Loes M; Kors, Lotte; Teske, Gwendoline J D; Aten, Jan; Sutterwala, Fayyaz S; Florquin, Sandrine; Leemans, Jaklien C

    2014-05-01

    Metabolic syndrome (MetSyn) is a major health concern and associates with the development of kidney disease. The mechanisms linking MetSyn to renal disease have not been fully elucidated but are known to involve hyperuricemia, inflammation, and fibrosis. Since the innate immune receptor Nlrp3 is an important mediator of obesity and inflammation, we sought to determine whether Nlrp3 is involved in the development of MetSyn-associated nephropathy by giving wild-type or Nlrp3-knockout mice a Western-style compared to a normal diet or water without or with fructose. A plausible driver of pathology, the Nlrp3-dependent cytokine IL-1β was not increased in the kidney. Interestingly, Nlrp3-dependent renal cholesterol accumulation, another well-known driver of renal pathology, was enhanced during MetSyn. We also determined the role of Nlrp3 and fructose-fortified water on the development of MetSyn and kidney function since fructose is an important driver of obesity and kidney disease. Surprisingly, fructose did not induce MetSyn but, irrespective of this, did induce Nlrp3-dependent renal inflammation. The presence of Nlrp3 was crucial for the development of Western-style diet-induced renal pathology as reflected by the prevention of renal inflammation, fibrosis, steatosis, microalbuminuria, and hyperuricemia in the Nlrp3-knockout mice. Thus, Nlrp3 may mediate renal pathology in the context of diet-induced MetSyn.

  15. Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells.

    PubMed

    Cilenti, Lucia; Kyriazis, George A; Soundarapandian, Mangala M; Stratico, Valerie; Yerkes, Adam; Park, Kwon Moo; Sheridan, Alice M; Alnemri, Emad S; Bonventre, Joseph V; Zervos, Antonis S

    2005-02-01

    Omi/HtrA2 is a mitochondrial proapoptotic serine protease that is able to induce both caspase-dependent and caspase-independent cell death. After apoptotic stimuli, Omi is released to the cytoplasm where it binds and cleaves inhibitor of apoptosis proteins. In this report, we investigated the role of Omi in renal cell death following cisplatin treatment. Using primary mouse proximal tubule cells, as well as established renal cell lines, we show that the level of Omi protein is upregulated after treatment with cisplatin. This upregulation is followed by the release of Omi from mitochondria to the cytoplasm and degradation of XIAP. Reducing the endogenous level of Omi protein using RNA interference renders renal cells resistant to cisplatin-induced cell death. Furthermore, we show that the proteolytic activity of Omi is necessary and essential for cisplatin-induced cell death in this system. When renal cells are treated with Omi's specific inhibitor, ucf-101, they become significantly resistant to cisplatin-induced cell death. Ucf-101 was also able to minimize cisplatin-induced nephrotoxic injury in animals. Our results demonstrate that Omi is a major mediator of cisplatin-induced cell death in renal cells and suggest a way to limit renal injury by specifically inhibiting its proteolytic activity.

  16. Protective Effects of Luteolin on Lipopolysaccharide-Induced Acute Renal Injury in Mice

    PubMed Central

    Xin, Shao-bin; Yan, Hao; Ma, Jing; Sun, Qiang; Shen, Li

    2016-01-01

    Background Sepsis can cause serious acute kidney injury in bacterium-infected patients, especially in intensive care patients. Luteolin, a bioactive flavonoid, has renal protection and anti-inflammatory effects. This study aimed to investigate the effect and underlying mechanism of luteolin in attenuating lipopolysaccharide (LPS)-induced renal injury. Material/Methods ICR mice were treated with LPS (25 mg/kg) with or without luteolin pre-treatment (40 mg/kg for three days). The renal function, histological changes, degree of oxidative stress, and tubular apoptosis in these mice were examined. The effects of luteolin on LPS-induced expression of renal tumor necrosis factor-α (TNF-α), NF-κB, MCP-1, ICAM-1, and cleaved caspase-3 were evaluated. Results LPS resulted in rapid renal damage of mice, increased level of blood urea nitrogen (BUN), and serum creatinine (Scr), tubular necrosis, and increased oxidative stress, whereas luteolin pre-treatment could attenuate this renal damage and improve the renal functions significantly. Treatment with LPS increased TNF-α, NF-κB, IL-1β, cleaved caspase-3, MCP-1, and ICAM-1 expression, while these disturbed expressions were reversed by luteolin pre-treatment. Conclusions These results indicate that luteolin ameliorates LPS-mediated nephrotoxicity via improving renal oxidant status, decreasing NF-κB activation and inflammatory and apoptosis factors, and then disturbing the expression of apoptosis-related proteins. PMID:28029146

  17. Cefepime-Induced Non-Convulsive Status Epilepticus in a Patient with Normal Renal Function

    PubMed Central

    Park, Hyeon-Mi; Noh, Young; Yang, Ji Won; Shin, Dong Hoon; Lee, Yeong-Bae

    2016-01-01

    Cefepime-induced encephalopathy including nonconvulsive status epilepticus has been known to develop in the patients with renal impairment. However, we report a 74-year-old woman with normal renal function who developed stuporous mental status during cefepime administration. Electroencephalogram (EEG) revealed 2 Hz rhythmic sharp-and-waves continuously, which suggested nonconvulsive status epilepticus (NCSE). After cefepime discontinuation, clinical symptoms recovered gradually and EEG findings showed only background slowing without epileptiform discharges. Cefepime-induced NCSE could be developed even in the patients with normal renal function, when they are elderly. Therefore, clinicians should be aware of the possibility of cefepime-induced NCSE when prescribing cefepime even to the patients with normal renal function. PMID:28101482

  18. Hydrogen peroxide-induced renal injury. A protective role for pyruvate in vitro and in vivo.

    PubMed Central

    Salahudeen, A K; Clark, E C; Nath, K A

    1991-01-01

    Hydrogen peroxide (H2O2) contributes to renal cellular injury. alpha-Keto acids nonenzymatically reduce H2O2 to water while undergoing decarboxylation at the 1-carbon (1-C) position. We examined, in vitro and in vivo, the protective role of sodium pyruvate in H2O2-induced renal injury. Pyruvate effectively scavenged H2O2 in vitro, and suppressed H2O2-induced renal lipid peroxidation. Injury to LLC-PK1 cells induced by hydrogen peroxide was attenuated by pyruvate to an extent comparable to that seen with catalase. Studies utilizing [1-14C]pyruvate further demonstrated 1-C decarboxylation concurrent with cytoprotection by pyruvate from H2O2-induced injury. Pyruvate was also protective in vivo. Infusion of pyruvate before and during the intrarenal infusion of H2O2 attenuated H2O2-induced proteinuria. Systemic administration of pyruvate was also protective in the glycerol model of acute renal failure, a model also characterized by increased generation of H2O2. These findings indicate that pyruvate, a ubiquitous alpha-keto acid, scavenges H2O2 and protects renal tissue in vitro and in vivo from H2O2-mediated injury. These data suggest a potential therapeutic role for pyruvate in diseases in which increased generation of H2O2 is incriminated in renal damage. Images PMID:1752950

  19. Curcumin ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in mice.

    PubMed

    Ueki, Masaaki; Ueno, Masaki; Morishita, Jun; Maekawa, Nobuhiro

    2013-05-01

    Inflammatory mechanisms may play an important role in the pathogenesis of cisplatin-induced nephrotoxicity. Curcumin is an orange-yellow polyphenol present in curry spice and has anti-inflammatory and antioxidant effects. The purpose of this study was to determine the protective effects of curcumin on cisplatin-induced nephrotoxicity. Mice were randomly divided into four groups: control, cisplatin, cisplatin + curcumin and curcumin. Mice were given cisplatin (20 mg/kg body weight, intraperitoneally) with or without curcumin treatment (100 mg/kg body weight, intraperitoneally, immediately after cisplatin injection). Serum and renal tumor necrosis factor (TNF)-alpha and renal monocyte chemoattractant protein (MCP)-1 concentrations, intercellular adhesion molecule-1 (ICAM-1) mRNA expression in kidney, renal function and histological changes were determined 72 h after cisplatin injection. Serum TNF-alpha concentration in the cisplatin + curcumin group significantly decreased compared with that in the cisplatin group. Renal TNF-alpha and MCP-1 concentrations and ICAM-1 mRNA expression in kidney in the cisplatin + curcumin group also significantly decreased compared with those in the cisplatin group. Consequently, cisplatin-induced renal dysfunction and renal tubular necrosis scores were attenuated by curcumin treatment. These results indicate that curcumin acts to reduce cisplatin-induced nephrotoxicity through its anti-inflammatory effects. Thus, curcumin may become a new therapeutic candidate for the treatment of cisplatin-induced nephrotoxicity.

  20. Increased sensitivity of the renal vasculature to adenosine in streptozotocin-induced diabetes mellitus rats.

    PubMed

    Pflueger, A C; Schenk, F; Osswald, H

    1995-10-01

    Adenosine (ADO) has been implicated as a pathophysiological factor in contrast media (CM)-induced acute renal failure, which has been encountered more often in patients with diabetes and impaired renal function. Therefore, we studied the renal vascular response to exogenous and endogenous ADO in streptozotocin-induced diabetic rats. We found that exogenous ADO (0.01-100 nmol), injected into the abdominal aorta, decreased renal blood flow (RBF) in a dose-dependent manner. The dose-response curve was shifted to the left by factor 30 in diabetic, compared with nondiabetic rats rats. Renal vascular response to endogenous ADO, assessed by postocclusive reduction of RBF after a 30-s renal artery occlusion, was significantly enhanced (P < 0.001) in diabetic rats (75.6 +/- 3.9%) compared with nondiabetic rats (36.5 +/- 2%). ADO A1-receptor blockade with 8-cyclopentyl-1,3-dipropylxanthine attenuated exogenous and endogenous ADO-induced renal vasoconstriction in both groups. We conclude that the ADO A1-receptor signal-transduction chain is altered in diabetic animals and that the enhanced vasoconstrictive action of ADO could be involved in the kidney pathophysiology of diabetes mellitus.

  1. Cinnabar Induces Renal Inflammation and Fibrogenesis in Rats

    PubMed Central

    Wang, Ying; Wang, Dapeng; Wu, Jie; Wang, Bohan; Wang, Liangjun; Gao, Xin; Huang, Hai; Ma, Honglin

    2015-01-01

    The purpose of this study was to investigate whether cinnabar causes renal inflammation and fibrosis in rats. Rats were dosed orally with cinnabar (1 g/kg/day) for 8 weeks or 12 weeks. The control rats were treated with solvent (5% carboxymethylcellulose solution) over the same time periods, respectively. Renal mercury (RHg), urinary mercury (UHg), serum creatinine (SCr), urine kidney injury molecule 1 (KIM-1), renal pathology, and renal mediators were examined. At both 8 weeks and 12 weeks, RHg, UHg, and urine KIM-1 were significantly higher in the cinnabar group than in the control group, although SCr was unchanged. Kidney lesions in the cinnabar-treated rats occurred mainly in the tubules and interstitium, including vacuolization, protein casts, infiltration of inflammatory cells, and slight increase in interstitial collagen. In addition, mild mesangial proliferation was observed in glomeruli. Moreover, the expression of inflammatory and fibrogenic mediators was upregulated in the cinnabar group. In conclusion, cinnabar may cause kidney damage due to the accumulation of mercury, and renal inflammation and slight fibrogenesis may occur in rats. In the clinic, the potential risk of renal injury due to the prolonged consumption of cinnabar should be considered even though the agent is relatively nontoxic. PMID:25734058

  2. Mode of Action: Oxalate Crystal-Induced Renal Tubule Degeneration and Glycolic Acid-Induced Dysmorphogenesis—Renal and Developmental Effects of Ethylene Glycol

    SciTech Connect

    Corley, Rick A.; Meek, M E.; Carney, E W.

    2005-10-01

    Ethylene glycol can cause both renal and developmental toxicity, with metabolism playing a key role in the mode of action (MOA) for each form of toxicity. Renal toxicity is ascribed to the terminal metabolite oxalic acid, which precipitates in the kidney in the form of calcium oxalate crystals and is believed to cause physical damage to the renal tubules. The human relevance of the renal toxicity of ethylene glycol is indicated by the similarity between animals and humans of metabolic pathways, the observation of renal oxalate crystals in toxicity studies in experimental animals and human poisonings, and cases of human kidney and bladder stones related to dietary oxalates and oxalate precursors. High-dose gavage exposures to ethylene glycol also cause axial skeletal defects in rodents (but not rabbits), with the intermediary metabolite, glycolic acid, identified as the causative agent. However, the mechanism by which glycolic acid perturbs development has not been investigated sufficiently to develop a plausible hypothesis of mode of action, nor have any cases of ethylene glycol-induced developmental effects been reported in humans. Given this, and the variations in sensitivity between animal species in response, the relevance to humans of ethylene glycol-induced developmental toxicity in animals is unknown at this time.

  3. Lower Blood Pressure-Induced Renal Hypoperfusion Promotes Cisplatin-Induced Nephrotoxicity.

    PubMed

    Mizuno, Tomohiro; Hayashi, Takahiro; Shimabukuro, Yuka; Murase, Maho; Hayashi, Hiroki; Ishikawa, Kazuhiro; Takahashi, Kazuo; Yuzawa, Yukio; Yamada, Shigeki; Nagamatsu, Tadashi

    2016-01-01

    Cisplatin-induced nephrotoxicity primarily occurs in the proximal tubules, and tubular injuries reduce glomerular filtration rates. Lower blood pressure causes renal hypoperfusion, which promotes ischemic acute kidney injury (AKI). Our study examined the relationship between lower blood pressure-induced renal hypoperfusion and cisplatin-induced nephrotoxicity. The relationship between cisplatin use and hypoalbuminemia is not clear. This study consisted of Japanese patients who received cisplatin as the first-line chemotherapy at Fujita Health University Hospital from April 2006 to December 2012. Hypoalbuminemia was defined as serum albumin levels ≤3.5 mg/dl. Patients who experienced lower blood pressure during chemotherapy were included in the lower blood pressure group (n = 229), and those who did not were included in the normal blood pressure group (n = 743). Total cisplatin dose in the normal blood pressure and lower blood pressure groups was 58.9 ± 23.8 and 55.0 ± 20.4 mg/m2, respectively. The rate of severe nephrotoxicity was higher and overall survival was shorter in the lower blood pressure group than in the normal blood pressure group. In a multivariable analysis, lower blood pressure significantly correlated with hypoalbuminemia. To prevent ischemic AKI, nutrition and cachexia controlling are important parts of cancer treatment. © 2016 S. Karger AG, Basel.

  4. High-NaCl diet impairs dynamic renal blood flow autoregulation in rats with adenine-induced chronic renal failure.

    PubMed

    Saeed, Aso; DiBona, Gerald F; Grimberg, Elisabeth; Nguy, Lisa; Mikkelsen, Minne Line Nedergaard; Marcussen, Niels; Guron, Gregor

    2014-03-15

    This study examined the effects of 2 wk of high-NaCl diet on kidney function and dynamic renal blood flow autoregulation (RBFA) in rats with adenine-induced chronic renal failure (ACRF). Male Sprague-Dawley rats received either chow containing adenine or were pair-fed an identical diet without adenine (controls). After 10 wk, rats were randomized to either remain on the same diet (0.6% NaCl) or to be switched to high 4% NaCl chow. Two weeks after randomization, renal clearance experiments were performed under isoflurane anesthesia and dynamic RBFA, baroreflex sensitivity (BRS), systolic arterial pressure variability (SAPV), and heart rate variability were assessed by spectral analytical techniques. Rats with ACRF showed marked reductions in glomerular filtration rate and renal blood flow (RBF), whereas mean arterial pressure and SAPV were significantly elevated. In addition, spontaneous BRS was reduced by ∼50% in ACRF animals. High-NaCl diet significantly increased transfer function fractional gain values between arterial pressure and RBF in the frequency range of the myogenic response (0.06-0.09 Hz) only in ACRF animals (0.3 ± 4.0 vs. -4.4 ± 3.8 dB; P < 0.05). Similarly, a high-NaCl diet significantly increased SAPV in the low-frequency range only in ACRF animals. To conclude, a 2-wk period of a high-NaCl diet in ACRF rats significantly impaired dynamic RBFA in the frequency range of the myogenic response and increased SAPV in the low-frequency range. These abnormalities may increase the susceptibility to hypertensive end-organ injury and progressive renal failure by facilitating pressure transmission to the microvasculature.

  5. Betaine supplementation protects against high-fructose-induced renal injury in rats.

    PubMed

    Fan, Chen-Yu; Wang, Ming-Xing; Ge, Chen-Xu; Wang, Xing; Li, Jian-Mei; Kong, Ling-Dong

    2014-03-01

    High fructose intake causes metabolic syndrome, being an increased risk of chronic kidney disease development in humans and animals. In this study, we examined the influence of betaine on high-fructose-induced renal damage involving renal inflammation, insulin resistance and lipid accumulation in rats and explored its possible mechanisms. Betaine was found to improve high-fructose-induced metabolic syndrome including hyperuricemia, dyslipidemia and insulin resistance in rats with systemic inflammation. Betaine also showed a protection against renal dysfunction and tubular injury with its restoration of the increased glucose transporter 9 and renal-specific transporter in renal brush bolder membrane and the decreased organic anion transporter 1 and adenosine-triphosphate-binding cassette transporter 2 in the renal cortex in this model. These protective effects were relevant to the anti-inflammatory action by inhibiting the production of inflammatory cytokines including interleukin (IL)-1β, IL-18, IL-6 and tumor necrosis factor-α in renal tissue of high-fructose-fed rat, being more likely to suppress renal NOD-like receptor superfamily, pyrin domain containing 3 inflammasome activation than nuclear factor κB activation. Subsequently, betaine with anti-inflammation ameliorated insulin signaling impairment by reducing the up-regulation of suppressor of cytokine signaling 3 and lipid accumulation partly by regulating peroxisome proliferator-activated receptor α/palmityltransferase 1/carnitine/organic cation transporter 2 pathway in kidney of high-fructose-fed rats. These results indicate that the inflammatory inhibition plays a pivotal role in betaine's improvement of high-fructose-induced renal injury with insulin resistance and lipid accumulation in rats.

  6. Stem Cell Conditioned Culture Media Attenuated Albumin-Induced Epithelial– Mesenchymal Transition in Renal Tubular Cells

    PubMed Central

    Hu, Junping; Zhu, Qing; Li, Pin-Lan; Wang, Weili; Yi, Fan; Li, Ningjun

    2015-01-01

    Background Proteinuria-induced epithelial-mesenchymal transition (EMT) plays an important role in progressive renal tubulointerstitial fibrosis in chronic renal disease. Stem cell therapy has been used for different diseases. Stem cell conditioned culture media (SCM) exhibits similar beneficial effects as stem cell therapy. The present study tested the hypothesis that SCM inhibits albumin-induced EMT in cultured renal tubular cells. Methods Rat renal tubular cells were treated with/without albumin (20 μmg/ml) plus SCM or control cell media (CCM). EMT markers and inflammatory factors were measured by Western blot and fluorescent images. Results Albumin induced EMT as shown by significant decreases in levels of epithelial marker E-cadherin, increases in mesenchymal markers fibroblast-specific protein 1 and α-smooth muscle actin, and elevations in collagen I. SCM inhibited all these changes. Meanwhile, albumin induced NF-κB translocation from cytosol into nucleus and that SCM blocked the nuclear translocation of NF-κB. Albumin also increased the levels of pro-inflammatory factor monocyte chemoattractant protein-1 (MCP)-1 by nearly 30 fold compared with control. SCM almost abolished albumin-induced increase of MCP-1. Conclusion These results suggest that SCM attenuated albumin-induced EMT in renal tubular cells via inhibiting activation of inflammatory factors, which may serve as a new therapeutic approach for chronic kidney diseases. PMID:25832005

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

    PubMed Central

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

    2015-01-01

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

  8. Recombinant N-Terminal Slit2 Inhibits TGF-β-Induced Fibroblast Activation and Renal Fibrosis.

    PubMed

    Yuen, Darren A; Huang, Yi-Wei; Liu, Guang-Ying; Patel, Sajedabanu; Fang, Fei; Zhou, Joyce; Thai, Kerri; Sidiqi, Ahmad; Szeto, Stephen G; Chan, Lauren; Lu, Mingliang; He, Xiaolin; John, Rohan; Gilbert, Richard E; Scholey, James W; Robinson, Lisa A

    2016-09-01

    Fibrosis and inflammation are closely intertwined injury pathways present in nearly all forms of CKD for which few safe and effective therapies exist. Slit glycoproteins signaling through Roundabout (Robo) receptors have been described to have anti-inflammatory effects through regulation of leukocyte cytoskeletal organization. Notably, cytoskeletal reorganization is also required for fibroblast responses to TGF-β Here, we examined whether Slit2 also controls TGF-β-induced renal fibrosis. In cultured renal fibroblasts, which we found to express Slit2 and Robo-1, the bioactive N-terminal fragment of Slit2 inhibited TGF-β-induced collagen synthesis, actin cytoskeletal reorganization, and Smad2/3 transcriptional activity, but the inactive C-terminal fragment of Slit2 did not. In mouse models of postischemic renal fibrosis and obstructive uropathy, treatment with N-terminal Slit2 before or after injury inhibited the development of renal fibrosis and preserved renal function, whereas the C-terminal Slit2 had no effect. Our data suggest that administration of recombinant Slit2 may be a new treatment strategy to arrest chronic injury progression after ischemic and obstructive renal insults by not only attenuating inflammation but also, directly inhibiting renal fibrosis. Copyright © 2016 by the American Society of Nephrology.

  9. Diabetes-Induced Reactive Oxygen Species: Mechanism of Their Generation and Role in Renal Injury

    PubMed Central

    Fakhruddin, Selim; Alanazi, Wael

    2017-01-01

    Diabetes induces the onset and progression of renal injury through causing hemodynamic dysregulation along with abnormal morphological and functional nephron changes. The most important event that precedes renal injury is an increase in permeability of plasma proteins such as albumin through a damaged glomerular filtration barrier resulting in excessive urinary albumin excretion (UAE). Moreover, once enhanced UAE begins, it may advance renal injury from progression of abnormal renal hemodynamics, increased glomerular basement membrane (GBM) thickness, mesangial expansion, extracellular matrix accumulation, and glomerulosclerosis to eventual end-stage renal damage. Interestingly, all these pathological changes are predominantly driven by diabetes-induced reactive oxygen species (ROS) and abnormal downstream signaling molecules. In diabetic kidney, NADPH oxidase (enzymatic) and mitochondrial electron transport chain (nonenzymatic) are the prominent sources of ROS, which are believed to cause the onset of albuminuria followed by progression to renal damage through podocyte depletion. Chronic hyperglycemia and consequent ROS production can trigger abnormal signaling pathways involving diverse signaling mediators such as transcription factors, inflammatory cytokines, chemokines, and vasoactive substances. Persistently, increased expression and activation of these signaling molecules contribute to the irreversible functional and structural changes in the kidney resulting in critically decreased glomerular filtration rate leading to eventual renal failure. PMID:28164134

  10. Simvastatin ameliorates renal lipidosis through the suppression of renal CXCL16 expression in mice with adriamycin-induced nephropathy

    PubMed Central

    Wang, Cong; Li, Qian; Zhen, Junhui; Xu, Yihuai; Sun, Shuzhen

    2015-01-01

    Aims: To investigate the roles of CXCL16 and ox-LDL in adriamycin (ADR)-induced nephropathy mice and to explore the mechanism of simvastatin on the renal protective effects of ADR nephropathy. Methods: Fifteen male Balb/c mice were randomly divided into normal control (NC), ADR nephropathy and simvastatin-treated ADR nephropathy (ADR-SIM) groups. ADR nephropathy was induced by a single intravenous injection of ADR into the tail vein. All mice were sacrificed at the end of the 7th week, with the blood, 24-h urine and kidneys collected. The levels of ox-LDL and total cholesterol in the serum, the serum CXCL16, ox-LDL and NF-κB expression were detected. Results: Compared with the NC group, the levels of serum total cholesterol and ox-LDL in the ADR and ADR-SIM groups were significantly higher, the level of serum albumin was significantly lower and the expression of CXCL16, ox-LDL and NF-κB in the renal tissue of ADR and ADR-SIM groups was significantly increased. Compared with the ADR group, the expressions of renal CXCL16, ox-LDL and NF-κB in the ADR-SIM group were significantly decreased. Levels of serum total cholesterol and ox-LDL were not significantly different between the two groups. Conclusions: Simvastatin exerts a protective effect on renal function and structure in mice with ADR nephropathy. The beneficial effects of simvastatin might be related to the decreasing expression of CXCL16 in glomerular podocytes followed by the decreasing endocytosis of ox-LDL in podocytes and inhibition of NF-κB pathway activation. PMID:26884839

  11. Staphylococcus aureus Sepsis Induces Early Renal Mitochondrial DNA Repair and Mitochondrial Biogenesis in Mice

    PubMed Central

    Bartz, Raquel R.; Fu, Ping; Suliman, Hagir B.; Crowley, Stephen D.; MacGarvey, Nancy Chou; Welty-Wolf, Karen; Piantadosi, Claude A.

    2014-01-01

    Acute kidney injury (AKI) contributes to the high morbidity and mortality of multi-system organ failure in sepsis. However, recovery of renal function after sepsis-induced AKI suggests active repair of energy-producing pathways. Here, we tested the hypothesis in mice that Staphyloccocus aureus sepsis damages mitochondrial DNA (mtDNA) in the kidney and activates mtDNA repair and mitochondrial biogenesis. Sepsis was induced in wild-type C57Bl/6J and Cox-8 Gfp-tagged mitochondrial-reporter mice via intraperitoneal fibrin clots embedded with S. aureus. Kidneys from surviving mice were harvested at time zero (control), 24, or 48 hours after infection and evaluated for renal inflammation, oxidative stress markers, mtDNA content, and mitochondrial biogenesis markers, and OGG1 and UDG mitochondrial DNA repair enzymes. We examined the kidneys of the mitochondrial reporter mice for changes in staining density and distribution. S. aureus sepsis induced sharp amplification of renal Tnf, Il-10, and Ngal mRNAs with decreased renal mtDNA content and increased tubular and glomerular cell death and accumulation of protein carbonyls and 8-OHdG. Subsequently, mtDNA repair and mitochondrial biogenesis was evidenced by elevated OGG1 levels and significant increases in NRF-1, NRF-2, and mtTFA expression. Overall, renal mitochondrial mass, tracked by citrate synthase mRNA and protein, increased in parallel with changes in mitochondrial GFP-fluorescence especially in proximal tubules in the renal cortex and medulla. Sub-lethal S. aureus sepsis thus induces widespread renal mitochondrial damage that triggers the induction of the renal mtDNA repair protein, OGG1, and mitochondrial biogenesis as a conspicuous resolution mechanism after systemic bacterial infection. PMID:24988481

  12. Nivolumab-Induced Development of Pulmonary Sarcoidosis in Renal Cell Carcinoma.

    PubMed

    Zhang, Meng; Schembri, Geoffrey

    2017-09-01

    A 64-year-old woman with metastatic clear cell renal carcinoma who had been on nivolumab immunotherapy for 10 months was referred for a FDG PET scan to monitor disease progress. New bilateral mediastinal and hilar FDG-avid lymphadenopathy was noted. Pathology on subsequent mediastinal nodal biopsy showed well-formed epithelioid granulomas with no evidence of malignancy consistent with sarcoidosis. This case illustrates that pulmonary sarcoidosis can be induced by immunotherapy in the treatment of renal cell carcinoma.

  13. Protective Role of Apelin Against Cyclosporine-Induced Renal Tubular Injury in Rats.

    PubMed

    Kim, J S; Yang, J W; Han, B G; Kwon, H J; Kim, J H; Choi, S O

    Cyclosporine (CsA) usually reduces glomerular filtration rate (GFR) but also can induce tubular injury without resulting in GFR reduction. Apelin is an endogenous ligand for the apelin receptor and has diverse physiologic roles related to hemodynamic or metabolic processes. We investigated the renoprotective role of apelin against CsA-induced tubular toxicity in rats. Rats were given CsA (15 mg/kg/day) and/or apelin-13 (15 μg/kg/day) for 7 days via subcutaneous injection. We performed serum and urinary assays of creatinine and neutrophil gelatinase-associated lipocalin (NGAL) to estimate renal injury and performed Western blotting for endothelial nitric oxide synthase and nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) to document the underlying mechanism. The CsA-treated group showed increased urinary creatinine excretion, polyuria, and renal glycosuria without GFR reduction, suggesting adequate CsA-induced renal tubular injury. Urinary NGAL excretion also increased significantly in the CsA group. Conversely, apelin attenuated CsA-induced tubular injury and had no effect on urinary NGAL excretion. In histopathologic examination, the apelin-treated group had lower tubulo-interstitial injury scores compared with those in the CsA group. Regarding the effects of apelin, our results indicate that apelin provides protection against CsA-induced tubular injury by activating nitric oxide and/or the NFATc1 pathway. Notably, we also found that CsA inhibits renal glucose reabsorption by reducing Na(+)-K(+) ATPase expression and that apelin reverses reduced renal glucose reabsorption by CsA in tubular cells. Our study demonstrates the renoprotective effect of apelin against CsA-induced renal tubular toxicity and provides novel insights into the effects of CsA and apelin on renal tubular cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion

    PubMed Central

    Mulay, Shrikant R.; Kulkarni, Onkar P.; Rupanagudi, Khader V.; Migliorini, Adriana; Darisipudi, Murthy N.; Vilaysane, Akosua; Muruve, Daniel; Shi, Yan; Munro, Fay; Liapis, Helen; Anders, Hans-Joachim

    2012-01-01

    Nephrocalcinosis, acute calcium oxalate (CaOx) nephropathy, and renal stone disease can lead to inflammation and subsequent renal failure, but the underlying pathological mechanisms remain elusive. Other crystallopathies, such as gout, atherosclerosis, and asbestosis, trigger inflammation and tissue remodeling by inducing IL-1β secretion, leading us to hypothesize that CaOx crystals may induce inflammation in a similar manner. In mice, intrarenal CaOx deposition induced tubular damage, cytokine expression, neutrophil recruitment, and renal failure. We found that CaOx crystals activated murine renal DCs to secrete IL-1β through a pathway that included NLRP3, ASC, and caspase-1. Despite a similar amount of crystal deposits, intrarenal inflammation, tubular damage, and renal dysfunction were abrogated in mice deficient in MyD88; NLRP3, ASC, and caspase-1; IL-1R; or IL-18. Nephropathy was attenuated by DC depletion, ATP depletion, or therapeutic IL-1 antagonism. These data demonstrated that CaOx crystals trigger IL-1β–dependent innate immunity via the NLRP3/ASC/caspase-1 axis in intrarenal mononuclear phagocytes and directly damage tubular cells, leading to the release of the NLRP3 agonist ATP. Furthermore, these results suggest that IL-1β blockade may prevent renal damage in nephrocalcinosis. PMID:23221343

  15. Activation of AMPK by metformin inhibits TGF-β-induced collagen production in mouse renal fibroblasts.

    PubMed

    Lu, Jiamei; Shi, Jianhua; Li, Manxiang; Gui, Baosong; Fu, Rongguo; Yao, Ganglian; Duan, Zhaoyang; Lv, Zhian; Yang, Yanyan; Chen, Zhao; Jia, Lining; Tian, Lifang

    2015-04-15

    To clarify whether activation of adenosine monophosphate-activated protein kinase (AMPK) by metformin inhibits transforming growth factor beta (TGF-β)-induced collagen production in primary cultured mouse renal fibroblasts and further to address the molecular mechanisms. Primary cultured mouse renal fibroblasts were stimulated with TGF-β1 and the sequence specific siRNA of Smad3 or connective tissue growth factor (CTGF) was applied to investigate the involvement of these molecular mediators in TGF-β1-induced collagen type I production. Cells were pre-incubated with AMPK agonist metformin or co-incubated with AMPK agonist metformin and AMPK inhibitor Compound C before TGF-β1 stimulation to clarify whether activation of AMPK inhibition of TGF-β1-induced renal fibroblast collagen type I expression. Our results demonstrate that TGF-β1 time- and dose-dependently induced renal fibroblast collagen type I production; TGF-β1 also stimulated Smad3-dependent CTGF expression and caused collagen type I generation; this effect was blocked by knockdown of Smad3 or CTGF. Activation of AMPK by metformin reduced TGF-β1-induced collagen type I production by suppression of Smad3-driven CTGF expression. This study suggests that activation of AMPK might be a novel strategy for the treatment of chronic kidney disease (CKD) partially by inhibition of renal interstitial fibrosis (RIF). Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Protective effect of angiotensin II-induced increase in nitric oxide in the renal medullary circulation.

    PubMed

    Zou, A P; Wu, F; Cowley, A W

    1998-01-01

    This study examined the effect of intravenous infusion of subpressor doses of angiotensin (Ang II) on renal medullary blood flow (MBF), medullary partial oxygen pressure (PO2), and nitric oxide (NO) concentration under normal conditions and during reduction of the medullary nitric oxide synthase (NOS) activity in anesthetized rats. With laser Doppler flowmetry and polarographic measurement of PO2 with microelectrodes, Ang II (5 ng/kg per minute) did not alter renal cortical and medullary blood flows or medullary PO2. N(omega)-nitro-L-arginine methyl ester (L-NAME) was infused into the renal medullary interstitial space at a dose of 1.4 microg/kg per minute, a dose that did not significantly alter basal levels of MBF or PO2. Intravenous infusion of Ang II at the same dose in the presence of L-NAME decreased MBF by 23% and medullary PO2 by 28%, but it had no effect on cortical blood flow or arterial blood pressure. An in vivo microdialysis-oxyhemoglobin NO trapping technique was used in other rats to determine tissue NO concentrations using the same protocol. Ang II infusion increased tissue NO concentrations by 85% in the renal cortex and 150% in the renal medulla. Renal medullary interstitial infusion of L-NAME (1.4 microg/kg per minute) reduced medullary NO concentrations and substantially blocked Ang II-induced increases in NO concentrations in the renal medulla, but not in the renal cortex. Tissue slices of the renal cortex and medulla were studied to determine the effects of Ang II and L-NAME on the nitrite/nitrate production. Ang II stimulated the nitrite/nitrate production predominately in the renal medulla, which was significantly attenuated by L-NAME. We conclude that small elevations of circulating Ang II levels increase medullary NO production and concentrations, which plays an important role in buffering the vasoconstrictor effects of this peptide and in maintaining a constancy of MBF.

  17. OBESITY-INDUCED HYPERTENSION: INTERACTION OF NEUROHUMORAL AND RENAL MECHANISMS

    PubMed Central

    Hall, John E.; do Carmo, Jussara M.; da Silva, Alexandre A.; Wang, Zhen; Hall, Michael E.

    2015-01-01

    Excess weight gain, especially when associated with increased visceral adiposity, is a major cause of hypertension, accounting for 65–75% of the risk for human primary (essential) hypertension. Increased renal tubular sodium reabsorption impairs pressure natriuresis and plays an important role in initiating obesity hypertension. The mediators of abnormal kidney function and increased blood pressure during development of obesity hypertension include 1) physical compression of the kidneys by fat in and around the kidneys, 2) activation of the renin-angiotensin-aldosterone system (RAAS), and 3) increased sympathetic nervous system (SNS) activity. Activation of the RAAS system is likely due, in part, to renal compression as well as SNS activation. However, obesity also causes mineralocorticoid receptor activation independent of aldosterone or angiotensin II. The mechanisms for SNS activation in obesity have not been fully elucidated but appear to require leptin and activation of the brain melanocortin system. With prolonged obesity and development of target organ injury, especially renal injury, obesity-associated hypertension becomes more difficult to control, often requiring multiple antihypertensive drugs and treatment of other risk factors, including dyslipidemia, insulin resistance and diabetes, and inflammation. Unless effective anti-obesity drugs are developed, the impact of obesity on hypertension and related cardiovascular, renal and metabolic disorders is likely to become even more important in the future as the prevalence of obesity continues to increase. PMID:25767285

  18. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms.

    PubMed

    Hall, John E; do Carmo, Jussara M; da Silva, Alexandre A; Wang, Zhen; Hall, Michael E

    2015-03-13

    Excess weight gain, especially when associated with increased visceral adiposity, is a major cause of hypertension, accounting for 65% to 75% of the risk for human primary (essential) hypertension. Increased renal tubular sodium reabsorption impairs pressure natriuresis and plays an important role in initiating obesity hypertension. The mediators of abnormal kidney function and increased blood pressure during development of obesity hypertension include (1) physical compression of the kidneys by fat in and around the kidneys, (2) activation of the renin-angiotensin-aldosterone system, and (3) increased sympathetic nervous system activity. Activation of the renin-angiotensin-aldosterone system is likely due, in part, to renal compression, as well as sympathetic nervous system activation. However, obesity also causes mineralocorticoid receptor activation independent of aldosterone or angiotensin II. The mechanisms for sympathetic nervous system activation in obesity have not been fully elucidated but may require leptin and activation of the brain melanocortin system. With prolonged obesity and development of target organ injury, especially renal injury, obesity-associated hypertension becomes more difficult to control, often requiring multiple antihypertensive drugs and treatment of other risk factors, including dyslipidemia, insulin resistance and diabetes mellitus, and inflammation. Unless effective antiobesity drugs are developed, the effect of obesity on hypertension and related cardiovascular, renal and metabolic disorders is likely to become even more important in the future as the prevalence of obesity continues to increase.

  19. Acute Renal Failure Induced by Chinese Herbal Medication in Nigeria

    PubMed Central

    Akpan, Effiong Ekong; Ekrikpo, Udeme E.

    2015-01-01

    Traditional herbal medicine is a global phenomenon especially in the resource poor economy where only the very rich can access orthodox care. These herbal products are associated with complications such as acute renal failure and liver damage with a high incidence of mortalities and morbidities. Acute renal failure from the use of herbal remedies is said to account for about 30–35% of all cases of acute renal failure in Africa. Most of the herbal medications are not usually identified, but some common preparation often used in Nigeria includes “holy water” green water leaves, bark of Mangifera indica (mango), shoot of Anacardium occidentale (cashew), Carica papaya (paw-paw) leaves, lime water, Solanum erianthum (Potato tree), and Azadirachta indica (Neem) trees. We report a rare case of a young man who developed acute renal failure two days after ingestion of Chinese herb for “body cleansing” and general wellbeing. He had 4 sessions of haemodialysis and recovered kidney function fully after 18 days of admission. PMID:26199625

  20. Metformin attenuates albumin-induced alterations in renal tubular cells in vitro.

    PubMed

    Allouch, Soumaya; Munusamy, Shankar

    2017-12-01

    Proteinuria (albuminuria) plays a crucial role in the etiology of chronic kidney disease (CKD) via alteration of multiple signaling pathways and cellular process in renal cells. The objectives of this study are to investigate the effects of activation of the energy-sensing molecule AMP-activated kinase (AMPK) in renal cells using metformin on endoplasmic reticulum (ER) stress, AKT, mTOR, epithelial-to-mesenchymal transition (EMT), autophagy, and apoptosis that are thought to mediate renal cell injury during proteinuria, and to dissect the AMPK- and non-AMPK mediated effects of metformin using an in vitro model of albumin-induced renal cell injury. Rat renal proximal tubular (NRK-52E) cells were exposed to 10 and 15 mg/ml of albumin for 72 h in the presence of 1 mM Metformin and/or 0.5 µM compound C, and assessed for alterations in the aforementioned pathways. Metformin treatment restored AMPK phosphorylation and augmented autophagy in renal cells exposed to albumin. In addition, metformin treatment attenuated the albumin-induced phosphorylation of AKT and the downstream targets of mTOR, and prevented albumin-mediated inductions of EMT marker (α-SMA), pro-apoptotic ER stress marker CHOP, and apoptotic caspases -12 and -3 in renal cells. Blockade of metformin-induced AMPK activation with compound C blunted the ER defense response and autophagy but had no effect on the markers of EMT and apoptosis in our model. Our studies suggest that metformin protects renal cells against proteinuric cytotoxicity via suppression of AKT and mTOR activation, inhibition of EMT and apoptosis, and augmentation of autophagy and ER defense response through AMPK-independent and AMPK-dependent mechanisms, respectively. © 2017 Wiley Periodicals, Inc.

  1. Ochratoxin A induced premature senescence in human renal proximal tubular cells.

    PubMed

    Yang, Xuan; Liu, Sheng; Huang, Chuchu; Wang, Haomiao; Luo, Yunbo; Xu, Wentao; Huang, Kunlun

    2017-05-01

    Ochratoxin A (OTA) has many nephrotoxic effects and is a promising compound for the study of nephrotoxicity. Human renal proximal tubular cells (HKC) are an important model for the study of renal reabsorption, renal physiology and pathology. Since the induction of OTA in renal senescence is largely unknown, whether OTA can induce renal senescence, especially at a sublethal dose, and the mechanism of OTA toxicity remain unclear. In our study, a sublethal dose of OTA led to an enhanced senescent phenotype, β-galactosidase staining and senescence associated secretory phenotype (SASP). Cell cycle arrest and cell shape alternations also confirmed senescence. In addition, telomere analysis by RT-qPCR allowed us to classify OTA-induced senescence as a premature senescence. Western blot assays showed that the p53-p21 and the p16-pRB pathways and the ezrin-associated cell spreading changes were activated during the OTA-induced senescence of HKC. In conclusion, our results demonstrate that OTA promotes the senescence of HKC through the p53-p21 and p16-pRB pathways. The understanding of the mechanisms of OTA-induced senescence is critical in determining the role of OTA in cytotoxicity and its potential carcinogenicity. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  2. Salt-Induced Renal Injury in Spontaneously Hypertensive Rats: Effects of Nebivolol

    PubMed Central

    Varagic, Jasmina; Ahmad, Sarfaraz; Brosnihan, K. Bridget; Habibi, Javad; Tilmon, Roger D.; Sowers, James R.; Ferrario, Carlos M.

    2010-01-01

    Background We investigated renal effects of nebivolol, a selective β1-receptor blocker with additional antioxidative ability, in spontaneously hypertensive rats (SHR) where increased salt intake induces oxidative stress and worsens renal function as a result of further activation of the renin-angiotensin and sympathetic nervous systems. Methods Male SHR were given an 8% salt diet (HS; n = 22) for 5 weeks; their age-matched controls (n = 9) received standard chow. Nebivolol was given at a dose of 10 mg/kg/day for 5 weeks in 11 HS rats. Results HS increased blood pressure, plasma renin concentration, urinary protein excretion, and renal nitroxidative stress while decreasing renal blood flow and angiotensin 1–7 receptor (mas) protein expression. There was no change in angiotensin II type 1 receptor expression among the experimental groups. Nebivolol did not alter the salt-induced increase in blood pressure but reduced urinary protein excretion, plasma renin concentration, and nitroxidative stress. Nebivolol also increased neuronal NOS expression while preventing the salt-induced decrease in renal blood flow and mas protein expression. Conclusion Nebivolol prevented salt-induced kidney injury and associated proteinuria in SHR through a blood pressure-independent mechanism. Its protective effects may be related to reduction in oxidative stress, increases in neuronal NOS and restoration of angiotensin II type 1/mas receptor balance. PMID:21042014

  3. Nephroprotective action of Peucedanum grande against cadmium chloride induced renal toxicity in Wistar rats.

    PubMed

    Aslam, Mohammad; Ahmad, Shiekh Tanveer; Dayal, Rameshver; Javid, Kalim; Umar, Sadiq; Asiaf, Asia; Nafees, Sana; Bhat, Jalal Uddin; Wani, Arjumand; Samim, Mohammad; Singh, Surender

    2012-01-01

    Cadmium is a known industrial pollutant which accumulates in the kidney and its exposure leads to the production of reactive oxygen species (ROS). The present study was carried out to evaluate the protective effects of Peucedanum grande against CdCl2 induced renal toxicity in Wistar rats. Wistar rats were subjected to oral pre-treatment of P. grande (60 and 120 mg/kg b.wt) against the renal toxicity induced by administration of CdCl2 (3mg/kg b.wt). Efficacy of P. grande against the renal toxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities and histopathological changes. P. grande pretreatment prevented deteriorative effects induced by CdCl2 through a protective mechanism that involved reduction of increased oxidative stress as well as by restoration of histopathological changes against CdCl2 administration.

  4. Amiodarone-induced hypothyroidism with EPO-resistant anemia in a patient with chronic renal failure.

    PubMed

    Chang, Peter M S; Ng, Yee-Yung

    2008-11-01

    The overall incidence of amiodarone-induced thyroid dysfunction ranges from 2% to 24%. One third to half of patients with hypothyroidism have anemia due to some decrease in normal red blood cell mass and erythropoietin (EPO) resistance. Therefore, for patients with chronic renal disease under medication with amiodarone, early regular thyroid function test should be checked in order to avoid amiodarone-induced hypothyroidism and EPO-resistant anemia. If amiodarone-induced hypothyroidism and EPO-resistant anemia occur in patients with chronic renal failure, early thyroxine should be given instead of waiting for spontaneous recovery by amiodarone discontinuation only. Here, we report a patient with chronic renal failure who developed EPO-resistant anemia after amiodarone treatment for arrhythmia. The hemoglobin level responded to EPO therapy rapidly after thyroxine administration and amiodarone discontinuation.

  5. Wnt antagonist DICKKOPF-3 (Dkk-3) induces apoptosis in human renal cell carcinoma.

    PubMed

    Ueno, Koji; Hirata, Hiroshi; Majid, Shahana; Chen, Yi; Zaman, Mohd S; Tabatabai, Z Laura; Hinoda, Yuji; Dahiya, Rajvir

    2011-06-01

    The Wnt signaling pathway is activated in most cancers while Wnt antagonist genes are inactivated. However, the functional significance and mechanisms of inactivation of Wnt antagonist Dkk-3 gene in renal cell carcinoma (RCC) has not been reported. In this study, we examined potential epigenetic mechanisms regulating Dkk-3 expression in RCC cells and whether Dkk-3 expression affects cell growth and apoptosis. The expression of Dkk-3 is regulated by histone modification rather than CpG island DNA methylation in renal cancer cells. Renal cancer cell proliferation was significantly inhibited and apoptosis was promoted in Dkk-3 transfected renal cancer cells. Dkk-3 did not inhibit the Wnt/beta-catenin signaling pathway but induced apoptosis via the noncanonical JNK pathway in renal cancer cells. Expression of p21, MDM-2, and Puma genes were increased after transfecting RCC cell lines with a Dkk-3 expression plasmid. Overexpression of Dkk-3 induced G(0)/G(1) arrest together with an increase in p21 expression. Growth of stable Dkk-3 transfected cells in nude mice was decreased compared to controls. Our data show for the first time that mRNA expression of Dkk-3 is regulated by histone modification and that Dkk-3 inhibits renal cancer growth through modulation of cell cycle and apoptotic pathways.

  6. Vasopressin Mediates the Renal Damage Induced by Limited Fructose Rehydration in Recurrently Dehydrated Rats.

    PubMed

    García-Arroyo, Fernando E; Tapia, Edilia; Blas-Marron, Mónica G; Gonzaga, Guillermo; Silverio, Octaviano; Cristóbal, Magdalena; Osorio, Horacio; Arellano-Buendía, Abraham S; Zazueta, Cecilia; Aparicio-Trejo, Omar Emiliano; Reyes-García, Juan G; Pedraza-Chaverri, José; Soto, Virgilia; Roncal-Jiménez, Carlos; Johnson, Richard J; Sánchez-Lozada, Laura G

    2017-01-01

    Recurrent dehydration and heat stress cause chronic kidney damage in experimental animals. The injury is exacerbated by rehydration with fructose-containing beverages. Fructose may amplify dehydration-induced injury by directly stimulating vasopressin release and also by acting as a substrate for the aldose reductase-fructokinase pathway, as both of these systems are active during dehydration. The role of vasopressin in heat stress associated injury has not to date been explored. Here we show that the amplification of renal damage mediated by fructose in thermal dehydration is mediated by vasopressin. Fructose rehydration markedly enhanced vasopressin (copeptin) levels and activation of the aldose reductase-fructokinase pathway in the kidney. Moreover, the amplification of the renal functional changes (decreased creatinine clearance and tubular injury with systemic inflammation, renal oxidative stress, and mitochondrial dysfunction) were prevented by the blockade of V1a and V2 vasopressin receptors with conivaptan. On the other hand, there are also other operative mechanisms when water is used as rehydration fluid that produce milder renal damage that is not fully corrected by vasopressin blockade. Therefore, we clearly showed evidence of the cross-talk between fructose, even at small doses, and vasopressin that interact to amplify the renal damage induced by dehydration. These data may be relevant for heat stress nephropathy as well as for other renal pathologies due to the current generalized consumption of fructose and deficient hydration habits.

  7. Paeoniflorin ameliorates acute necrotizing pancreatitis and pancreatitis‑induced acute renal injury.

    PubMed

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

    2016-08-01

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

  8. Vasopressin Mediates the Renal Damage Induced by Limited Fructose Rehydration in Recurrently Dehydrated Rats

    PubMed Central

    García-Arroyo, Fernando E.; Tapia, Edilia; Blas-Marron, Mónica G; Gonzaga, Guillermo; Silverio, Octaviano; Cristóbal, Magdalena; Osorio, Horacio; Arellano-Buendía, Abraham S.; Zazueta, Cecilia; Aparicio-Trejo, Omar Emiliano; Reyes-García, Juan G.; Pedraza-Chaverri, José; Soto, Virgilia; Roncal-Jiménez, Carlos; Johnson, Richard J.; Sánchez-Lozada, Laura G

    2017-01-01

    Recurrent dehydration and heat stress cause chronic kidney damage in experimental animals. The injury is exacerbated by rehydration with fructose-containing beverages. Fructose may amplify dehydration-induced injury by directly stimulating vasopressin release and also by acting as a substrate for the aldose reductase-fructokinase pathway, as both of these systems are active during dehydration. The role of vasopressin in heat stress associated injury has not to date been explored. Here we show that the amplification of renal damage mediated by fructose in thermal dehydration is mediated by vasopressin. Fructose rehydration markedly enhanced vasopressin (copeptin) levels and activation of the aldose reductase-fructokinase pathway in the kidney. Moreover, the amplification of the renal functional changes (decreased creatinine clearance and tubular injury with systemic inflammation, renal oxidative stress, and mitochondrial dysfunction) were prevented by the blockade of V1a and V2 vasopressin receptors with conivaptan. On the other hand, there are also other operative mechanisms when water is used as rehydration fluid that produce milder renal damage that is not fully corrected by vasopressin blockade. Therefore, we clearly showed evidence of the cross-talk between fructose, even at small doses, and vasopressin that interact to amplify the renal damage induced by dehydration. These data may be relevant for heat stress nephropathy as well as for other renal pathologies due to the current generalized consumption of fructose and deficient hydration habits.

  9. N-acetylcysteine improves renal hemodynamics in rats with cisplatin-induced nephrotoxicity.

    PubMed

    Abdelrahman, Aly M; Al Salam, Suhail; AlMahruqi, Ahmed S; Al husseni, Ishaq S; Mansour, Mohamed A; Ali, Badreldin H

    2010-01-01

    This work investigated the effect of N-acetylcysteine (NAC), on renal hemodynamics in cisplatin (CP)-induced nephrotoxicity in Wistar-Kyoto (WKY) rats. The animals were divided into four groups (n = 5 or 6). The first and second groups received normal saline (control) and intraperitoneal (i.p.) N-acetylcysteine (500 mg kg(-1) per day for 9 days), respectively. The third and fourth groups were given a single intraperitoneal (i.p.) injection of CP (5 mg kg(-1)) and an i.p. injection of CP (5 mg kg(-1)) together with i.p. NAC (500 mg kg(-1) per day for 9 days), respectively. At the end of the experiment, rats were anesthetized and blood pressure and renal blood flow were monitored, followed by intravenous (i.v.) injection of norepinephrine (NE) for measurement of renal vasoconstrictor responses. CP caused a significant reduction in renal blood flow but did not affect NE-induced renal vasoconstriction. In addition, CP significantly increased plasma concentrations of urea and creatinine and urinary N-acetyl-beta-D-glucosaminidase (NAG) activity and kidney relative weight. CP decreased body weight and creatinine clearance. Histopathologically, CP caused remarkable renal damage compared with control. NAC alone did not produce any significant change in any of the variables measured. However, NAC significantly ameliorated CP-induced hemodynamic, biochemical and histopathological changes. The concentration of platinum in the kidneys of CP ? NAC treated rats was less than in CP-treated rats by 37%. The results show that administration of i.p. NAC (500 mg kg(-1) per day for 9 days) reversed the renal hemodynamic changes as well as the biochemical and histopathological indices of CP-induced nephrotoxicity in WKY rats.

  10. Hypergravity upregulates renal inducible nitric oxide synthase expression and nitric oxide production

    PubMed Central

    Yoon, Gun; Oh, Choong Sik; Kim, Hyun-Soo

    2016-01-01

    Exposure to hypergravity severely decreases renal blood flow, potentially causing renal dysfunction. Nitric oxide (NO), which is endogenously synthesized by inducible NO synthase (iNOS), plays an important role in the regulation of renal function. The purpose of this study was to examine the effect of hypergravity exposure on the production of NO in kidneys. To determine whether hypergravity induces renal hypoxia and alters renal iNOS expression and NO production, mice were exposed to short-term hypergravity at +3Gz for 1 h. The time course of iNOS mRNA expression, hypoxia-inducible factor (HIF)-1α expression, and NO production was examined. Renal HIF-1α levels were significantly elevated immediately after centrifugation, and this increase was sustained for 3 h post-exposure. iNOS mRNA levels were also significantly increased immediately after exposure and were maintained during the reoxygenation period. Immunohistochemical staining for iNOS revealed that the cortical tubular epithelium exhibited moderate to strong cytoplasmic iNOS immunoreactivity immediately after hypergravity exposure and during the reoxygenation period. The time course of NO production was similar to that of iNOS expression. Our results suggest that both hypoxia and reoxygenation might be involved in the upregulation of HIF-1α in the kidneys of mice exposed to hypergravity. Significant increases in renocortical iNOS expression immediately after centrifugation and during the reoxygenation period suggest that iNOS expression induced by hypergravity exposure might play a protective role against hypoxia/reoxygenation injury in the renal cortex. Further investigations are necessary to clarify the role of iNOS and NO in kidneys exposed to hypergravity. PMID:27174912

  11. Memory CD4 T Cells Induce Antibody-Mediated Rejection of Renal Allografts.

    PubMed

    Gorbacheva, Victoria; Fan, Ran; Fairchild, Robert L; Baldwin, William M; Valujskikh, Anna

    2016-11-01

    Despite advances in immunosuppression, antibody-mediated rejection is a serious threat to allograft survival. Alloreactive memory helper T cells can induce potent alloantibody responses and often associate with poor graft outcome. Nevertheless, the ability of memory T cells to elicit well characterized manifestations of antibody-mediated rejection has not been tested. We investigated helper functions of memory CD4 T cells in a mouse model of renal transplantation. Whereas the majority of unsensitized C57Bl/6 recipients spontaneously accepted fully MHC-mismatched A/J renal allografts, recipients containing donor-reactive memory CD4 T cells rapidly lost allograft function. Increased serum creatinine levels, high serum titers of donor-specific alloantibody, minimal T cell infiltration, and intense C4d deposition in the grafts of sensitized recipients fulfilled all diagnostic criteria for acute renal antibody-mediated rejection in humans. IFNγ neutralization did not prevent the renal allograft rejection induced by memory helper T cells, and CD8 T cell depletion at the time of transplantation or depletion of both CD4 and CD8 T cells also did not prevent the renal allograft rejection induced by memory helper T cells starting at day 4 after transplantation. However, B cell depletion inhibited alloantibody generation and significantly extended allograft survival, indicating that donor-specific alloantibodies (not T cells) were the critical effector mechanism of renal allograft rejection induced by memory CD4 T cells. Our studies provide direct evidence that recipient T cell sensitization may result in antibody-mediated rejection of renal allografts and introduce a physiologically relevant animal model with which to investigate mechanisms of antibody-mediated rejection and novel therapeutic approaches for its prevention and treatment. Copyright © 2016 by the American Society of Nephrology.

  12. Ghrelin Protects against Renal Damages Induced by Angiotensin-II via an Antioxidative Stress Mechanism in Mice

    PubMed Central

    Fujimura, Keiko; Wakino, Shu; Minakuchi, Hitoshi; Hasegawa, Kazuhiro; Hosoya, Koji; Komatsu, Motoaki; Kaneko, Yuka; Shinozuka, Keisuke; Washida, Naoki; Kanda, Takeshi; Tokuyama, Hirobumi; Hayashi, Koichi; Itoh, Hiroshi

    2014-01-01

    We explored the renal protective effects by a gut peptide, Ghrelin. Daily peritoneal injection with Ghrelin ameliorated renal damages in continuously angiotensin II (AngII)-infused C57BL/6 mice as assessed by urinary excretion of protein and renal tubular markers. AngII-induced increase in reactive oxygen species (ROS) levels and senescent changes were attenuated by Ghrelin. Ghrelin also inhibited AngII-induced upregulations of transforming growth factor-β (TGF-β) and plasminogen activator inhibitor-1 (PAI-1), ameliorating renal fibrotic changes. These effects were accompanied by concomitant increase in mitochondria uncoupling protein, UCP2 as well as in a key regulator of mitochondria biosynthesis, PGC1α. In renal proximal cell line, HK-2 cells, Ghrelin reduced mitochondria membrane potential and mitochondria-derived ROS. The transfection of UCP2 siRNA abolished the decrease in mitochondria-derived ROS by Ghrelin. Ghrelin ameliorated AngII-induced renal tubular cell senescent changes and AngII-induced TGF-β and PAI-1 expressions. Finally, Ghrelin receptor, growth hormone secretagogue receptor (GHSR)-null mice exhibited an increase in tubular damages, renal ROS levels, renal senescent changes and fibrosis complicated with renal dysfunction. GHSR-null mice harbored elongated mitochondria in the proximal tubules. In conclusion, Ghrelin suppressed AngII-induced renal damages through its UCP2 dependent anti-oxidative stress effect and mitochondria maintenance. Ghrelin/GHSR pathway played an important role in the maintenance of ROS levels in the kidney. PMID:24747517

  13. Characterization of the renal response to protein ingestion in dogs with experimentally induced renal failure.

    PubMed

    Brown, S A; Finco, D R

    1992-04-01

    Effects of a protein meal (2.7 g of casein/kg of body weight) on glomerular filtration rate (GFR) and renal plasma flow (RPF) were assessed in dogs after 15/16 nephrectomy (n = 10), and were compared with observations in dogs with intact kidneys (n = 5). Increase in GFR and RPF was observed in both groups of dogs between 1.5 and 8 hours after protein ingestion. A maximal value for GFR was observed between 4 and 5 hours after protein ingestion in dogs of both groups. Enhancement of urinary protein excretion was evident in partially nephrectomized dogs after protein ingestion (P less than 0.05), a result that was confirmed by 24-hour total urine collection from partially nephrectomized dogs fed a balanced ration. A qualitatively similar vasodilatory response was observed in partially nephrectomized dogs and in dogs with intact kidneys, and the mean maximal increase of GFR and RPF expressed as a percentage of baseline values in the latter dogs (47.0 +/- 8.1 and 43.6 +/- 10.3%, respectively) exceeded that observed in partially nephrectomized dogs (20.8 +/- 2.2 and 22.7 +/- 6.3%, respectively; P less than 0.01). The incremental response of the kidneys to protein ingestion was directly related to the degree of renal function, as reflected in the linear regression relationship between the incremental increase in GFR and the baseline value for GFR (P less than 0.01, R2 = 0.721).

  14. Capsaicin Ameliorates Cisplatin-Induced Renal Injury through Induction of Heme Oxygenase-1

    PubMed Central

    Jung, Sung-Hyun; Kim, Hyung-Jin; Oh, Gi-Su; Shen, AiHua; Lee, Subin; Choe, Seong-Kyu; Park, Raekil; So, Hong-Seob

    2014-01-01

    Cisplatin is one of the most potent chemotherapy agents. However, its use is limited due to its toxicity in normal tissues, including the kidney and ear. In particular, nephrotoxicity induced by cisplatin is closely associated with oxidative stress and inflammation. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in the heme metabolism, has been implicated in a various cellular processes, such as inflammatory injury and anti-oxidant/oxidant homeostasis. Capsaicin is reported to have therapeutic potential in cisplatin-induced renal failures. However, the mechanisms underlying its protective effects on cisplatin-induced nephrotoxicity remain largely unknown. Herein, we demonstrated that administration of capsaicin ameliorates cisplatin-induced renal dysfunction by assessing the levels of serum creatinine and blood urea nitrogen (BUN) as well as tissue histology. In addition, capsaicin treatment attenuates the expression of inflammatory mediators and oxidative stress markers for renal damage. We also found that capsaicin induces HO-1 expression in kidney tissues and HK-2 cells. Notably, the protective effects of capsaicin were completely abrogated by treatment with either the HO inhibitor ZnPP IX or HO-1 knockdown in HK-2 cells. These results suggest that capsaicin has protective effects against cisplatin-induced renal dysfunction through induction of HO-1 as well as inhibition oxidative stress and inflammation. PMID:24642709

  15. Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity

    PubMed Central

    Manchandani, Pooja; Zhou, Jian; Babic, Jessica T.; Ledesma, Kimberly R.; Truong, Luan D.

    2017-01-01

    ABSTRACT Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 ± 0.4 μg/g, 9.9 ± 1.5 μg/g, and 21.7 ± 4.8 μg/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity. PMID:28096166

  16. Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity.

    PubMed

    Manchandani, Pooja; Zhou, Jian; Babic, Jessica T; Ledesma, Kimberly R; Truong, Luan D; Tam, Vincent H

    2017-04-01

    Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 ± 0.4 μg/g, 9.9 ± 1.5 μg/g, and 21.7 ± 4.8 μg/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity. Copyright © 2017 American Society for Microbiology.

  17. Stevens-Johnson syndrome induced by sorafenib for metastatic renal cell carcinoma.

    PubMed

    Ikeda, Masaomi; Fujita, Tetsuo; Amoh, Yasuyuki; Mii, Sumiyuki; Matsumoto, Kazumasa; Iwamura, Masatsugu

    2013-01-01

    Sorafenib is an orally administered active multikinase inhibitor for metastatic renal cell carcinoma that is now considered a standard agent. Skin toxicity, such as hand-foot skin reaction, is one of the frequent adverse effects of sorafenib. On the other hand, sorafenib-induced erythema multiforme is very rare, and Stevens-Johnson syndrome and toxic epidermal necrolysis induced by sorafenib have not been reported. We report the first case of Stevens-Johnson syndrome caused by sorafenib for metastatic renal cell carcinoma. © 2013 S. Karger AG, Basel.

  18. Mycelia glycoproteins from Cordyceps sobolifera ameliorate cyclosporine-induced renal tubule dysfunction in rats.

    PubMed

    Chyau, Charny-Cherng; Chen, Chin-Chu; Chen, Jun-Chang; Yang, Te-Cheng; Shu, Kuo-Hsiung; Cheng, Chi-Hung

    2014-05-14

    Cordyceps sorbolifera has been used in Traditional Chinese Medicine for improving the renal function. Cyclosporine A (CsA) is an important immunosuppressive agent in the prevention of renal allograft rejection, but long-term usage of CsA could lead to chronic nephrotoxicity and renal graft failure. The study was aimed to investigate whether the mycelia glycoproteins of Cordyceps sobolifera (CSP) exert prevention effects on CsA-induced nephrotoxicity. Sprague-Dawley (SD) rats were randomly assigned into four groups (n=6 per group): normal saline (control group), CSP group, CsA group, and CSP-CsA group (CsA combined treatment with CSP). Glomerular and tubular functions were assessed and histological studies were performed. CSP, prepared by hot water extraction, ethanol precipitation and membrane dialysis, was found to be composed of three glycoproteins with average molecular weights of 543, 31, and 6.3 kDa, respectively. CsA impaired urea clearance and creatinine clearance were significantly improved by concomitant administration of CSP. TUNEL histochemical stain revealed that CSP significantly decreased CsA-induced apoptosis in renal tubular cells. The reducing effect of caspase-3 activation by CSP was suggested through the over-expression of the anti-apoptosis protein Bcl-2 in renal tubule cells. In assessment of CSP protection of renal tubule function, we found that CSP restored CsA induced magnesium wasting by increasing the magnesium reabsorption channels TRMP6 and TRMP7. The results suggested that CSP had a significant suppressive activity on CsA-induced apoptosis and protective activity against nephron loss possibly via its restoring activity by increasing the magnesium reabsorption channels TRMP6 and TRMP7 on CsA induced magnesium wasting. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Renal afferent signaling diuretic response is impaired in streptozotocin-induced diabetic rats.

    PubMed

    Chien, C T; Chien, H F; Cheng, Y J; Chen, C F; Hsu, S M

    2000-01-01

    Renal afferent signaling diuretic response is impaired in streptozotocin-induced diabetic rats. Renal insufficiency develops in diabetes and shows structural and functional abnormalities. Renal afferents, including chemoreceptors and mechanoreceptors located in the vascular and ureteropelvic portions of the kidney, may reflect changes in the environment and trigger an afferent nerve-mediated regulatory function that is known as the renorenal reflex. In this study, the involvement of these renal sensory receptors during the early diabetic state is defined. Diabetes was induced in rats after a tail vein injection of streptozotocin (STZ; 60 mg/kg intravenously). Four groups of rats, control (C), diabetic (DM), diabetic with acute insulin treatment (DMAI, 9 U/rat, subcutaneously, on the experimental day), and chronic insulin treatment (DMCI, 9 U/rat, subcutaneously, daily) were studied. Spontaneous firing type 2-renal chemoreceptor (CR2), arterial mechanoreceptor (MRa), ureteropelvic mechanoreceptor (MRu), and venous mechanoreceptor (MRv) were identified by single-unit analysis of renal afferent nervous activity. The receptor activities were confirmed by their response patterns to stimuli elicited by renal arterial occlusion (RAO), backflow of urine, increasing arterial pressure, increasing ureteropelvic pressure (UP), or renal venous occlusion (RVO). The response of these afferent receptors to a challenge of volume expansion and their functional activities on renorenal reflexes were also examined. Immunostaining with PGP 9.5 was applied for examination of the nerve distribution in the diabetic kidney. The tissue level of histamine in the renal pelvis was determined. We explored the effect of histamine on renal receptor activity in these animals to address the possible role of histamine in MRu receptor activity. In early diabetics, signaling activities in MRa and MRv were maintained; however, activity in CR2 and MRu was depressed. For CR2, the reduced basal discharge

  20. Improper hydration induces global gene expression changes associated with renal development in infant mice.

    PubMed

    Kim, Chong-Su; Shin, Dong-Mi

    2016-01-01

    The kidney is a major organ in which fluid balance and waste excretion is regulated. For the kidney to achieve maturity with functions, normal renal developmental processes need to occur. Comprehensive genetic programs underlying renal development during the prenatal period have been widely studied. However, postnatal renal development, from infancy to the juvenile period, has not been studied yet. Here, we investigated whether structural and functional kidney development was still ongoing in early life by analyzing the renal transcriptional networks of infant (4 weeks old) and juvenile (7 weeks old) mice. We further examined the effects of dehydration on kidney development to unravel the mechanistic bases underlying deteriorative impact of pediatric dehydration on renal development. 3-week-old infant mice that just finished weaning period were provided limited access to a water for fifteen minutes per day for one week (RES 1W) and four weeks (RES 4W) to induce dehydration while control group consumed water ad libitum with free access to the water bottle. Transcriptome analysis was conducted to understand physiological changes during postnatal renal development and dehydration. Kidneys in 4-week- and 7-week-old mice showed significantly distinctive functional gene networks. Gene sets related to cell cycle regulators, fetal kidney patterning molecules, and immature basement membrane integrity were upregulated in infantile kidneys while heightened expressions of genes associated with ion transport and drug metabolism were observed in juvenile kidneys. Dehydration during infancy suppressed renal growth by interrupting the SHH signaling pathway, which targets cell cycle regulators. Importantly, it is likely that disruption of the developmental program ultimately led to a decline in gene expression associated with basement membrane integrity. Altogether, we demonstrate transcriptional events during renal development in infancy and show that the impacts of inadequate

  1. Protective Effects of Berberine on Renal Injury in Streptozotocin (STZ)-Induced Diabetic Mice

    PubMed Central

    Zhang, Xiuli; He, Hui; Liang, Dan; Jiang, Yan; Liang, Wei; Chi, Zhi-Hong; Ma, Jianfei

    2016-01-01

    Diabetic nephropathy (DN) is a serious diabetic complication with renal hypertrophy and expansion of extracellular matrices in renal fibrosis. Epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells may be involved in the main mechanism. Berberine (BBR) has been shown to have antifibrotic effects in liver, kidney and lung. However, the mechanism of cytoprotective effects of BBR in DN is still unclear. In this study, we investigated the curative effects of BBR on tubulointerstitial fibrosis in streptozotocin (STZ)-induced diabetic mice and the high glucose (HG)-induced EMT in NRK 52E cells. We found that BBR treatment attenuated renal fibrosis by activating the nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway in the diabetic kidneys. Further revealed that BBR abrogated HG-induced EMT and oxidative stress in relation not only with the activation of Nrf2 and two Nrf2-targeted antioxidative genes (NQO-1 and HO-1), but also with the suppressing the activation of TGF-β/Smad signaling pathway. Importantly, knockdown Nrf2 with siRNA not only abolished the BBR-induced expression of HO-1 and NQO-1 but also removed the inhibitory effect of BBR on HG-induced activation of TGF-β/Smad signaling as well as the anti-fibrosis effects. The data from present study suggest that BBR can ameliorate tubulointerstitial fibrosis in DN by activating Nrf2 pathway and inhibiting TGF-β/Smad/EMT signaling activity. PMID:27529235

  2. Hesperidin attenuates cisplatin-induced acute renal injury by decreasing oxidative stress, inflammation and DNA damage.

    PubMed

    Sahu, Bidya Dhar; Kuncha, Madhusudana; Sindhura, G Jeevana; Sistla, Ramakrishna

    2013-03-15

    Nephrotoxicity is an important complication in cancer patients undergoing cisplatin therapy. Oxidative stress, inflammation and apoptosis/necrosis are the major patho-mechanisms of cisplatin induced nephrotoxicity. In the present study, hesperidin, a naturally-occurring bioflavonoid has been demonstrated to have protective effect on cisplatin-induced renal injury in rats. Cisplatin intoxication resulted in structural and functional renal impairment which was revealed by massive histopathological changes and elevated blood urea nitrogen and serum creatinine levels, respectively. Renal injury was associated with oxidative stress/lipid peroxidation as evident by increased reactive oxygen species (ROS) and malondialdehyde (MDA) formation with decreased levels of antioxidants such as reduced glutathione, vitamin C, catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase and glutathione-S-transferase. Cisplatin administration also triggered inflammatory response in rat kidneys by inducing pro-inflammatory cytokine, TNF-α, with the increased expression of myeloperoxidase (MPO). Furthermore, cisplatin increased the activity of caspase-3 and DNA damage with decreased tissue nitric oxide levels. Hesperidin treatment significantly attenuated the cisplatin-induced oxidative stress/lipid peroxidation, inflammation (infiltration of leukocytes and pro-inflammatory cytokine), apoptosis/necrosis (caspase-3 activity with DNA damage) as well as increased expression of nitric oxide in the kidney and improved renal function. Thus, our results suggest that hesperidin co-administration may serve as a novel and promising preventive strategy against cisplatin-induced nephrotoxicity. Copyright © 2012 Elsevier GmbH. All rights reserved.

  3. Blockade of the N-Methyl-D-Aspartate Glutamate Receptor Ameliorates Lipopolysaccharide-Induced Renal Insufficiency

    PubMed Central

    Huang, Ho-Shiang; Ma, Ming-Chieh

    2015-01-01

    N-methyl-D-aspartate (NMDA) receptor activation in rat kidney reduces renal perfusion and ultrafiltration. Hypoperfusion-induced ischemia is the most frequent cause of functional insufficiency in the endotoxemic kidney. Here, we used non-hypotensive rat model of lipopolysaccharide-induced endotoxemia to examine whether NMDA receptor hyperfunction contributes to acute kidney injury. Lipopolysaccharide-induced renal damage via increased enzymuria and hemodynamic impairments were ameliorated by co-treatment with the NMDA receptor blocker, MK-801. The NMDA receptor NR1 subunit in the rat kidney mainly co-localized with serine racemase, an enzyme responsible for synthesizing the NMDA receptor co-agonist, D-serine. The NMDA receptor hyperfunction in lipopolysaccharide-treated kidneys was demonstrated by NR1 and serine racemase upregulation, particularly in renal tubules, and by increased D-serine levels. Lipopolysaccharide also induced cell damage in cultured tubular cell lines and primary rat proximal tubular cells. This damage was mitigated by MK-801 and by small interfering RNA targeting NR1. Lipopolysaccharide increased cytokine release in tubular cell lines via toll-like receptor 4. The release of interleukin-1β from these cells are the most abundant. An interleukin-1 receptor antagonist not only attenuated cell death but also abolished lipopolysaccharide-induced NR1 and serine racemase upregulation and increases in D-serine secretion, suggesting that interleukin-1β-mediated NMDA receptor hyperfunction participates in lipopolysaccharide-induced tubular damage. The results of this study indicate NMDA receptor hyperfunction via cytokine effect participates in lipopolysaccharide-induced renal insufficiency. Blockade of NMDA receptors may represent a promising therapeutic strategy for the treatment of sepsis-associated renal failure. PMID:26133372

  4. Hydroxyethylstarch impairs renal function and induces interstitial proliferation, macrophage infiltration and tubular damage in an isolated renal perfusion model

    PubMed Central

    Hüter, Lars; Simon, Tim-Philipp; Weinmann, Lenard; Schuerholz, Tobias; Reinhart, Konrad; Wolf, Gunter; Amann, Kerstin Ute; Marx, Gernot

    2009-01-01

    Introduction The aim of the study was to evaluate some of the underlying pathomechanisms of hydroxyethylstarch (HES) induced adverse effects on renal function using 24 porcine kidneys in an isolated perfusion model over six hours. Methods Infusion of either 10% HES 200/0.5, 6% HES 130/0.42 or Ringer's lactate (RL) was performed to achieve an haematocrit of 20% in eight kidneys from four animals per group. Physiological and pathophysiological parameters were determined (including N-acetyl-beta-aminoglucosidase as a marker for lysosomal tubular damage). Histological investigations and immunohistological stainings of the kidneys were performed. Results Initially after haemodilution, HES 130/0.42 and HES 200/0.5 reduced urine output compared with RL (P < 0.01). After six hours, N-acetyl-beta-aminoglucosidase was significantly higher in HES 200/0.5 (81 ± 23 U/L) compared with HES 130/0.42 (38 ± 12 U/L) and RL (21 ± 13 U/L; P < 0.001). Osmotic nephrosis-like lesions (OL) of the tubuli were present in all groups showing a significantly lower number of OL in RL (1.1 ± 0.4; P = 0.002) compared with both HES groups (HES 200/0.5 = 2.1 ± 0.6; HES 130/0.42 = 2.0 ± 0.5). Macrophage infiltration was significantly higher in HES 200/0.5 compared with HES 130/0.42 (1.3 ± 1.0 vs. 0.2 ± 0.04; P = 0.044). There was a significant increase in interstitial cell proliferation in the HES 200/0.5 group vs. HES 130/0.42 (18.0 ± 6.9 vs. 6.5 ± 1.6; P = 0.006) with no significant difference in RL (13.5 ± 4.0). Conclusions We observed impaired diuresis and sodium excretion by HES and identified renal interstitial proliferation, macrophage infiltration and tubular damage as potential pathological mechanisms of HES-induced adverse effects on renal function using an isolated porcine renal perfusion model. Furthermore, we demonstrated that 10% HES 200/0.5 had more of a pro-inflammatory effect compared with 6% HES 130/0.42 and caused more pronounced tubular damage than 6% HES 130/0.42 and

  5. Dalbergioidin Ameliorates Doxorubicin-Induced Renal Fibrosis by Suppressing the TGF-β Signal Pathway

    PubMed Central

    Ren, Xianguo; Bo, Yun; Fan, Junting; Chen, Maosheng; Xu, Daliang; Dong, Yang; He, Haowei; Ren, Xianzhi; Qu, Rong; Jin, Yulian

    2016-01-01

    We investigated the effect of Dalbergioidin (DAL), a well-known natural product extracted from Uraria crinita, on doxorubicin- (DXR-) induced renal fibrosis in mice. The mice were pretreated for 7 days with DAL followed by a single injection of DXR (10 mg/kg) via the tail vein. Renal function was analyzed 5 weeks after DXR treatment. DXR caused nephrotoxicity. The symptoms of nephrotic syndrome were greatly improved after DAL treatment. The indices of renal fibrosis, the phosphorylation of Smad3, and the expression of alpha-smooth muscle actin (α-SMA), fibronectin, collagen III (Col III), E-cadherin, TGF-β, and Smad7 in response to DXR were all similarly modified by DAL. The present findings suggest that DAL improved the markers for kidney damage investigated in this model of DXR-induced experimental nephrotoxicity. PMID:28100935

  6. Acetaminophen inhibits hemoprotein-catalyzed lipid peroxidation and attenuates rhabdomyolysis-induced renal failure

    PubMed Central

    Boutaud, Olivier; Moore, Kevin P.; Reeder, Brandon J.; Harry, David; Howie, Alexander J.; Wang, Shuhe; Carney, Clare K.; Masterson, Tina S.; Amin, Taneem; Wright, David W.; Wilson, Michael T.; Oates, John A.; Roberts, L. Jackson

    2010-01-01

    Hemoproteins, hemoglobin and myoglobin, once released from cells can cause severe oxidative damage as a consequence of heme redox cycling between ferric and ferryl states that generates radical species that induce lipid peroxidation. We demonstrate in vitro that acetaminophen inhibits hemoprotein-induced lipid peroxidation by reducing ferryl heme to its ferric state and quenching globin radicals. Severe muscle injury (rhabdomyolysis) is accompanied by the release of myoglobin that becomes deposited in the kidney, causing renal injury. We previously showed in a rat model of rhabdomyolysis that redox cycling between ferric and ferryl myoglobin yields radical species that cause severe oxidative damage to the kidney. In this model, acetaminophen at therapeutic plasma concentrations significantly decreased oxidant injury in the kidney, improved renal function, and reduced renal damage. These findings also provide a hypothesis for potential therapeutic applications for acetaminophen in diseases involving hemoprotein-mediated oxidative injury. PMID:20133658

  7. Captopril-induced sialadenitis in a patient with end-stage renal disease

    PubMed Central

    Mahdiabadi, Fatemeh Musavi; Nikvarz, Naemeh

    2016-01-01

    Sialadenitis is a rare adverse effect of captopril. We report a case of captopril-induced sialadenitis in a patient with end-stage renal disease (ESRD). A 20-year-old man with ESRD encountered parotid and submandibular swelling after receiving two doses of captopril, administered sublingually. Despite of prescribing dexamethasone, resuming hemodialysis, and discontinuing other drugs that also can cause parotitis, he improved later than what was reported in patients with normal renal function. In conclusion recovery from captopril-induced sialadenitis in patients with ESRD may be more prolonged than that of patients with normal renal function; moreover, early hemodialysis which helps in drug removal may be the most effective treatment. PMID:27162811

  8. A rare case of acute renal failure secondary to rhabdomyolysis probably induced by donepezil.

    PubMed

    Sahin, Osman Zikrullah; Ayaz, Teslime; Yuce, Suleyman; Sumer, Fatih; Sahin, Serap Baydur

    2014-01-01

    Introduction. Acute renal failure (ARF) develops in 33% of the patients with rhabdomyolysis. The main etiologic factors are alcoholism, trauma, exercise overexertion, and drugs. In this report we present a rare case of ARF secondary to probably donepezil-induced rhabdomyolysis. Case Presentation. An 84-year-old male patient was admitted to the emergency department with a complaint of generalized weakness and reduced consciousness for two days. He had a history of Alzheimer's disease for one year and he had taken donepezil 5 mg daily for two months. The patient's physical examination revealed apathy, loss of cooperation, and decreased muscle strength. Laboratory studies revealed the following: urea: 128 mg/dL; Creatinine 6.06 mg/dL; creatine kinase: 3613 mg/dL. Donepezil was discontinued and the patient's renal function tests improved gradually. Conclusion. Rhabdomyolysis-induced acute renal failure may develop secondary to donepezil therapy.

  9. A Rare Case of Acute Renal Failure Secondary to Rhabdomyolysis Probably Induced by Donepezil

    PubMed Central

    Sahin, Osman Zikrullah; Ayaz, Teslime; Yuce, Suleyman; Sumer, Fatih

    2014-01-01

    Introduction. Acute renal failure (ARF) develops in 33% of the patients with rhabdomyolysis. The main etiologic factors are alcoholism, trauma, exercise overexertion, and drugs. In this report we present a rare case of ARF secondary to probably donepezil-induced rhabdomyolysis. Case Presentation. An 84-year-old male patient was admitted to the emergency department with a complaint of generalized weakness and reduced consciousness for two days. He had a history of Alzheimer's disease for one year and he had taken donepezil 5 mg daily for two months. The patient's physical examination revealed apathy, loss of cooperation, and decreased muscle strength. Laboratory studies revealed the following: urea: 128 mg/dL; Creatinine 6.06 mg/dL; creatine kinase: 3613 mg/dL. Donepezil was discontinued and the patient's renal function tests improved gradually. Conclusion. Rhabdomyolysis-induced acute renal failure may develop secondary to donepezil therapy. PMID:24864216

  10. Dalbergioidin Ameliorates Doxorubicin-Induced Renal Fibrosis by Suppressing the TGF-β Signal Pathway.

    PubMed

    Ren, Xianguo; Bo, Yun; Fan, Junting; Chen, Maosheng; Xu, Daliang; Dong, Yang; He, Haowei; Ren, Xianzhi; Qu, Rong; Jin, Yulian; Zhao, Weihong; Xu, Changliang

    2016-01-01

    We investigated the effect of Dalbergioidin (DAL), a well-known natural product extracted from Uraria crinita, on doxorubicin- (DXR-) induced renal fibrosis in mice. The mice were pretreated for 7 days with DAL followed by a single injection of DXR (10 mg/kg) via the tail vein. Renal function was analyzed 5 weeks after DXR treatment. DXR caused nephrotoxicity. The symptoms of nephrotic syndrome were greatly improved after DAL treatment. The indices of renal fibrosis, the phosphorylation of Smad3, and the expression of alpha-smooth muscle actin (α-SMA), fibronectin, collagen III (Col III), E-cadherin, TGF-β, and Smad7 in response to DXR were all similarly modified by DAL. The present findings suggest that DAL improved the markers for kidney damage investigated in this model of DXR-induced experimental nephrotoxicity.

  11. Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects

    PubMed Central

    Yasuda, Hideo; Yuen, Peter S.T.; Hu, Xuzhen; Zhou, Hua; Star, Robert A.

    2008-01-01

    Acute kidney injury (AKI) occurs in about half of patients in septic shock and the mortality of AKI with sepsis is extremely high. An effective therapeutic intervention is urgently required. Statins are HMG-CoA reductase inhibitors that also have pleiotropic actions. They have been reported to increase survival of septic or infectious patients. But the effect of simvastatin, a widely used statin, on sepsis-induced AKI is unknown. The effects of simvastatin and TNF-alpha neutralizing antibody were studied in a clinically relevant model of sepsis-induced AKI using cecal ligation and puncture (CLP) in elderly mice. Simvastatin siginificantly improved CLP-induced mortality and AKI. Simvastatin attenuated CLP-induced tubular damage and reversed CLP-induced reduction of intrarenal microvascular perfusion and renal tubular hypoxia at 24 hours. Simvastatin also restored towards normal CLP-induced renal vascular protein leak and serum TNF-alpha. Neither delayed simvastatin therapy nor TNF-alpha neutralizing antibody improved CLP-induced AKI. Simvastatin improved sepsis-induced AKI by direct effects on the renal vasculature, reversal of tubular hypoxia, and had a systemic anti-inflammatory effect. PMID:16557230

  12. Multiple Low-Dose Radiation Prevents Type 2 Diabetes-Induced Renal Damage through Attenuation of Dyslipidemia and Insulin Resistance and Subsequent Renal Inflammation and Oxidative Stress

    PubMed Central

    Shao, Minglong; Lu, Xuemian; Cong, Weitao; Xing, Xiao; Tan, Yi; Li, Yunqian; Li, Xiaokun; Jin, Litai; Wang, Xiaojie; Dong, Juancong; Jin, Shunzi; Zhang, Chi; Cai, Lu

    2014-01-01

    Background Dyslipidemia and lipotoxicity-induced insulin resistance, inflammation and oxidative stress are the key pathogeneses of renal damage in type 2 diabetes. Increasing evidence shows that whole-body low dose radiation (LDR) plays a critical role in attenuating insulin resistance, inflammation and oxidative stress. Objective The aims of the present study were to investigate whether LDR can prevent type 2 diabetes-induced renal damage and the underlying mechanisms. Methods Mice were fed with a high-fat diet (HFD, 40% of calories from fat) for 12 weeks to induce obesity followed by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg) to develop a type 2 diabetic mouse model. The mice were exposed to LDR at different doses (25, 50 and 75 mGy) for 4 or 8 weeks along with HFD treatment. At each time-point, the kidney weight, renal function, blood glucose level and insulin resistance were examined. The pathological changes, renal lipid profiles, inflammation, oxidative stress and fibrosis were also measured. Results HFD/STZ-induced type 2 diabetic mice exhibited severe pathological changes in the kidney and renal dysfunction. Exposure of the mice to LDR for 4 weeks, especially at 50 and 75 mGy, significantly improved lipid profiles, insulin sensitivity and protein kinase B activation, meanwhile, attenuated inflammation and oxidative stress in the diabetic kidney. The LDR-induced anti-oxidative effect was associated with up-regulation of renal nuclear factor E2-related factor-2 (Nrf-2) expression and function. However, the above beneficial effects were weakened once LDR treatment was extended to 8 weeks. Conclusion These results suggest that LDR exposure significantly prevented type 2 diabetes-induced kidney injury characterized by renal dysfunction and pathological changes. The protective mechanisms of LDR are complicated but may be mainly attributed to the attenuation of dyslipidemia and the subsequent lipotoxicity-induced insulin resistance

  13. Resistance of the rat to development of lead-induced renal functional deficits

    SciTech Connect

    O'Flaherty, E.J.; Adams, W.D.; Hammond, P.B.; Taylor, E.

    1986-01-01

    Lead nephropathy, characterized functionally by depression of effective renal plasma flow (ERPF), glomerular filtration rate (GFR), and maximum glucose reabsorption rate, is associated with prolonged occupational exposure to lead. Production of comparable lead-related renal functional deficits in rats has been difficult to achieve. The authors have examined in rats some of the factors that might be expected to influence the development of lead-induced renal functional damage, using GFR (as inulin clearance). ERPF (as para-aminohippurate clearance), and maximum glucose readsorption rates as indices of renal functional competence. Although lead produces a significant weight loss, this can be accounted for by reduced food intake and is not associated with reduction in renal function. Even exposure to large amounts of lead in conjunction with other factors; such as controlled diet (NIH-07 and AIN-76) and early age of initial exposure, that might have been expected to increase the rats' susceptibility has not resulted in the development of renal functional deficits. It is unlikely that the rat can be successfully explored as an animal model of human lead nephropathy with accompanying functional deficits.

  14. Mangiferin attenuates renal ischemia-reperfusion injury by inhibiting inflammation and inducing adenosine production.

    PubMed

    Wang, Bin; Wan, Jingyuan; Gong, Xia; Kuang, Ge; Cheng, Xiahong; Min, Su

    2015-03-01

    Ischemia reperfusion injury (IRI) is a leading cause of acute kidney injury, which is associated with high morbidity. The aims of the present study were to examine whether mangiferin attenuates renal IRI in an animal model and to identify the underlying mechanism(s). Male mice were subjected to right renal ischemia for 30min followed by reperfusion for 24h or to a sham operation during which the left kidney was removed. After the 24h reperfusion, all mice were humanely euthanized and kidney tissues collected. Renal damage and apoptosis were investigated by examining hematoxylin and eosin-stained tissues, and by TUNEL assay and immunohistochemistry. Renal function was examined by measuring the concentrations of creatinine, blood urea nitrogen, and potassium (K(+)) in the serum. MPO activity, the levels of NO, TNF-α, IL-1β, and adenosine, and CD73 expression in renal tissue were also examined. Mangiferin reduced ischemia reperfusion-induced injury, improved kidney function, and inhibited both proinflammatory responses and tubular apoptosis. In addition, treatment with mangiferin increased adenosine production and CD73 expression in kidney's suffering IRI. Mangiferin appears to attenuate renal IRI by inhibiting proinflammatory responses and tubular apoptosis and by increasing adenosine production. These effects are associated with the adenosine-CD73 signaling pathway. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Basiliximab induced non-cardiogenic pulmonary edema in two pediatric renal transplant recipients.

    PubMed

    Dolan, Niamh; Waldron, Mary; O'Connell, Marie; Eustace, Nick; Carson, Kevin; Awan, Atif

    2009-11-01

    We report two cases of non-cardiogenic pulmonary edema as a complication of basiliximab induction therapy in young pediatric renal transplant patients identified following a retrospective review of all pediatric renal transplant cases performed in the National Paediatric Transplant Centre, Childrens University Hospital, Temple Street, Dublin, Ireland. Twenty-eight renal transplantations, of which five were living-related (LRD) and 23 were from deceased donors (DD), were performed in 28 children between 2003 and 2006. In six cases, transplantations were pre-emptive. Immunosuppression was induced pre-operatively using a combination of basiliximab, tacrolimus and methylprednisolone in all patients. Basiliximab induction was initiated 2 h prior to surgery in all cases and, in 26 patients, basiliximab was re-administered on post-operative day 4. Two patients, one LRD and one DD, aged 6 and 11 years, respectively, developed acute non-cardiogenic pulmonary edema within 36 h of surgery. Renal dysplasia was identified as the primary etiological factor for renal failure in both cases. Both children required assisted ventilation for between 4 and 6 days. While both grafts had primary function, the DD transplant patient subsequently developed acute tubular necrosis and was eventually lost within 3 weeks due to thrombotic microangiopathy and severe acute antibody-mediated rejection despite adequate immunosuppression. Non-cardiogenic pulmonary edema is a potentially devastating post-operative complication of basiliximab induction therapy in young pediatric patients following renal transplantation. Early recognition and appropriate supportive therapy is vital for patient and, where possible, graft survival.

  16. Eupafolin nanoparticle improves acute renal injury induced by LPS through inhibiting ROS and inflammation.

    PubMed

    Zhang, Hao; Chen, Ming-Kun; Li, Ke; Hu, Cheng; Lu, Min-Hua; Situ, Jie

    2017-01-01

    Acute renal injury is a common severe clinical syndrome, occurring in many clinical situations. It is necessary to explore effective drugs to treat it. Eupafolin is a flavonoid compound, derived from Phyla nodiflora, which has been previously reported to possess a variety of pharmacological activities, including anti-inflammatory and antioxidant effects. However, it is known little about how it works in acute renal injury. Also, eupafolin is characterized by skin penetration and poor water solubility, limiting its clinical applications. Thus, we synthesized an eupafolin nanoparticle delivery system. We found that eupafolin nanoparticle could address the physicochemical defects of raw eupafolin and increase water solubility without any toxicity to normal renal cells via reducing particle size. Eupafolin nanoparticle attenuated LPS-induced acute renal injury in mice through inhibiting oxidative stress and inflammation accompanied with up-regulated SOD activity and down-regulated pro-inflammatory cytokines. Additionally, inactivation of NF-κB and MAPKs of p38, ERK1/2 and JNK signaling pathways was a main molecular mechanism by which eupafolin nanoparticle improved renal injury. Together, eupafolin nanoparticle exhibits effective anti-oxidant and anti-inflammatory activities, which could be used as a potential drug to ameliorate acute renal injury clinically.

  17. Açai berry extract attenuates glycerol-induced acute renal failure in rats.

    PubMed

    Unis, Amina

    2015-03-01

    Acute renal failure (ARF) is one of the most common problems encountered in hospitalized critically ill patients. In recent years great effort has been focused on the introduction of herbal medicine as a novel therapeutic agent for prevention of ARF. Hence, the current study was designed to investigate the effect of Açai berry extract (ABE) on glycerol-induced ARF in rats. Results of the present study showed that rat groups that received oral ABE in a dose of 100 and 200 mg/kg/day for 7 days before or 7 days after induction of ARF by a single intramuscular glycerol injection reported a significant improvement in kidney functions tests [decrease in serum urea, serum creatinine, and blood urea nitrogen (BUN)] when compared to the ARF model groups. Moreover, there was significant amelioration in renal oxidative stress markers [renal catalase (CAT), renal reduced glutathione (GSH)] and renal histopathological changes in the ABE-treated groups when compared to ARF model groups. The most significant improvement was reported in the groups where ABE was administered in a dose 200 mg/kg/day. These results indicate that ABE has a potential role in ameliorating renal damage involved in ARF.

  18. Human CD133+ Renal Progenitor Cells Induce Erythropoietin Production and Limit Fibrosis After Acute Tubular Injury

    PubMed Central

    Aggarwal, Shikhar; Grange, Cristina; Iampietro, Corinne; Camussi, Giovanni; Bussolati, Benedetta

    2016-01-01

    Persistent alterations of the renal tissue due to maladaptive repair characterize the outcome of acute kidney injury (AKI), despite a clinical recovery. Acute damage may also limit the renal production of erythropoietin, with impairment of the hemopoietic response to ischemia and possible lack of its reno-protective action. We aimed to evaluate the effect of a cell therapy using human CD133+ renal progenitor cells on maladaptive repair and fibrosis following AKI in a model of glycerol-induced rhabdomyolysis. In parallel, we evaluated the effect of CD133+ cells on erythropoietin production. Administration of CD133+ cells promoted the restoration of the renal tissue, limiting the presence of markers of injury and pro-inflammatory molecules. In addition, it promoted angiogenesis and protected against fibrosis up to day 60. No effect of dermal fibroblasts was observed. Treatment with CD133+ cells, but not with PBS or fibroblasts, limited anemia and increased erythropoietin levels both in renal tissue and in circulation. Finally, CD133+ cells contributed to the local production of erythropoietin, as observed by detection of circulating human erythropoietin. CD133+ cells appear therefore an effective source for cell repair, able to restore renal functions, including erythropoietin release, and to limit long term maldifferentiation and fibrosis. PMID:27853265

  19. Overexpression of E2A proteins induces epithelial-mesenchymal transition in human renal proximal tubular epithelial cells suggesting a potential role in renal fibrosis.

    PubMed

    Slattery, Craig; McMorrow, Tara; Ryan, Michael P

    2006-07-24

    Epithelial-mesenchymal transition (EMT), a process whereby renal tubular epithelial cells lose phenotype and gain fibroblast-like characteristics, has been demonstrated to contribute significantly to the development of renal fibrosis. The immunosuppressant cyclosporine A (CsA) has been shown to induce renal fibrosis, a major complication of CsA therapy. The mechanisms that drive CsA-induced fibrosis remain undefined, however, CsA has been demonstrated to induce EMT in human renal proximal tubular epithelial cells (RPTEC). E2A transcription factors were identified as being upregulated by CsA treatment. To further examine the role of E2A proteins in EMT, E12 and E47 were overexpressed, alone and in combination, in human RPTEC. Both E12 and E47 elicited EMT effects on tubular epithelial cells with E47 more potent in inducing the fibroblast-like phenotype. These results indicate the important role of the E2A gene products in the progression of CsA-induced EMT and provide novel insights into CsA-induced renal fibrosis.

  20. Metformin Prevents Renal Fibrosis in Mice with Unilateral Ureteral Obstruction and Inhibits Ang II-Induced ECM Production in Renal Fibroblasts.

    PubMed

    Shen, Yang; Miao, Naijun; Xu, Jinlan; Gan, Xinxin; Xu, Dan; Zhou, Li; Xue, Hong; Zhang, Wei; Lu, Limin

    2016-01-22

    Renal fibrosis is the final common pathway of chronic kidney disease (CKD), and no effective medication is available clinically for managing its progression. Metformin was initially developed as an anti-diabetic drug and recently gained attention for its potential in the treatment of other diseases. In this study, we investigated its effects on renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) in vivo and in angiotensin II (Ang II)-treated renal fibroblast NRK-49F cells in vitro. Our data showed that UUO induced renal fibrosis and combined with the activation of ERK signaling, the upregulation of fibronectin, collagen I, and transforming growth factor-β (TGF-β). The administration of metformin inhibited the activation of ERK signaling and attenuated the production of extracellular matrix (ECM) proteins and collagen deposition in the obstructed kidneys. In cultured renal fibroblasts, Ang II increased the expression of fibronectin and collagen I and also activated ERK signaling and TGF-β in a time-dependent manner. Pretreatment of the cells with metformin blocked Ang II-induced ERK signaling activation and ECM overproduction. Our results show that metformin prevents renal fibrosis, possibly through the inhibition of ERK signaling, and may be a novel strategy for the treatment of renal fibrosis.

  1. Does Renal Tubular Injury-Induced Local Tissue Hypoxia Involve Post-Transplantation Erythrocytosis?

    PubMed

    Unal, A; Ata, S; Karakurkcu, C; Ciraci, M Z; Kocyigit, I; Sipahioglu, M H; B Tokgoz; Oymak, O

    2017-10-01

    The pathogenesis of post-transplantation erythrocytosis (PTE) is not well understood and appears to be multifactorial. Our hypothesis in this study was that several factors, including toxicity of calcineurin inhibitor, immunologic factors, and chronic allograft nephropathy, can trigger local tissue hypoxia in peritubular interstitium, which is where production of erythropoietin (EPO) takes place. This local interstitial tissue hypoxia can cause an increase in renal EPO production, which induces the development of PTE. This cross-sectional study included 15 renal transplant recipients, in whom polycythemia developed after kidney transplantation, with elevated hematocrit level to >51%. Forty-eight age- and gender-matched renal transplant recipients with normal hematocrit level were included as the renal transplant control group. In addition, 13 age- and gender-matched healthy subjects were also included as the healthy control group. We used urine hypoxia-inducible factor-2 alpha (HIF-2α) levels to evaluate whether there is local tissue hypoxia in renal allograft. HIF-2α levels were measured by double antibody sandwich enzyme-linked immunosorbent assay (ELISA). Serum EPO and insulin-like growth factor-1 (IGF-1) levels were also measured. HIF-2α levels were significantly lower in the polycythemia group than the other two groups, but there was no significant difference between the healthy control group and the renal transplant control group with regard to HIF-2α levels. There was no significant difference among the 3 study groups in terms of levels of serum EPO and IGF-1. Local tissue hypoxia in renal allograft does not seem to play an important role in the development of PTE. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Discoidin domain receptor 1 null mice are protected against hypertension-induced renal disease.

    PubMed

    Flamant, Martin; Placier, Sandrine; Rodenas, Anita; Curat, Cyrile Anne; Vogel, Wolfgang F; Chatziantoniou, Christos; Dussaule, Jean-Claude

    2006-12-01

    A frequent complication of hypertension is the development of chronic renal failure. This pathology usually is initiated by inflammatory events and is characterized by the abnormal accumulation of collagens within the renal tissue. The purpose of this study was to investigate the role of discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor that displays tyrosine-kinase activity, in the development of renal fibrosis. To this end, hypertension was induced with angiotensin in mice that were genetically deficient of DDR1 and in wild-type controls. After 4 or 6 wk of angiotensin II administration, wild-type mice developed hypertension that was associated with perivascular inflammation, glomerular sclerosis, and proteinuria. Systolic pressure increase was similar in the DDR1-deficient mice, but the histologic lesions of glomerular fibrosis and inflammation were significantly blunted and proteinuria was markedly prevented. Immunostaining for lymphocytes, macrophages, and collagens I and IV was prominent in the renal cortex of wild-type mice but substantially reduced in DDR1 null mice. In separate experiments, renal cortical slices of DDR1 null mice showed a blunted response of chemokines to LPS that was accompanied by a considerable protection against the LPS-induced mortality. These results indicate the importance of DDR1 in mediating inflammation and fibrosis. Use of DDR1 inhibitors could provide a completely novel therapeutic approach against diseases that have these combined pathologies.

  3. Effects of renal impairment on aluminum (Al) kinetics and Al-induced toxicity

    SciTech Connect

    Yokel, R.A.; McNamara, P.J.

    1986-03-01

    Al-induced toxicity most commonly occurs in the renally impaired. To study the influence of renal impairment on Al kinetics and toxicity, renally impaired rabbits were prepared by the remnant kidney procedure. Six weeks after partial nephrectomy creatinine clearance was 21% of controls and serum creatinine, BUN, Ca, and PO/sub 4/ were 222, 248, 122, and 50% of presurgery levels respectively. Serum Al kinetics after i.v. Al were: Al clearance 27%, initial and steady state volumes of distribution 50 and 80%, half life 362% and mean residence time 300% of controls (renally intact rabbits). Beginning 9 weeks after partial nephrectomy, rabbits received 145 to 160 ..mu..mole Al/kg s.c. daily, 5 x weekly x 4 weeks. Acquisition of a classically conditioned reflex (nictitating membrane extension) was impaired comparable to that produced by 100-200 ..mu..mole Al in controls but retention and extinction deficits were greater than those seen after 400 ..mu..mole Al in controls. Tissue Al concentrations were less than those seen after 200 ..mu..mole Al in controls. Body weight was comparable to that produced by 400 ..mu..mole Al in controls. These results suggest that renal impairment alters Al serum distribution, impairs its clearance, and increases the Al-induced impairment of memory and body weight gain.

  4. Renal Denervation Improves the Baroreflex and GABA System in Chronic Kidney Disease-induced Hypertension

    PubMed Central

    Chen, Hsin-Hung; Cheng, Pei-Wen; Ho, Wen-Yu; Lu, Pei-Jung; Lai, Chi-Cheng; Tseng, Yang-Ming; Fang, Hua-Chang; Sun, Gwo-Ching; Hsiao, Michael; Liu, Chun-Peng; Tseng, Ching-Jiunn

    2016-01-01

    Hypertensive rats with chronic kidney disease (CKD) exhibit enhanced gamma-aminobutyric acid (GABA)B receptor function and regulation within the nucleus tractus solitarii (NTS). For CKD with hypertension, renal denervation (RD) interrupts the afferent renal sympathetic nerves, which are connecting to the NTS. The objective of the present study was to investigate how RD improves CKD-induced hypertension. Rats underwent 5/6 nephrectomy for 8 weeks, which induced CKD and hypertension. RD was induced by applying phenol to surround the renal artery in CKD. RD improved blood pressure (BP) by lowering sympathetic nerve activity and markedly restored the baroreflex response in CKD. The GABAB receptor expression was increased in the NTS of CKD; moreover, the central GABA levels were reduced in the cerebrospinal fluid, and the peripheral GABA levels were increased in the serum. RD restored the glutamic acid decarboxylase activity in the NTS in CKD, similar to the effect observed for central treatment with baclofen, and the systemic administration of gabapentin reduced BP. RD slightly improved renal function and cardiac load in CKD. RD may improve CKD-induced hypertension by modulating the baroreflex response, improving GABA system dysfunction and preventing the development and reducing the severity of cardiorenal syndrome type 4 in CKD rats. PMID:27917928

  5. Recurrent bone fractures due to tenofovir-induced renal phosphate wasting.

    PubMed

    Koenig, Katrin F; Kalbermatter, Stefan; Menter, Thomas; Graber, Peter; Kiss, Denes

    2014-03-01

    A 42-y-old HIV-infected man suffered from several stress fractures due to tenofovir-induced proximal tubular injury. Laboratory examination revealed hypophosphatemia due to renal phosphate wasting. Therefore, more attention has to be paid to the monitoring of serum phosphate and alkaline phosphatase levels, since tenofovir-related nephrotoxicity increases the risk of osteomalacia.

  6. Geranylgeranylacetone protects against morphine-induced hepatic and renal damage in mice.

    PubMed

    Luo, Fu-Cheng; Zhao, Lu; Deng, Juan; Liang, Min; Zeng, Xian-Si; Liu, Hua; Bai, Jie

    2013-02-01

    The acute or chronic administration of opioid drugs may induce oxidative damage and cellular apoptosis in the liver and kidney, and hence result in hepatic and renal damage. Thioredoxin-1 (Trx-1) and heat shock protein 70 (Hsp70) are emerging as important modulators of cellular functions. They have been shown to be involved in cellular protective mechanisms against a variety of toxic stressors. The present study was designed to investigate the effects of geranylgeranylacetone (GGA), a pharmacological inducer of Trx-1 and Hsp70, on morphine-induced hepatic and renal damage. Morphine induced apoptosis in the liver and kidney through the mitochondria-mediated apoptosis pathway, but not the endoplasmic reticulum-mediated pathway. The activation of caspases-9 and -3 was attenuated by pre‑treatment with GGA. In addition, the morphine-induced increase of malondialdehyde (MDA) levels was suppressed by GGA. Furthermore, GGA enhanced morphine-induced expression of Trx-1 and Hsp70 in the liver and kidney. The findings of this study suggest that GGA may be a safe and novel therapeutic agent for morphine‑induced hepatic and renal damage.

  7. Amelioration of cisplatin-induced acute renal failure with 8-cyclopentyl-1,3-dipropylxanthine.

    PubMed Central

    Knight, R. J.; Collis, M. G.; Yates, M. S.; Bowmer, C. J.

    1991-01-01

    1. The effect of the selective adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), on the development of cisplatin-induced acute renal failure was investigated in the rat. 2. CPX at doses of 0.03, 0.1 and 0.3 mg kg-1, i.v. caused increasing degrees of antagonism of adenosine-induced bradycardia in anaesthetized rats. The magnitude of antagonism was not directly proportional to the increment in dose, but for each dose, it was similar in rats injected with either saline or cisplatin. CPX at a dose of 0.03 mg kg-1 significantly antagonized adenosine-induced bradycardia for up to 2.5 h, while doses of 0.1 and 0.3 mg kg-1 produced significant blockade for periods longer than 5 h. 3. Administration of cisplatin (6 mg kg-1, i.v.) caused acute renal failure characterized by decreased inulin and p-aminohippurate clearances, increased urine volume but decreased excretion of Na+, K+ and Cl- ions and by increased plasma levels of urea and creatinine. Kidney weight was increased in cisplatin-treated rats and renal tubule necrosis occurred. 4. Administration of CPX (0.03 mg kg-1, i.v.; twice daily for two days) to rats given cisplatin did not reduce the severity of the resultant renal failure. However, treatment with 0.1 mg kg-1 CPX attenuated the increases in plasma creatinine/urea levels observed in rats on days 3 and 7 after induction of renal failure. In addition, this dose significantly reduced renal tubule damage and increased inulin and p-aminohippurate clearances. A similar pattern of protection was noted with CPX at a dose of 0.3 mg kg-1 although the increase in inulin clearance was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1810593

  8. Activation of PPAR-γ inhibits PDGF-induced proliferation of mouse renal fibroblasts.

    PubMed

    Lu, Jiamei; Shi, Jianhua; Gui, Baosong; Yao, Ganglian; Wang, Li; Ou, Yan; Zhu, Dan; Ma, Liqun; Ge, Heng; Fu, Rongguo

    2016-10-15

    Recent studies have shown that activation of peroxisome proliferators activated receptor-γ (PPAR-γ) ameliorates renal interstitial fibrosis (RIF) in animal model. Yet, the underlying molecular mechanisms remain still largely unknown. Here, we investigated the hypothesis that activation of PPAR-γ regulates renal remodeling by modulating proliferation of primary cultured renal fibroblasts. In our present study, platelet-derived growth factor-AA (PDGF-AA), a key isoform of PDGF superfamily as mitogen in RIF, was applied to stimulate renal fibroblasts, the selective inhibitor or sequence specific siRNA of PI3K, skp2 or PPAR-γ was used to investigate the involvement of above molecular mediators in PDGF-AA-induced cell proliferation. Our results demonstrate that PDGF-AA induced proliferation of renal fibroblasts by activating PI3K/AKT signaling and resultant skp2 production. Pre-stimulation of cells with rosiglitazone or adenovirus carrying PPAR-γ cDNA (AdPPAR-γ) blocked PDGF-AA-stimulated cell proliferation, this effect was particularly coupled to PPAR-γ inhibition of AKT phosphorylation and skp2 expression. Inhibition of PPAR-γ by GW9662 restored the suppression of activated PPAR-γ on phosphorylation of AKT and subsequent skp2 production. Our results indicate that activation of PI3K/AKT signaling and resultant skp2 generation mediated PDGF-induced proliferation of renal fibroblasts. Activation of PPAR-γ inhibited cell proliferation by inhibition of AKT phosphorylation and its down-streams.

  9. Renal Protective Effect of Probucol in Rats with Contrast-Induced Nephropathy and its Underlying Mechanism

    PubMed Central

    Wang, Na; Wei, Ri-bao; Li, Qing-ping; Yang, Xi; Li, Ping; Huang, Meng-jie; Wang, Rui; Cai, Guang-yan; Chen, Xiang-mei

    2015-01-01

    Background Contrast-induced nephropathy (CIN) refers to acute renal damage that occurs after the use of contrast agents. This study investigated the renal protective effect of probucol in a rat model of contrast-induced nephropathy and the mechanism of its effect. Material/Methods Twenty-eight Wistar rats were randomly divided into the control group, model group, N-acetylcysteine(NAC) group, and probucol group. We used a rat model of iopromide-induced CIN. One day prior to modeling, the rats received gavage. At 24 h after the modeling, blood biochemistry and urine protein were assessed. Malondialdehyde (MDA) and superoxide dismutase (SOD) were measured in renal tissue. Kidney sections were created for histopathological examination. Results The model group of rats showed significantly elevated levels of blood creatinine, urea nitrogen, 24-h urine protein, histopathological scores, and parameters of oxidative stress (P<0.05). Both the NAC and probucol groups demonstrated significantly lower Scr, BUN, and urine protein levels compared to the model group (P<0.05), with no significant difference between these 2 groups. The NAC group and the probucol group had significantly lower MDA and higher SOD than the model group at 24 h after modeling (P<0.05). The 8-OHdG-positive tubule of the probucol group and NAC group were significantly lower than those of the model group (p=0.046, P=0.0008), with significant difference between these 2 groups (P=0.024). Conclusions Probucol can effectively reduce kidney damage caused by contrast agent. The underlying mechanism may be that probucol accelerates the recovery of renal function and renal pathology by reducing local renal oxidative stress. PMID:26408630

  10. Role of calcitonin gene-related peptide in hypertension-induced renal damage.

    PubMed

    Bowers, Mark C; Katki, Khurshed A; Rao, Arundhati; Koehler, Michael; Patel, Parag; Spiekerman, Alvin; DiPette, Donald J; Supowit, Scott C

    2005-07-01

    Calcitonin gene-related peptide, a potent vasodilator neuropeptide, is localized in perivascular sensory nerves. We have reported that alpha-calcitonin gene-related peptide knockout mice have elevated baseline blood pressure and enhanced hypertension-induced renal damage compared with wild-type controls. Thus, the aim of this study was to determine the mechanism and functional significance of this increased hypertension-induced renal damage. We previously demonstrated by telemetric recording that the deoxycorticosterone-salt protocol produces a 35% increase in mean arterial pressure in both alpha-calcitonin gene-related peptide knockout and wild-type mice. Both strains of mice were studied at 0, 14, and 21 days after deoxycorticosterone-salt hypertension. Renal sections from hypertensive wild-type mice showed no pathological changes at any time point studied. However, on days 14 and 21, hypertensive knockout mice displayed progressive increases in glomerular proliferation, crescent formation, and tubular protein casts, as well as the inflammatory markers intercellular adhesion molecule-1, vascular adhesion molecule-1, and monocyte chemoattractant protein-1. There was a significant increase in 24-hour urinary isoprostane, a marker of oxidative stress-induced lipid peroxidation, levels at days 14 and 21 in the hypertensive knockout compared with hypertensive wild-type mice. Urinary microalbumin was significantly higher (2-fold) at day 21 and creatinine clearance was significantly decreased 4-fold in the hypertensive knockout compared with hypertensive wild-type mice. Therefore, in the absence of alpha-calcitonin gene-related peptide, deoxycorticosterone-salt hypertension induces enhanced oxidative stress, inflammation, and renal histopathologic damage, resulting in reduced renal function. Thus, sensory nerves, via alpha-calcitonin gene-related peptide, appear to be renoprotective against hypertension-induced damage.

  11. A randomised controlled trial evaluating renal protective effects of selenium with vitamins A, C, E, verapamil, and losartan against extracorporeal shockwave lithotripsy-induced renal injury.

    PubMed

    El-Nahas, Ahmed R; Elsaadany, Mohamed M; Taha, Diaa-Eldin; Elshal, Ahmed M; El-Ghar, Mohamed Abo; Ismail, Amani M; Elsawy, Essam A; Saleh, Hazem H; Wafa, Ehab W; Awadalla, Amira; Barakat, Tamer S; Sheir, Khaled Z

    2017-01-01

    To evaluate the protective effects of selenium with vitamins A, C and E (selenium ACE, i.e. antioxidants), verapamil (calcium channel blocker), and losartan (angiotensin receptor blocker) against extracorporeal shockwave lithotripsy (ESWL)-induced renal injury. A randomised controlled trial was conducted between August 2012 and February 2015. Inclusion criteria were adult patients with a single renal stone (<2 cm) suitable for ESWL. Patients with diabetes, hypertension, congenital renal anomalies, moderate or marked hydronephrosis, or preoperative albuminuria (>300 mg/L) were excluded. ESWL was performed using the electromagnetic DoLiS lithotripter. Eligible patients were randomised into one of four groups using sealed closed envelopes: Group1, control; Group 2, selenium ACE; Group 3, losartan; and Group 4, verapamil. Albuminuria and urinary neutrophil gelatinase-associated lipocalin (uNGAL) were estimated after 2-4 h and 1 week after ESWL. The primary outcome was differences between albuminuria and uNGAL. Dynamic contrast-enhanced magnetic resonance imaging was performed before ESWL, and at 2-4 h and 1 week after ESWL to compare changes in renal perfusion. Of 329 patients assessed for eligibility, the final analysis comprised 160 patients (40 in each group). Losartan was the only medication that showed significantly lower levels of albuminuria after 1 week (P < 0.001). For perfusion changes, there was a statistically significant decrease in the renal perfusion in patients with obstructed kidneys in comparison to before ESWL (P = 0.003). These significant changes were present in the control or antioxidant group, whilst in the losartan and verapamil groups renal perfusion was not significantly decreased. Losartan was found to protect the kidney against ESWL-induced renal injury by significantly decreasing post-ESWL albuminuria. Verapamil and losartan maintained renal perfusion in patients with post-ESWL renal obstruction. © 2016 The Authors BJU International

  12. 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.

  13. Fatal hepatic and renal toxicity as a complication of trabectedin therapy for radiation-induced sarcoma.

    PubMed

    Pick, Amy M; Nystrom, Kelly K

    2010-12-01

    Trabectedin therapy was prescribed for a patient with radiation-induced sarcoma. Two doses of trabectedin were given before therapy was discontinued with the patient experiencing renal and liver failure. Despite discontinuing trabectedin the patient continued to experience increases in liver transaminases, bilirubin, blood urea nitrogen, and serum creatinine. Hemodialysis was initiated with no improvement. With all other causes being ruled out, trabectedin likely caused hepatic and renal failure leading to death in this patient. Recent literature suggests that patients may benefit from prophylactic dexamethasone as a means of reducing hepatic toxicity.

  14. Statin-induced rhabdomyolysis in patient with renal failure and underlying undiagnosed hypothyroidism

    PubMed Central

    Ambapkar, Sachinkumar N.; Shetty, Naresh; Dwivedy, Arpita; Malve, Harshad Onkarrao

    2016-01-01

    Rhabdomyolysis is a syndrome characterized by muscle necrosis which causes the release of myoglobin into the bloodstream. The manifestations of this syndrome range from asymptomatic elevation of serum muscle enzymes to life-threatening cases associated with extremely high enzyme levels, electrolyte imbalance, and acute renal failure. Symptoms of rhabdomyolysis include dark urine, muscle weakness, and fatigue. Statins are commonly used drugs for the prevention and management of dyslipidemia. We present an interesting and critical case on statin-induced rhabdomyolysis with renal failure and previously undiagnosed idiopathic hypothyroidism. PMID:27275082

  15. Morphologic evidence that analgesic-induced kidney pathology contributes to the progression of tumors of the renal pelvis.

    PubMed

    Stewart, J H; Hobbs, J B; McCredie, M R

    1999-10-15

    Whether phenacetin-containing analgesics cause renal pelvic tumors by virtue of the weak mutagenicity of phenacetin, or indirectly through local effects of analgesic-induced renal papillary scarring, is debated. Because phenacetin consumption ceased in New South Wales, Australia in 1975, cases of renal pelvic carcinoma seen 14-15 years later (many of which were associated with long-standing analgesic-induced renal papillary pathology) provided an opportunity to examine the temporal relation between phenacetin exposure and those histologic characteristics of the tumors and adjacent renal tissue that may implicate analgesics in their etiology. The authors conducted a "blinded" histopathologic review of tumors of the renal pelvis and adjacent noncancerous renal tissue from 100 cases for which epidemiologic data regarding risk factor exposure (specifically phenacetin-containing analgesics, tobacco, infection, and kidney stones) had been obtained in a population-based case-control study from New South Wales in 1989 and 1990. A history of consumption of phenacetin-containing analgesics was associated strongly with the presence and severity of diffuse renal papillary scarring, and less strongly with papillary calcification. The histologic grade of the renal pelvic tumors tended to rise significantly with consumption of phenacetin-containing analgesics in a dose-dependent fashion and with the degree of papillary scarring, but was not related to smoking. In multivariate analysis it was the degree of papillary scarring (to a greater extent than the amount of phenacetin consumption) that was associated significantly and strongly with a higher histologic grade. Only diffuse papillary calcification was associated significantly with squamous change in the renal pelvic tumors. Based on the results of the current study, the authors conclude that 1) in phenacetin-related tumors of the renal pelvis, the presence and severity of analgesic-induced renal papillary scarring correlates

  16. [Functional magnetic resonance imaging for evaluation of radiation-induced renal damage].

    PubMed

    Haneder, S; Boda-Heggemann, J; Schoenberg, S O; Michaely, H J

    2012-03-01

    The diagnosis of radiation-induced (especially chronic) renal alterations/damage is difficult and currently relies primarily on clinical evaluation. The importance of renal diagnostic evaluation will increase continuously due to the increasing number of long-term survivors after radiotherapy. This article evaluates the potentia diagnostic contribution of magnetic resonance (MR) imaging with a focus on functional MRI. The following functional MRI approaches are briefly presented and evaluated: blood oxygenation level-dependent imaging (BOLD), diffusion-weighted imaging (DWI) or diffusion tensor imaging (DTI), MR perfusion measurements and (23)Na imaging. In summary, only DWI and contrast-enhanced MR perfusion currently seem to be suitable approaches for a broader, clinical implementation. However, up to now valid data from larger patient studies are lacking for both techniques in regard to radiation-induced renal alterations. The BOLD and (23)Na imaging procedures have a huge potential but are currently neither sufficiently evaluated with regard to radiation-induced renal alterations nor technically simple and reliable for implementation into the clinical routine.

  17. Curcumin counteracts cisplatin-induced nephrotoxicity by preventing renal tubular cell apoptosis.

    PubMed

    Topcu-Tarladacalisir, Yeter; Sapmaz-Metin, Melike; Karaca, Turan

    2016-11-01

    Curcumin has several biological functions particularly antioxidant and anti-inflammatory. The aims of this study are determination of the protective effects of curcumin on cisplatin-induced renal tubular cell apoptosis and related pathways in kidney. Eighteen male Wistar albino rats were randomly divided into three groups (n = 6): the control, cisplatin (CP), and cisplatin + curcumin (CP + CUR). Acute renal damage was induced by single dose of cisplatin (7.5 mg/kg) injected by intraperitoneally (i.p). The animals of curcumin-treated group were received daily 200 mg/kg curcumin per os (po), starting from 2 days before the injection of cisplatin to the day of sacrifice. Forty-eight hours after cisplatin injection, samples of cardiac blood and kidneys were harvested from the animals. In this study, the major finding is that curcumin treatment ameliorates the following conditions associated with cisplatin-induced nephrotoxicity: (1) the development of kidney injury (histopathology), (2) inflammatory responses [myeloperoxidase (MPO) and tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, IL-10 levels], (3) the degree of lipid peroxidation [malondialdehyde (MDA) level], (4) renal tubular cell apoptosis (active caspase-3) and expression of related proteins [p53, Fas, and Fas ligand (Fas-L)] by immunohistochemistry, (5) renal dysfunction (serum urea and creatinine). In a conclusion, this study suggests that curcumin has antiapoptotic effect against cisplatin nephrotoxicity, in addition to anti-inflammatory and antioxidant properties.

  18. Agmatine improves renal function in gentamicin-induced nephrotoxicity in rats.

    PubMed

    El-Kashef, Dalia H; El-Kenawi, Asmaa E; Abdel Rahim, Mona; Suddek, Ghada M; Salem, Hatem A

    2016-03-01

    The present study was designed to explore the possible protective effects of agmatine, a known nitric oxide (NO) synthase inhibitor, against gentamicin-induced nephrotoxicity in rats. For this purpose, we quantitatively evaluated gentamicin-induced renal structural and functional alterations using histopathological and biochemical approaches. Furthermore, the effect of agmatine on gentamicin-induced hypersensitivity of urinary bladder rings to acetylcholine (ACh) was evaluated. Twenty-four male Wistar albino rats were randomly divided into 3 groups, namely control, gentamicin (100 mg/kg, i.p.), and gentamicin plus agmatine (40 mg/kg, orally). At the end of the study, all rats were sacrificed and then blood and urine samples and kidneys were taken. Administration of agmatine significantly decreased kidney/body mass ratio, serum creatinine, lactate dehydrogenase (LDH), renal malondialdehyde (MDA), myeloperoxidase (MPO), NO, and tumor necrosis factor-alpha (TNF-α) while it significantly increased creatinine clearance and renal superoxide dismutase (SOD) activity when compared with the gentamicin-treated group. Additionally, agmatine ameliorated tissue morphology as evidenced by histological evaluation and reduced the responses of isolated bladder rings to ACh. Our study indicates that agmatine administration with gentamicin attenuates oxidative-stress associated renal injury by reducing oxygen free radicals and lipid peroxidation, restoring NO level and inhibiting inflammatory mediators such as TNF-α.

  19. The role of a renal thirst factor in drinking induced by extracellular stimuli

    PubMed Central

    Fitzsimons, J. T.

    1969-01-01

    1. Rats in normal fluid balance drank water 1-2 hr after complete ligation of the inferior vena cava either above or below the renal veins. At the same time there was a fall in urine flow and excretion of electrolyte, especially after caval ligation above the renal veins, so that the animals ended the initial 6 hr period in positive fluid balance. 2. Caval ligation was relatively ineffective as a stimulus to drinking after bilateral nephrectomy, but was effective in rats made anuric by ureteric ligation. 3. Rats subjected to caval ligation and offered a choice between water and 1·8% saline (w/v) drank water, despite the increasing hypotonicity of the body fluids thereby resulting. 4. During the secondary polydipsia, which generally occurred on about the third day after caval ligation as renal function was recovering, there was an increased preference for 1·8% saline. 5. Constriction of the aorta above the renal arteries, or constriction of both renal arteries, also caused drinking, oliguria and the development of positive fluid balance. 6. Constriction of the aorta below the renal arteries, or after nephrectomy, was ineffective as a stimulus to drinking. 7. Saline extracts of renal cortex caused rats in normal water balance to drink. Activity was destroyed by boiling the extract for 10 min. Renal medullary and hepatic extracts were without effect on drinking. 8. It proved impossible to separate dipsogenic and pressor activities of renal extracts during the different stages of fractionation which lead to the production of renin; disappearance of one activity was invariably accompanied by disappearance of the other. 9. Dipsogenic and pressor actions were greater in nephrectomized rats than in normal rats. 10. Both extractable dipsogenic factor and extractable pressor activity were reduced by treating the rat with DOCA and saline for several weeks beforehand. 11. The renal dipsogen therefore has similar properties to renin. It may prove to be identical with renin

  20. Antioxidant effect of carnosine treatment on renal oxidative stress in streptozotocin-induced diabetic rats.

    PubMed

    Yay, A; Akkuş, D; Yapıslar, H; Balcıoglu, E; Sonmez, M F; Ozdamar, S

    2014-11-01

    Nitric oxide (NO) plays a significant role in the development of diabetic nephropathy. We investigated the effects of an antioxidant, carnosine, on streptozotocin (STZ)-induced renal injury in diabetic rats. We used four groups of eight rats: group 1, control; group 2, carnosine treated; group 3, untreated diabetic; group 4, carnosine treated diabetic. Kidneys were removed and processed, and sections were stained with periodic acid-Schiff (PAS) and subjected to eNOS immunohistochemistry. Examination by light microscopy revealed degenerated glomeruli, thickened basement membrane and glycogen accumulation in the tubules of diabetic kidneys. Carnosine treatment prevented the renal morphological damage caused by diabetes. Moreover, administration of carnosine decreased somewhat the oxidative damage of diabetic nephropathy. Appropriate doses of carnosine might be a useful therapeutic option to reduce oxidative stress and associated renal injury in diabetes mellitus.

  1. Activation of Renal (Pro)Renin Receptor Contributes to High Fructose-Induced Salt Sensitivity.

    PubMed

    Xu, Chuanming; Lu, Aihua; Lu, Xiaohan; Zhang, Linlin; Fang, Hui; Zhou, Li; Yang, Tianxin

    2017-02-01

    A high-fructose diet is shown to induce salt-sensitive hypertension, but the underlying mechanism largely remains unknown. The major goal of the present study was to test the role of renal (pro)renin receptor (PRR) in this model. In Sprague-Dawley rats, high-fructose intake increased renal expression of full-length PRR, which were attenuated by allopurinol. High-fructose intake also upregulated renal mRNA and protein expression of sodium/hydrogen exchanger 3 and Na/K/2Cl cotransporter, as well as in vivo Na/K/2Cl cotransporter activity, all of which were nearly completely blocked by a PRR decoy inhibitor PRO20 or allopurinol treatment. Parallel changes were observed for indices of intrarenal renin-angiotensin-system including renal and urinary renin and angiotensin II levels. Radiotelemetry demonstrated that high-fructose or a high-salt diet alone did not affect mean arterial pressure, but the combination of the 2 maneuvers induced a ≈10-mm Hg increase of mean arterial pressure, which was blunted by PRO20 or allopurinol treatment. In cultured human kidney 2 cells, both fructose and uric acid increased protein expression of soluble PRR in a time- and dose-dependent manner; fructose-induced PRR upregulation was inhibited by allopurinol. Taken together, our data suggest that fructose via uric acid stimulates renal expression of PRR/soluble PRR that stimulate sodium/hydrogen exchanger 3 and Na/K/2Cl cotransporter expression and intrarenal renin-angiotensin system to induce salt-sensitive hypertension.

  2. Cell Therapy Using Human Induced Pluripotent Stem Cell-Derived Renal Progenitors Ameliorates Acute Kidney Injury in Mice.

    PubMed

    Toyohara, Takafumi; Mae, Shin-Ichi; Sueta, Shin-Ichi; Inoue, Tatsuyuki; Yamagishi, Yukiko; Kawamoto, Tatsuya; Kasahara, Tomoko; Hoshina, Azusa; Toyoda, Taro; Tanaka, Hiromi; Araoka, Toshikazu; Sato-Otsubo, Aiko; Takahashi, Kazutoshi; Sato, Yasunori; Yamaji, Noboru; Ogawa, Seishi; Yamanaka, Shinya; Osafune, Kenji

    2015-09-01

    Acute kidney injury (AKI) is defined as a rapid loss of renal function resulting from various etiologies, with a mortality rate exceeding 60% among intensive care patients. Because conventional treatments have failed to alleviate this condition, the development of regenerative therapies using human induced pluripotent stem cells (hiPSCs) presents a promising new therapeutic option for AKI. We describe our methodology for generating renal progenitors from hiPSCs that show potential in ameliorating AKI. We established a multistep differentiation protocol for inducing hiPSCs into OSR1+SIX2+ renal progenitors capable of reconstituting three-dimensional proximal renal tubule-like structures in vitro and in vivo. Moreover, we found that renal subcapsular transplantation of hiPSC-derived renal progenitors ameliorated the AKI in mice induced by ischemia/reperfusion injury, significantly suppressing the elevation of blood urea nitrogen and serum creatinine levels and attenuating histopathological changes, such as tubular necrosis, tubule dilatation with casts, and interstitial fibrosis. To our knowledge, few reports demonstrating the therapeutic efficacy of cell therapy with renal lineage cells generated from hiPSCs have been published. Our results suggest that regenerative medicine strategies for kidney diseases could be developed using hiPSC-derived renal cells. This report is the first to demonstrate that the transplantation of renal progenitor cells differentiated from human induced pluripotent stem (iPS) cells has therapeutic effectiveness in mouse models of acute kidney injury induced by ischemia/reperfusion injury. In addition, this report clearly demonstrates that the therapeutic benefits come from trophic effects by the renal progenitor cells, and it identifies the renoprotective factors secreted by the progenitors. The results of this study indicate the feasibility of developing regenerative medicine strategy using iPS cells against renal diseases.

  3. Cell Therapy Using Human Induced Pluripotent Stem Cell-Derived Renal Progenitors Ameliorates Acute Kidney Injury in Mice

    PubMed Central

    Toyohara, Takafumi; Mae, Shin-Ichi; Sueta, Shin-Ichi; Inoue, Tatsuyuki; Yamagishi, Yukiko; Kawamoto, Tatsuya; Kasahara, Tomoko; Hoshina, Azusa; Toyoda, Taro; Tanaka, Hiromi; Araoka, Toshikazu; Sato-Otsubo, Aiko; Takahashi, Kazutoshi; Sato, Yasunori; Yamaji, Noboru; Ogawa, Seishi; Yamanaka, Shinya

    2015-01-01

    Acute kidney injury (AKI) is defined as a rapid loss of renal function resulting from various etiologies, with a mortality rate exceeding 60% among intensive care patients. Because conventional treatments have failed to alleviate this condition, the development of regenerative therapies using human induced pluripotent stem cells (hiPSCs) presents a promising new therapeutic option for AKI. We describe our methodology for generating renal progenitors from hiPSCs that show potential in ameliorating AKI. We established a multistep differentiation protocol for inducing hiPSCs into OSR1+SIX2+ renal progenitors capable of reconstituting three-dimensional proximal renal tubule-like structures in vitro and in vivo. Moreover, we found that renal subcapsular transplantation of hiPSC-derived renal progenitors ameliorated the AKI in mice induced by ischemia/reperfusion injury, significantly suppressing the elevation of blood urea nitrogen and serum creatinine levels and attenuating histopathological changes, such as tubular necrosis, tubule dilatation with casts, and interstitial fibrosis. To our knowledge, few reports demonstrating the therapeutic efficacy of cell therapy with renal lineage cells generated from hiPSCs have been published. Our results suggest that regenerative medicine strategies for kidney diseases could be developed using hiPSC-derived renal cells. Significance This report is the first to demonstrate that the transplantation of renal progenitor cells differentiated from human induced pluripotent stem (iPS) cells has therapeutic effectiveness in mouse models of acute kidney injury induced by ischemia/reperfusion injury. In addition, this report clearly demonstrates that the therapeutic benefits come from trophic effects by the renal progenitor cells, and it identifies the renoprotective factors secreted by the progenitors. The results of this study indicate the feasibility of developing regenerative medicine strategy using iPS cells against renal diseases

  4. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats.

    PubMed

    Blasi, Eileen R; Rocha, Ricardo; Rudolph, Amy E; Blomme, Eric A G; Polly, Melissa L; McMahon, Ellen G

    2003-05-01

    We evaluated the role of aldosterone as a mediator of renal inflammation and fibrosis in a rat model of aldosterone/salt hypertension using the selective aldosterone blocker, eplerenone. Unnephrectomized, Sprague-Dawley rats were given 1% NaCl (salt) to drink and randomized to receive treatment for 28 days: vehicle infusion (control); 0.75 microg/hour aldosterone subcutaneous infusion; or aldosterone infusion + 100 mg/kg/day oral dose of eplerenone. Blood pressure and urinary albumin were measured and kidneys were evaluated histologically. Renal injury, inflammation, and fibrosis were assessed by immunohistochemistry, in situ hybridization, and reverse transcription-polymerase chain reaction (RT-PCR). Aldosterone/salt induced severe hypertension compared to controls (220 +/- 4 mm Hg vs. 131 +/- 4 mm Hg, P < 0.05), which was partially attenuated by eplerenone (179 +/- 4 mm Hg, P < 0.05). In aldosterone/salt treated rats, renal histopathologic evaluation revealed severe vascular and glomerular sclerosis, fibrinoid necrosis and thrombosis, interstitial leukocyte infiltration, and tubular damage and regeneration. Aldosterone/salt increased circulating osteopontin (925.0 +/- 80.2 ng/mL vs. 53.6 +/- 6.3 ng/mL) and albuminuria (75.8 +/- 10.9 mg/24 hours vs. 13.2 +/- 3.0 mg/24 hours) compared to controls and increased expression of proinflammatory molecules. Treatment with eplerenone reduced systemic osteopontin (58.3 +/- 4.2 ng/mL), albuminuria (41.5 +/- 7.2 mg/24 hours), and proinflammatory gene expression: osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta). These findings indicate that aldosterone/salt-induced renal injury and fibrosis has inflammatory components involving macrophage infiltration and cytokine up-regulation. Attenuation of renal damage and inflammation by eplerenone supports the protective effects of aldosterone blockade in hypertensive renal disease.

  5. Chronic inhibition of nuclear factor kappa B attenuates aldosterone/salt-induced renal injury.

    PubMed

    Ding, Wei; Yang, Lei; Zhang, Minmin; Gu, Yong

    2012-04-20

    Recent studies suggested that nuclear factor kappa B (NF-κB) plays a key role in the pathogenesis of renal injury. This study investigated whether NF-κB inhibition attenuates progressive renal damage in aldosterone/salt-induced renal injury and its mechanisms. Adult male rats were uninephrectomized and treated with one of the following for 4 weeks: vehicle (0.5% ethanol, subcutaneously); vehicle/1% NaCl (1% NaCl in drinking solution); aldosterone/1% NaCl (1% NaCl in drinking solution and aldosterone, 0.75 μg/h, subcutaneously); or aldosterone/1%NaCl+pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB (100 mg/kg/day, by gavage). The activity of NF-κB was measured by EMSA and immunohistochemistry, CTGF and ICAM-1 were measured by Western blot and real-time PCR, and TGF-β and CTGF were measured by immunohistochemistry. Rats that received aldosterone/1% NaCl exhibited hypertension and severe renal injury. Renal cortical mRNA levels of CTGF, TGF-β, ICAM-1 and collagen IV, protein expression of CTGF and ICAM-1, and NF-κB-DNA binding activity were significantly upregulated in rats that received aldosterone/1% NaCl. Treatment with PDTC significantly decreased the percentage of cells positive for CTGF and TGF-β; mRNA levels of CTGF, TGF-β, ICAM-1 and collagen IV, and protein levels of CTGF and ICAM-1 were also inhibited by PDTC. These data suggest that the NF-κB signal pathway plays a role in the progression of aldosterone/salt-induced renal injury. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Chelerythrine chloride induces apoptosis in renal cancer HEK-293 and SW-839 cell lines.

    PubMed

    Chen, Xiao-Meng; Zhang, Meng; Fan, Peng-Li; Qin, Yu-Hua; Zhao, Hong-Wei

    2016-06-01

    Previous studies have demonstrated that the benzo[c]phenanthridine alkaloid chelerythrine chloride (CC) has inhibitory effects on various tumors. However, the anticancer activity of CC and its underlying mechanisms have not been elucidated in renal cancer cells. The present study examined the effects of CC on growth inhibition and apoptosis of renal cancer cells in vitro and in vivo. Flow cytometry and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays revealed that CC markedly suppressed the growth of HEK-293 and human renal cancer SW-839 cells in a time- and dose-dependent manner. The xenograft mouse model, which was performed in nude mice, exhibited a reduced tumor growth following CC treatment. In addition, the present study revealed that CC significantly decreased the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, which was accompanied by upregulation of p53, B-cell lymphoma 2 (Bcl-2)-associated X protein, cleaved caspase-3 and cleaved poly (adenosine diphosphate-ribose) polymerase (PARP), and downregulation of Bcl-2, caspase-3 and PARP. Furthermore, the use of PD98059, a specific mitogen-activated protein kinase kinase inhibitor, potentiated the proapoptotic effects of CC, which indicated that CC may induce apoptosis in renal cancer cells partly via inhibition of ERK activity. Overall, the results of the present study demonstrated that CC may be developed as a potential anticancer treatment for patients with renal cancer.

  7. Chemical Profiles and Protective Effect of Hedyotis diffusa Willd in Lipopolysaccharide-Induced Renal Inflammation Mice

    PubMed Central

    Ye, Jian-Hong; Liu, Meng-Hua; Zhang, Xu-Lin; He, Jing-Yu

    2015-01-01

    Protective effect of Hedyotis diffusa (H. diffusa) Willd against lipopolysaccharide (LPS)-induced renal inflammation was evaluated by the productions of cytokines and chemokine, and the bioactive constituents of H. diffusa were detected by the ultra-fast liquid chromatography -diode array detector-quadrupole-time of flight mass spectrometry (UFLC-DAD-Q-TOF-MS/MS) method. As the results showed, water extract of H. diffusa (equal to 5.0 g/kg body weight) obviously protected renal tissues, significantly suppressed the productions of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein (MCP)-1, as well as significantly promoted the production of IL-10 in serum and renal tissues. According the chemical profiles of H. diffusa, flavonoids, iridoid glycosides and anthraquinones were greatly detected in serum from H. diffusa extract treatment mice. Two main chemotypes, including eight flavonoids and four iridoid glycosides were found in renal tissues from H. diffusa extract treatment mice. The results demonstrated that water extract of H. diffusa had protective effect on renal inflammation, which possibly resulted from the bioactive constituents consisting of flavonoids, iridoids and anthraquinones. PMID:26580602

  8. A Beverage Containing Fermented Black Soybean Ameliorates Ferric Nitrilotriacetate-Induced Renal Oxidative Damage in Rats

    PubMed Central

    Okazaki, Yasumasa; Iqbal, Mohammad; Kawakami, Norito; Yamamoto, Yorihiro; Toyokuni, Shinya; Okada, Shigeru

    2010-01-01

    It is beneficial to seek scientific basis for the effects of functional foods. Natural pigments derived from plants are widely known as possible antioxidants. Black soybean contains a larger amount of anthocyanins than regular soybean. Here we studied the antioxidative effect of a beverage obtained via citric acid fermentation of black soybean (BBS), using a rat model of renal oxidative injury induced by a renal carcinogen, ferric nitrilotriacetate. BBS (10 ml/kg) was orally administered 30 min before ferric nitrilotriacetate treatment. Renal lipid peroxidation was significantly suppressed in the BBS-pretreated animals concomitant with decrease in 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2'-deoxyguanosine. Maintenance of renal activities of antioxidative enzymes including catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, glucose-6-phosphate dehydrogenase and quinone reductase was significantly better in the BBS-pretreated rats. Elevation of serum creatinine and urea nitrogen was significantly suppressed in the BBS-pretreated rats. These data suggest that dietary intake of BBS is useful for the prevention of renal tubular oxidative damage mediate by iron, and warrant further investigation. PMID:21103028

  9. Cardiovascular and renal manifestations of glutathione depletion induced by buthionine sulfoximine.

    PubMed

    Vargas, Félix; Rodríguez-Gómez, Isabel; Pérez-Abud, Rocío; Vargas Tendero, Pablo; Baca, Yolanda; Wangensteen, Rosemary

    2012-06-01

    Oxidative stress contributes to the development of several cardiovascular diseases, including diabetes, renal insufficiency, and arterial hypertension. Animal studies have evidenced the association between higher blood pressure (BP) and increased oxidative stress, and treatment with antioxidants has been shown to reduce BP, while BP reduction due to antihypertensive drugs is associated with reduced oxidative stress. In 2000, it was first reported that oxidative stress and arterial hypertension were produced in normal Sprague-Dawley rats by oral administration of buthionine sulfoximine (BSO), which induces glutathione (GSH) depletion, indicating that oxidative stress may induce hypertension. The contribution of several potential pathogenic factors has been evaluated in the BSO rat model, the prototype of oxidative stress-induced hypertension, including vascular reactivity, endothelium-derived factors, renin-angiotensin system activity, TXA(2)-PGH(2) production, sodium sensitivity, renal dopamine-induced natriuresis, and sympathetic tone. This review summarizes the main factors implicated in the pathogenesis of BSO-induced hypertension and the alterations associated with GSH depletion that are related to renal function or BP control.

  10. Effect of taurine on advanced glycation end products-induced hypertrophy in renal tubular epithelial cells

    SciTech Connect

    Huang, J.-S. Chuang, L.-Y.; Guh, J.-Y.; Yang, Y.-L.; Hsu, M.-S.

    2008-12-01

    Mounting evidence indicates that advanced glycation end products (AGE) play a major role in the development of diabetic nephropathy (DN). Taurine is a well documented antioxidant agent. To explore whether taurine was linked to altered AGE-mediated renal tubulointerstitial fibrosis in DN, we examined the molecular mechanisms of taurine responsible for inhibition of AGE-induced hypertrophy in renal tubular epithelial cells. We found that AGE (but not non-glycated BSA) caused inhibition of cellular mitogenesis rather than cell death by either necrosis or apoptosis. There were no changes in caspase 3 activity, bcl-2 protein expression, and mitochondrial cytochrome c release in BSA, AGE, or the antioxidant taurine treatments in these cells. AGE-induced the Raf-1/extracellular signal-regulated kinase (ERK) activation was markedly blocked by taurine. Furthermore, taurine, the Raf-1 kinase inhibitor GW5074, and the ERK kinase inhibitor PD98059 may have the ability to induce cellular proliferation and cell cycle progression from AGE-treated cells. The ability of taurine, GW5074, or PD98059 to inhibit AGE-induced hypertrophy was verified by the observation that it significantly decreased cell size, cellular hypertrophy index, and protein levels of RAGE, p27{sup Kip1}, collagen IV, and fibronectin. The results obtained in this study suggest that taurine may serve as the potential anti-fibrotic activity in DN through mechanism dependent of its Raf-1/ERK inactivation in AGE-induced hypertrophy in renal tubular epithelial cells.

  11. Onion (Allium cepa) extract prevents cadmium induced renal dysfunction

    PubMed Central

    Ige, S. F.; Salawu, E. O.; Olaleye, S. B.; Adeeyo, O. A.; Badmus, J.; Adeleke, A. A.

    2009-01-01

    Cadmium (Cd), a heavy metal, is known for its adverse effects on the body. In this study, the lowering effect of Cd on renal clearance (RC) was investigated, and Allium cepa extract (AcE) (an antioxidant) was pre-administered orally to prevent Cd's adverse effects. Seventy-two Wistar rats, grouped into three (n = 24), were used for this study. While Group C was given 1.0 ml of AcE daily (orally), Group A and Group B were given distilled water. AcE administration was done for eight weeks. Afterwards B and C were then given 1.5 ml/kg BW of 0.3 mg/L 3CdSO4.8H2O intraperitoneally for three consecutive days. The results obtained showed that Cd causes significant reduction in the 24 hour urine volume (from 3.017 ± 0.125 to 2.433 ± 0.118 ml), RC (from 3.258 ± 0.114 to 1.357 ± 0.104 ml/h for creatinine; and from 0.350 ± 0.057 to 0.185 ± 0.055 ml/h for urea), plasma and tissue SOD and CAT activity (form 1.644 ± 0.036 to 1.307 ± 0.056 u/g protein for plasma SOD; 0.391 ± 0.029 to 0.2692 ± 0.031 u/protein for plasma CAT; 1.695 ± 0.034 to 1.327 ± 0.049 u/g protein for tissues SOD; and from 0.350 ± 0.027 to 0.273 ± 0.043 u for tissue CAT), and significant MDA increased in plasma (from 1496.79 ± 1.321 to 1679.48 ± 143.29 μg/g protein) and tissue (from 1265.22 ± 2.285 to 1669.87 ± 14.61 μg/dL). AcE, however, prevents these Cd's adverse effects. This findings lead to the conclusion Cd exposure causes renal dysfunction, but oral administration of onion could prevent it. PMID:20535248

  12. Involvement of MEK/ERK pathway in cephaloridine-induced injury in rat renal cortical slices.

    PubMed

    Kohda, Yuka; Hiramatsu, Jun; Gemba, Munekazu

    2003-07-20

    We have previously reported that free radical-mediated injury induced by cephaloridine (CER) is enhanced by phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, in rat renal cortical slices. We have also shown that PKC activation in mitochondria is involved in CER-induced nephrotoxicity in rats. We investigated the role of a downstream PKC pathway, a MEK/ERK pathway, in free radical-induced injury in rat renal cortical slices exposed to CER. Immediately after preparing slices from rat renal cortex, the slices were incubated in the medium containing MEK inhibitors. ERK1/2 activation was determined by Western blot analysis for phosphorylated ERK (pERK) 1/2 protein in nucleus fraction prepared from the slices exposed to CER. Prominently, CER caused not only increases in lipid peroxidation as an index of free radical generation and in LDH leakage as that of cell injury in the slices, but also marked activation of ERK1/2 in nucleus fraction. PD98059 and U0126, MEK1/2 inhibitors, significantly attenuated CER-induced increases in lipid peroxidation and LDH leakage in the slices. PD98059 also suppressed ERK1/2 activation in nucleus fraction prepared from the slices treated with CER. Inhibition of other MAP kinase pathways, p38 MAP kinase and c-Jun N-terminal kinase (JNK) had no effect on CER-induced increases in lipid peroxidation level and LDH leakage in the slices. The present results suggest that a MEK/ERK pathway down stream of a PKC pathway is probably involved in free radical-induced injury in rat renal cortical slices exposed to CER.

  13. Renal transport of urate during diuretic-induced hypouricemia.

    PubMed

    Reese, O G; Steele, T H

    1976-06-01

    The effect of two weeks administration of a uricosuric diuretic (SKF-62698) on renal urate handling has been examined in 11 normal men. Plasma urate concentrations had declined by more than 60 per cent after two weeks. Urate excretion per unit of glomerular filtration rate and urate clearance (Curate) per unit of glomerular filtration rate were increased after the administration of SKF-62698. The importance of intact tubular secretion of urate in producing these changes was assessed by administering pyrazinamide, an agent that curtails urate secretion, to each participant. The decrements in urate excretion and clearance produced by pyrazinamide both increased significantly, whereas the residual urate excretion rates and clearances not suppressible by pyrazinamide were only minimally altered by SKF-62698 treatment. These results suggest that the excretion of secreted urate was enhanced by prolonged administration of SKF-62698, probably secondary to the inhibition of postsecretory urate reabsorption. In addition, because the nonsuppressible urate excretion did not decline despite a 63 per cent reduction in the plasma urate, it is likely that the reabsorption of filtered urate also was impaired by SKF-62698.

  14. Lin28 sustains early renal progenitors and induces Wilms tumor.

    PubMed

    Urbach, Achia; Yermalovich, Alena; Zhang, Jin; Spina, Catherine S; Zhu, Hao; Perez-Atayde, Antonio R; Shukrun, Rachel; Charlton, Jocelyn; Sebire, Neil; Mifsud, William; Dekel, Benjamin; Pritchard-Jones, Kathy; Daley, George Q

    2014-05-01

    Wilms Tumor, the most common pediatric kidney cancer, evolves from the failure of terminal differentiation of the embryonic kidney. Here we show that overexpression of the heterochronic regulator Lin28 during kidney development in mice markedly expands nephrogenic progenitors by blocking their final wave of differentiation, ultimately resulting in a pathology highly reminiscent of Wilms tumor. Using lineage-specific promoters to target Lin28 to specific cell types, we observed Wilms tumor only when Lin28 is aberrantly expressed in multiple derivatives of the intermediate mesoderm, implicating the cell of origin as a multipotential renal progenitor. We show that withdrawal of Lin28 expression reverts tumorigenesis and markedly expands the numbers of glomerulus-like structures and that tumor formation is suppressed by enforced expression of Let-7 microRNA. Finally, we demonstrate overexpression of the LIN28B paralog in a significant percentage of human Wilms tumor. Our data thus implicate the Lin28/Let-7 pathway in kidney development and tumorigenesis.

  15. Temsirolimus induced structural transition of cancerous renal cystatin to normal form in rats: In vitro mechanistic approach underlying renal cancer prevention.

    PubMed

    Shamsi, Anas; Ahmed, Azaj; Bano, Bilqees

    2017-03-01

    Globally, renal cell carcinomas (RCCs) represent a major portion of patients suffering from cancer. Temsirolimus is an anti-renal cancer drug that has already been approved in poor-risk metastatic RCC (mRCC) patients. In our present study, we have evaluated the in vitro effect of varying concentrations of temsirolimus on cancerous rat kidney cystatin; renal cancer was induced in rats making use of dimethylnitrosamine (DMN). It has already been reported that cancerous rat kidney cystatin performs its activity in an efficacious manner as compared to normal rat kidney cystatin, so here an attempt was made to see the effect of temsirolimus on this increased activity of cystatin in renal cancers. Anti-papain activity assay was utilized to see this effect and it was found that temsirolimus reduces the increased activity of cancerous rat kidney cystatin similar to that of normal rat kidney cystatin. Further, to have an insight into temsirolimus induced structural alterations in cancerous rat kidney cystatin; various spectroscopic assays viz. UV, Fluorescence, Circular dichroism (CD) and FTIR spectroscopy were employed. UV and Fluorescence spectroscopy shows cancerous rat kidney cystatin transformation to normal form in the presence of temsirolimus. FTIR and CD spectroscopy confirmed the complete structural reversion of cancerous rat kidney cystatin to normal form in the presence of 40μM temsirolimus. Thus, it can said that temsirolimus causes renal cystatin to revert to normal form; the increased activity of renal cystatin observed in incidences of renal cancer is restored back to normal thereby halting the progression of renal cancer.

  16. Effect of chaetocin on renal cell carcinoma cells and cytokine-induced killer cells.

    PubMed

    Rombo, Roman; Weiher, Hans; Schmidt-Wolf, Ingo G H

    2016-01-01

    We examined the cytotoxic effects of chaetocin on clear cell renal cell carcinoma (ccRCC) cells and the possibility to combine the effects of chaetocin with the effects of cytokine-induced killer cells (CIK) assayed by MTT assay and FACS analysis. Chaetocin is a thiodioxopiperazine produced by fungi belonging to the chaetomiaceae family. In 2007, it was first reported that chaetocin shows potent and selective ex vivo anti-cancer activity by inducing reactive oxygen species. CIK cells are generated from CD3+/CD56- T lymphocytes with double negative CD4-/CD8- phenotype that are isolated from human blood. The addition of distinct interleukins and antibodies results in the generation of CIK cells that are able to specifically target and destroy renal carcinoma cells. The results of this research state that the anti-ccRCC activity of chaetocin is weak and does not show a high grade of selectivity on clear cell renal cell carcinoma cells. Although the CIK cells show a high grade of selective anti-ccRCC activity, this effect could not be improved by the addition of chaetocin. So chaetocin seems to be no suitable agent for specific targeting ccRCC cells or for the combination therapy with CIK cells in renal cancer.

  17. Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury

    PubMed Central

    Farrar, Conrad A.; Tran, David; Li, Ke; Wu, Weiju; Peng, Qi; Schwaeble, Wilhelm; Zhou, Wuding

    2016-01-01

    Physiochemical stress induces tissue injury as a result of the detection of abnormal molecular patterns by sensory molecules of the innate immune system. Here, we have described how the recently discovered C-type lectin collectin-11 (CL-11, also known as CL-K1 and encoded by COLEC11) recognizes an abnormal pattern of L-fucose on postischemic renal tubule cells and activates a destructive inflammatory response. We found that intrarenal expression of CL-11 rapidly increases in the postischemic period and colocalizes with complement deposited along the basolateral surface of the proximal renal tubule in association with L-fucose, the potential binding ligand for CL-11. Mice with either generalized or kidney-specific deficiency of CL-11 were strongly protected against loss of renal function and tubule injury due to reduced complement deposition. Ex vivo renal tubule cells showed a marked capacity for CL-11 binding that was induced by cell stress under hypoxic or hypothermic conditions and prevented by specific removal of L-fucose. Further analysis revealed that cell-bound CL-11 required the lectin complement pathway–associated protease MASP-2 to trigger complement deposition. Given these results, we conclude that lectin complement pathway activation triggered by ligand–CL-11 interaction in postischemic tissue is a potent source of acute kidney injury and is amenable to sugar-specific blockade. PMID:27088797

  18. Protodioscin ameliorates fructose-induced renal injury via inhibition of the mitogen activated protein kinase pathway.

    PubMed

    Shen, Jinyang; Yang, Xiaolin; Meng, Zhaoqing; Guo, Changrun

    2016-11-15

    High dietary fructose can cause metabolic syndrome and renal injury. The effects of protodioscin on metabolic syndrome and renal injury were investigated in mice receiving high-dose fructose. Mice received 30% (w/v) fructose in water and standard chow for 6 weeks to induce metabolic syndrome and were divided into four groups to receive carboxymethylcellulose sodium, allopurinol (5 mg/kg) and protodioscin (5 and 10 mg/kg) continuously for 6 weeks, respectively. The glucose intolerance, serum uric acid (UA), blood urea nitrogen (BUN), creatinine (Cr), total cholesterol (TC), triglyceride (TG), interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were determined. Protodioscin significantly improved glucose intolerance and reduced the levels of serum UA, BUN, Cr, TC and TG. Histological examinations showed that protodioscin ameliorated glomerular and tubular pathological changes. Protodioscin significantly reduced renal concentrations of IL-1β, IL-6 and TNF-α by inhibiting the activation of nuclear factor-κB, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase and extracellular signal-regulated kinase. In addition, the effect of protodioscin on the mitogen activated protein kinases (MAPK) pathway was examined. Taken together, protodioscin is a potential drug candidate for high dietary fructose-induced metabolic syndrome and renal injury. Copyright © 2016 Elsevier GmbH. All rights reserved.

  19. Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction.

    PubMed

    Wang, Lin; Lee, Ji-Yang Sophie; Kwak, Joon Hyeok; He, Yanjuan; Kim, Sung Il; Choi, Mary E

    2008-03-01

    Tubulointerstitial fibrosis is a hallmark of chronic progressive kidney disease leading to end-stage renal failure. An endogenous product of heme oxygenase activity, carbon monoxide (CO), has been shown to exert cytoprotection against tissue injury. Here, we explored the effects of exogenous administration of low-dose CO in an in vivo model of renal fibrosis induced by unilateral ureteral obstruction (UUO) and examined whether CO can protect against kidney injury. UUO in mice leads to increased extracellular matrix (ECM) deposition and tubulointerstitial fibrosis within 4 to 7 days. Kidneys of mice exposed to low-dose CO, however, had markedly reduced ECM deposition after UUO. Moreover, low-dose CO treatment inhibited the induction of alpha-smooth muscle actin (alpha-SMA) and major ECM proteins, type 1 collagen and fibronectin, in kidneys after UUO. In contrast, these anti-fibrotic effects of CO treatment were abrogated in mice carrying null mutation of Mkk3, suggesting involvement of the MKK3 signaling pathway in mediating the CO effects. Additionally, in vitro CO exposure markedly inhibited TGF-beta(1)-induced expression of alpha-SMA, collagen, and fibronectin in renal proximal tubular epithelial cells. Our findings suggest that low-dose CO exerts protective effects, via the MKK3 pathway, to inhibit development of renal fibrosis in obstructive nephropathy.

  20. Effect of chaetocin on renal cell carcinoma cells and cytokine-induced killer cells

    PubMed Central

    Rombo, Roman; Weiher, Hans; Schmidt-Wolf, Ingo G.H.

    2016-01-01

    We examined the cytotoxic effects of chaetocin on clear cell renal cell carcinoma (ccRCC) cells and the possibility to combine the effects of chaetocin with the effects of cytokine-induced killer cells (CIK) assayed by MTT assay and FACS analysis. Chaetocin is a thiodioxopiperazine produced by fungi belonging to the chaetomiaceae family. In 2007, it was first reported that chaetocin shows potent and selective ex vivo anti-cancer activity by inducing reactive oxygen species. CIK cells are generated from CD3+/CD56- T lymphocytes with double negative CD4-/CD8- phenotype that are isolated from human blood. The addition of distinct interleukins and antibodies results in the generation of CIK cells that are able to specifically target and destroy renal carcinoma cells. The results of this research state that the anti-ccRCC activity of chaetocin is weak and does not show a high grade of selectivity on clear cell renal cell carcinoma cells. Although the CIK cells show a high grade of selective anti-ccRCC activity, this effect could not be improved by the addition of chaetocin. So chaetocin seems to be no suitable agent for specific targeting ccRCC cells or for the combination therapy with CIK cells in renal cancer. PMID:27141211

  1. Protective effect of oral L-arginine administration on gentamicin-induced renal failure in rats.

    PubMed

    Can, C; Sen, S; Boztok, N; Tuglular, I

    2000-03-03

    We investigated the effects of orally supplemented L-arginine, the substrate of nitric oxide (NO) and N(omega)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide-synthase inhibitor in gentamicin-induced renal failure. Rats were given gentamicin (100 mg/kg/day s.c.), gentamicin and L-arginine (2 g/l, drinking water), gentamicin and L-NAME (100 mg/l, drinking water) or gentamicin plus L-arginine and L-NAME. After 8 days, the gentamicin group developed marked renal failure, characterized by a significantly decreased creatinine clearance and increased blood creatinine, fractional excretion of sodium, fractional excretion of lithium, urine gamma glutamyl transferase, systolic blood pressure and daily urine volume when compared to controls. Renal histological analysis confirmed tubular necrosis. L-arginine administration caused normalization of these parameters, whereas L-NAME led to aggravation of the failure. Concomitant administration of L-NAME and L-arginine to gentamicin-treated rats caused no significant changes when compared to the rats receiving gentamicin alone. We conclude that L-arginine supplementation has beneficial effects in gentamicin-induced renal failure in rats and that these effects are reversed by the NO-synthase inhibitor, L-NAME.

  2. Haloalkylamine-induced renal papillary necrosis: a histopathological study of structure-activity relationships.

    PubMed Central

    Powell, C. J.; Grasso, P.; Ioannides, C.; Wilson, J.; Bridges, J. W.

    1991-01-01

    The haloalkylamine 2-bromoethanamine (BEA) causes necrosis of renal papillae of rats within 24 h of a single intraperitoneal dose greater than or equal to 100 mg/kg. Nine structural analogues of BEA, differing by halide substitution, alkyl chain elongation or amine substitution, were tested for their ability to induce renal papillary lesions in rats. Three compounds (2-chloroethanamine, 3-bromopropanamine and 2-chloro-N,N-dimethylethanamine) induced lesions which were morphologically indistinguishable from those of BEA. All the molecular structural variations investigated reduced papillotoxicity compared with BEA, the parent compound. A variety of non-renal lesions including hepatic, adrenal, testicular and lymphoid necroses were also encountered. The most toxic compound was 2-fluorethanamine, a 5 mg/kg dose of which was lethal and induced renal corticomedullary mineralization and centrilobular hepatic necrosis. One analogue, 3-bromo-2-hydroxypropanamine, caused rapid and extensive necrosis of the adrenal pars fasciculata and reticularis, simulating human Waterhouse Friderichsen syndrome. The three newly identified renal papillotoxins are all theoretically capable of generating direct-acting alkylating species in solution and their activity as direct-acting mutagens in the Ames bacterial mutagenicity test with TA100 (indicating base pair substitution) closely correlated with their potency as papillotoxins. We therefore hypothesize that non-enzymically formed direct-acting alkylating species mediate these papillary lesions, and that the target selectivity of haloalkylamine toxicity most probably results from the accumulation of these alkylating species in papillary tissue. Images Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 PMID:1768609

  3. C-met inhibition blocks bone metastasis development induced by renal cancer stem cells

    PubMed Central

    D'Amico, Lucia; Belisario, Dimas; Migliardi, Giorgia; Grange, Cristina; Bussolati, Benedetta; D'Amelio, Patrizia; Perera, Timothy; Dalmasso, Ettore; Carbonare, Luca Dalle; Godio, Laura; Comoglio, Paolo; Trusolino, Livio; Ferracini, Riccardo; Roato, Ilaria

    2016-01-01

    Cancer stem cells (CSCs) are key players in bone metastasis. In some renal tumors CSCs overexpress the HGF receptor c-MET, speculating that c-MET targeting could lead to bone metastasis inhibition. To address this hypothesis we isolated renal CD105+/CD24−CSCs, expressing c-MET receptor from a primary renal carcinoma. Then, to study their ability to metastasize to bone, we injected renal CSCs in NOD/SCID mice implanted with a human bone and we tested the effect of a c-MET inhibitor (JNJ-38877605) on bone metastasis development. JNJ-38877605 inhibited the formation of metastases at bone implant site. We showed that JNJ-38877605 inhibited the activation of osteoclasts induced by RCC stem cells and it stimulated osteoblast activity, finally resulting in a reduction of bone turnover consistent with the inhibition of bone metastases. We measured the circulating levels of osteotropic factors induced by RCC stem cells in the sera of mice treated with c-Met inhibitor, showing that IL-11 and CCL20 were reduced in mice treated with JNJ-38877605, strongly supporting the involvement of c-MET in the regulation of this process. To address the clinical relevance of c-MET upregulation during tumor progression, we analysed c-MET in renal cancer patients detecting an increased expression in the bone metastatic lesions by IHC. Then, we dosed CCL20 serum levels resulting significantly increased in patients with bone metastases compared to non-metastatic ones. Collectively, our data highlight the importance of the c-MET pathway in the pathogenesis of bone metastases induced by RCC stem cells in mice and humans. PMID:27322553

  4. Pentoxifylline prevents the meglumine antimonate-induced renal toxicity in rats, but not that induced by the inorganic antimony pentachloride.

    PubMed

    de Moura, Flávio José Dutra; Leal, Pushkin Pires; de Souza Furtado, Rogério; Muniz-Junqueira, Maria Imaculada; Veiga, Joel Paulo Russomano

    2008-01-14

    Tumor necrosis factor-alpha (TNF-alpha) is a mediator of inflammation and has an important role in human and experimental renal diseases. Pentoxifylline (PTX) has been shown to inhibit cytokine synthesis, including TNF-alpha. The aim of the present study was to examine the effect of PTX on meglumine antimonate (Sb(V)) and antimony pentachloride (SbCl(5))-induced renal toxicity in rats. Sixty Wistar rats were divided into six groups according to the treatment employed over the period of 7 days: group I-saline (NaCl 0.9%); group II-PTX plus saline; group III-meglumine antimonate (Sb(V)) plus saline; group IV-meglumine antimonate (Sb(V)) plus PTX; group V-SbCl(5) plus saline; group VI-SbCl(5) with PTX. The animals' urinary concentration ability was evaluated before and after the end of the treatment. Urine and blood osmolality, sodium and creatinine concentration, and urine volume per minute (V) were determined. Creatinine clearance (CrCl), fractional sodium excretion (FE(Na)), and urine to plasma osmolality ratio (U/P osm) were calculated. TNF-alpha concentration in blood was assessed. On the seventh day, the animals were sacrificed and their kidneys were submitted to histological analysis. The meglumine antimonate (Sb(V))-treated animals showed an impaired renal capacity to concentrate urine, with low values of the ratio U/P osm, reduction in CrCl, and an increment in TNF-alpha serum levels. PTX associated with meglumine antimonate (Sb(V)) reduced TNF-alpha serum levels and was effective in preventing renal functional alterations. Rats treated with SbCl(5) showed functional and histopathologic alterations compatible with acute tubular necrosis, and treatment with PTX did not prevent SbCl(5)-induced nephrotoxicity. PTX was effective in preventing renal functional alterations induced by meglumine antimonate (Sb(V)) in rats.

  5. [Neurologic complications induced by the treatment of the acute renal allograft rejection with the monoclonal antibody OKT3].

    PubMed

    Fernández, O; Romero, F; Bravo, M; Burgos, D; Cabello, M; González-Molina, M

    1993-10-01

    The treatment of the acute renal allograft rejection with the monoclonal antibody orthoclone OKT3 produces both systemic and neurologic alterations. In a series of 21 patients with an acute renal allograft rejection treated with this monoclonal antibody, 20 with a renal allograft transplantation and one with a renal and pancreatic allograft transplantation, 29% referred headache associated with fever and vomiting, and 14.2% presented severe neurological alterations induced by the treatment. We stress the need to know these secondary effects to differentiate them from other central nervous system disorders, particularly those of infectious origin.

  6. Renal ammonia and glutamine metabolism during liver insufficiency-induced hyperammonemia in the rat.

    PubMed Central

    Dejong, C H; Deutz, N E; Soeters, P B

    1993-01-01

    Renal glutamine uptake and subsequent urinary ammonia excretion could be an important alternative pathway of ammonia disposal from the body during liver failure (diminished urea synthesis), but this pathway has received little attention. Therefore, we investigated renal glutamine and ammonia metabolism in midly hyperammonemic, portacaval shunted rats and severely hyperammonemic rats with acute liver ischemia compared to their respective controls, to investigate whether renal ammonia disposal from the body is enhanced during hyperammonemia and to explore the limits of the pathway. Renal fluxes, urinary excretion, and renal tissue concentrations of amino acids and ammonia were measured 24 h after portacaval shunting, and 2, 4, and 6 h after liver ischemia induction and in the appropriate controls. Arterial ammonia increased to 247 +/- 22 microM after portacaval shunting compared to controls (51 +/- 8 microM) (P < 0.001) and increased to 934 +/- 54 microM during liver ischemia (P < 0.001). Arterial glutamine increased to 697 +/- 93 microM after portacaval shunting compared to controls (513 +/- 40 microM) (P < 0.01) and further increased to 3781 +/- 248 microM during liver ischemia (P < 0.001). In contrast to controls, in portacaval shunted rats the kidney net disposed ammonia from the body by diminishing renal venous ammonia release (from 267 +/- 33 to -49 +/- 59 nmol/100 g body wt per min) and enhancing urinary ammonia excretion from 113 +/- 24 to 305 +/- 52 nmol/100 g body wt per min (both P < 0.01). Renal glutamine uptake diminished in portacaval shunted rats compared to controls (-107 +/- 33 vs. -322 +/- 41 nmol/100 g body wt per min) (P < 0.01). However, during liver ischemia, net renal ammonia disposal from the body did not further increase (294 +/- 88 vs. 144 +/- 101 nmol/100 g body wt per min during portacaval shunting versus liver ischemia). Renal glutamine uptake was comparable in both hyperammonemic models. These results indicate that the rat kidney plays

  7. Inhibin-A and Decorin Secreted by Human Adult Renal Stem/Progenitor Cells Through the TLR2 Engagement Induce Renal Tubular Cell Regeneration.

    PubMed

    Sallustio, Fabio; Curci, Claudia; Aloisi, Alessandra; Toma, Chiara Cristina; Marulli, Elisabetta; Serino, Grazia; Cox, Sharon Natasha; De Palma, Giuseppe; Stasi, Alessandra; Divella, Chiara; Rinaldi, Rosaria; Schena, Francesco Paolo

    2017-08-15

    Acute kidney injury (AKI) is a public health problem worldwide. Several therapeutic strategies have been made to accelerate recovery and improve renal survival. Recent studies have shown that human adult renal progenitor cells (ARPCs) participate in kidney repair processes, and may be used as a possible treatment to promote regeneration in acute kidney injury. Here, we show that human tubular ARPCs (tARPCs) protect physically injured or chemically damaged renal proximal tubular epithelial cells (RPTECs) by preventing cisplatin-induced apoptosis and enhancing proliferation of survived cells. tARPCs without toll-like receptor 2 (TLR2) expression or TLR2 blocking completely abrogated this regenerative effect. Only tARPCs, and not glomerular ARPCs, were able to induce tubular cell regeneration process and it occurred only after damage detection. Moreover, we have found that ARPCs secreted inhibin-A and decorin following the RPTEC damage and that these secreted factors were directly involved in cell regeneration process. Polysaccharide synthetic vesicles containing these molecules were constructed and co-cultured with cisplatin damaged RPTECs. These synthetic vesicles were not only incorporated into the cells, but they were also able to induce a substantial increase in cell number and viability. The findings of this study increase the knowledge of renal repair processes and may be the first step in the development of new specific therapeutic strategies for renal repair.

  8. Pentoxifylline protects against endotoxin-induced acute renal failure in mice.

    PubMed

    Wang, Wei; Zolty, Einath; Falk, Sandor; Basava, Veena; Reznikov, Leonid; Schrier, Robert

    2006-11-01

    Acute renal failure (ARF) in septic patients drastically increases the mortality to 50-80%. Sepsis induces several proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), a major pathogenetic factor in septic ARF. Pentoxifylline has several functions including downregulation of TNF-alpha and endothelia-dependent vascular relaxation. We hypothesized that pentoxifylline may afford renal protection during endotoxemia either by downregulating TNF-alpha and/or by improving endothelial function. In wild-type mice, pentoxifylline protected against the fall in glomerular filtration rate (GFR; 105.2 +/- 6.6 vs. 50.2 +/- 6.6 microl/min, P < 0.01) at 16 h of LPS administration (2.5 mg/kg ip). This renal protective effect of pentoxifylline was associated with an inhibition of the rise in serum TNF-alpha (1.00 +/- 0.55 vs. 7.02 +/- 2.40 pg/ml, P < 0.05) and serum IL-1beta (31.3 +/- 3.6 vs. 53.3 +/- 5.9 pg/ml, P < 0.01) induced by LPS. Pentoxifylline also reversed the LPS-related increase in renal iNOS and ICAM-1 and rise in serum nitric oxide (NO). Enhanced red blood cell deformability by pentoxifylline may have increased shear rate and upregulated eNOS. Studies were therefore performed in eNOS knockout mice. The renal protection against endotoxemia with pentoxifylline was again observed as assessed by GFR (119.8 +/- 18.0 vs. 44.5 +/- 16.2 microl/min, P < 0.05) and renal blood flow (0.86 +/- 0.08 vs. 0.59 +/- 0.05 ml/min, P < 0.05). Renal vascular resistance significantly decreased with the pentoxifylline (91.0 +/- 5.8 vs. 178.0 +/- 7.6 mmHg.ml(-1).min(-1), P < 0.01). Thus pentoxifylline, an FDA-approved drug, protects against endotoxemia-related ARF and involves a decrease in serum TNF-alpha, IL-1beta, and NO as well as a decrease in renal iNOS and ICAM-1.

  9. Metformin improves metabolic memory in high fat diet (HFD)-induced renal dysfunction.

    PubMed

    Tikoo, Kulbhushan; Sharma, Ekta; Amara, Venkateswara Rao; Pamulapati, Himani; Dhawale, Vaibhav Shrirang

    2016-08-22

    Recently, we have shown that high fat diet (HFD) in vivo and in vitro generates metabolic memory by altering H3K36me2 and H3K27me3 on the promoter of FOXO1 (transcription factor of gluconeogenic genes) (Kumar et al., 2015). Here we checked the hypothesis, whether concomitant diet reversal and metformin could overcome HFD-induced metabolic memory and renal damage. Male adult Sprague Dawley rats were rendered insulin resistant by feeding high fat diet for 16 weeks. Then the rats were subjected to diet reversal (REV) alone and along with metformin (REV+MET) for 8 weeks. Biochemical and histological markers of insulin resistance and kidney function were measured. Blood pressure and in vivo vascular reactivity to Angiotensin II (200 mgkg-1) were also checked. Diet reversal could improve lipid profile but could not prevent renal complications induced by HFD. Interestingly, metformin along with diet reversal restored the levels of blood glucose, triglycerides, cholesterol, blood urea nitrogen and creatinine. In kidney, metformin increased the activation of AMPK, decreased inflammatory markers-COX-2, IL-1β and apoptotic markers-PARP, Caspase3. Metformin was effective in lowering the elevated basal blood pressure, acute change in mean arterial pressure (ΔMAP) in response to Ang II. It also attenuated the tubulointerstitial fibrosis and glomerulosclerosis induced by HFD-feeding in kidney. Here we report for the first time, that metformin treatment overcomes metabolic memory and prevents HFD-induced renal damage.

  10. Role of mitochondrial permeability transition in human renal tubular epithelial cell death induced by aristolochic acid

    SciTech Connect

    Qi Xinming; Cai Yan; Gong Likun; Liu Linlin; Chen Fangping; Xiao Ying; Wu Xiongfei; Li Yan; Xue Xiang |; Ren Jin . E-mail: cdser_simm@mail.shcnc.ac.cn

    2007-07-01

    Aristolochic acid (AA), a natural nephrotoxin and carcinogen, can induce a progressive tubulointerstitial nephropathy. However, the mechanism by which AA causes renal injury remains largely unknown. Here we reported that the mitochondrial permeability transition (MPT) plays an important role in the renal injury induced by aristolochic acid I (AAI). We found that in the presence of Ca{sup 2+}, AAI caused mitochondrial swelling, leakage of Ca{sup 2+}, membrane depolarization, and release of cytochrome c in isolated kidney mitochondria. These alterations were suppressed by cyclosporin A (CsA), an agent known to inhibit MPT. Culture of HK-2 cell, a human renal tubular epithelial cell line for 24 h with AAI caused a decrease in cellular ATP, mitochondrial membrane depolarization, cytochrome c release, and increase of caspase 3 activity. These toxic effects of AAI were attenuated by CsA and bongkrekic acid (BA), another specific MPT inhibitor. Furthermore, AAI greatly inhibited the activity of mitochondrial adenine nucleotide translocator (ANT) in isolated mitochondria. We suggested that ANT may mediate, at least in part, the AAI-induced MPT. Taken together, these results suggested that MPT plays a critical role in the pathogenesis of HK-2 cell injury induced by AAI and implied that MPT might contribute to human nephrotoxicity of aristolochic acid.

  11. Cinnamaldehyde impairs high glucose-induced hypertrophy in renal interstitial fibroblasts.

    PubMed

    Chao, Louis Kuoping; Chang, Wen-Teng; Shih, Yuan-Wei; Huang, Jau-Shyang

    2010-04-15

    Cinnamaldehyde is a major and a bioactive compound isolated from the leaves of Cinnamomum osmophloeum kaneh. To explore whether cinnamaldehyde was linked to altered high glucose (HG)-mediated renal tubulointerstitial fibrosis in diabetic nephropathy (DN), the molecular mechanisms of cinnamaldehyde responsible for inhibition of HG-induced hypertrophy in renal interstitial fibroblasts were examined. We found that cinnamaldehyde caused inhibition of HG-induced cellular mitogenesis rather than cell death by either necrosis or apoptosis. There were no changes in caspase 3 activity, cleaved poly(ADP-ribose) polymerase (PARP) protein expression, and mitochondrial cytochrome c release in HG or cinnamaldehyde treatments in these cells. HG-induced extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) (but not the Janus kinase 2/signal transducers and activators of transcription) activation was markedly blocked by cinnamaldehyde. The ability of cinnamaldehyde to inhibit HG-induced hypertrophy was verified by the observation that it significantly decreased cell size, cellular hypertrophy index, and protein levels of collagen IV, fibronectin, and alpha-smooth muscle actin (alpha-SMA). The results obtained in this study suggest that cinnamaldehyde treatment of renal interstitial fibroblasts that have been stimulated by HG reduces their ability to proliferate and hypertrophy through mechanisms that may be dependent on inactivation of the ERK/JNK/p38 MAPK pathway.

  12. CDP-choline circumvents mercury-induced mitochondrial damage and renal dysfunction.

    PubMed

    Buelna-Chontal, Mabel; Franco, Martha; Hernández-Esquivel, Luz; Pavón, Natalia; Rodríguez-Zavala, José S; Correa, Francisco; Jasso, Ricardo; Pichardo-Ramos, Gregorio; Santamaría, José; González-Pacheco, Héctor; Soto, Virgilia; Díaz-Ruíz, Jorge L; Chávez, Edmundo

    2017-09-08

    Heavy metal ions are known to produce harmful alterations on kidney function. Specifically, the accumulation of Hg(2+) in kidney tissue may induce renal failure. In this work, the protective effect of CDP-choline against the deleterious effects induced by Hg(2+) on renal function was studied. CDP-choline administered ip at a dose of 125 mg/kg body weight prevented the damage induced by Hg(2+) administration at a dose of 3 mg/kg body weight. The findings indicate that CDP-choline guards mitochondria against Hg(2+) -toxicity by preserving their ability to retain matrix content, such as accumulated Ca(2+) . This nucleotide also protected mitochondria from Hg(2+) -induced loss of the transmembrane electric gradient and from the generation of hydrogen peroxide and membrane TBARS. In addition, CDP-choline avoided the oxidative damage of mtDNA and inhibited the release of the interleukins IL-1 and IL6, recognized as markers of acute inflammatory reaction. After the administration of Hg(2+) and CDP, CDP-choline maintained nearly normal levels of renal function and creatinine clearance, as well as blood urea nitrogen (BUN) and serum creatinine. © 2017 International Federation for Cell Biology.

  13. Cinnamaldehyde impairs high glucose-induced hypertrophy in renal interstitial fibroblasts

    SciTech Connect

    Chao, Louis Kuoping; Chang, W.-T.; Shih, Y.-W.; Huang, J.-S.

    2010-04-15

    Cinnamaldehyde is a major and a bioactive compound isolated from the leaves of Cinnamomum osmophloeum kaneh. To explore whether cinnamaldehyde was linked to altered high glucose (HG)-mediated renal tubulointerstitial fibrosis in diabetic nephropathy (DN), the molecular mechanisms of cinnamaldehyde responsible for inhibition of HG-induced hypertrophy in renal interstitial fibroblasts were examined. We found that cinnamaldehyde caused inhibition of HG-induced cellular mitogenesis rather than cell death by either necrosis or apoptosis. There were no changes in caspase 3 activity, cleaved poly(ADP-ribose) polymerase (PARP) protein expression, and mitochondrial cytochrome c release in HG or cinnamaldehyde treatments in these cells. HG-induced extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) (but not the Janus kinase 2/signal transducers and activators of transcription) activation was markedly blocked by cinnamaldehyde. The ability of cinnamaldehyde to inhibit HG-induced hypertrophy was verified by the observation that it significantly decreased cell size, cellular hypertrophy index, and protein levels of collagen IV, fibronectin, and alpha-smooth muscle actin (alpha-SMA). The results obtained in this study suggest that cinnamaldehyde treatment of renal interstitial fibroblasts that have been stimulated by HG reduces their ability to proliferate and hypertrophy through mechanisms that may be dependent on inactivation of the ERK/JNK/p38 MAPK pathway.

  14. Aqueous extract of Berberis integerrima root improves renal dysfunction in streptozotocin induced diabetic rats

    PubMed Central

    Ashraf, Hossein; Heidari, Reza; Nejati, Vahid; Ilkhanipoor, Minoo

    2013-01-01

    Objective: Barberry root extract contains various alkaloids that are considered as antioxidants. Beneficial effect of aqueous extract of Berberis integerrima root (AEBIR) was evaluated for renal function in diabetic rats induced by STZ. Material and Methods: Diabetes was induced by i.p. injection of streptozotocin (65 mg/kg bw) to rats, after 15 h of fasting. Diabetic rats were randomly grouped and treated daily with AEBIR and glibenclamide by gavage for 42 days. After 6 weeks of study, all the rats were sacrificed and some biochemical parameters of serum and urine were measured and their kidneys tissues were processed for light microscopy. Results: Streptozotocin induced a significant rise in fasting blood glucose, serum creatinine, blood urea nitrogen, urine glucose, urine protein, urine albumin, and water intake and a significant decrease in body weight, serum protein, urine urea, and urine creatinine. There was a significant restoration of these parameters to near normal after administration of the AEBIR and also by glibenclamide (0.6 mg/kg bw). The activity of the extract at dose of 500 mg/kg in all parameters except blood glucose and urine glucose was more than that of the standard drug, glibenclamide (0.6 mg/kg, p.o.). Histopathological changes of kidney samples were comparable with respective control. Conclusion: These results suggested that aqueous extract of Berberis Integerrima root improves renal dysfunction in streptozotocin-induced diabetic rats through controlling blood glucose and renal protective effects. PMID:25050261

  15. Effect of photobiomodulation on ischemia/reperfusion-induced renal damage in diabetic rats.

    PubMed

    Asghari, Ahmad; Takhtfooladi, Mohammad Ashrafzadeh; Hoseinzadeh, Hesam Aldin

    2016-12-01

    This study was designed to investigate the possible effect of photobiomodulation (PBM) on renal damage induced by ischemia reperfusion (IR) in diabetic rats. Twenty streptozotocin-induced diabetic rats were randomly distributed into two groups, containing ten rats each: IR group (G1) and IR + PBM group (G2). After the right nephrectomy, the ischemia was produced in the left kidney for 30 min, followed by the reperfusion for 24 h. Then, a 685-nm laser diode with an output power of 15 mW (spot size = 0.28 cm(2) and energy density = 3.2 J/cm(2)) was employed. PBM was carried out by irradiating the rats over six points on the skin over the left kidney region three times, i.e., immediately after skin suturing and 1 and 2 h after initiating reperfusion for 6 min. At the end of reperfusion period, the rats were anesthetized, and blood samples were collected and used for the estimation of renal function (blood urea nitrogen (BUN) and creatinine). Then, the left kidney was harvested for histological and biochemical examination. The serum levels of BUN and creatinine were significantly higher in G1 compared to G2 (P < 0.05). G1 had higher renal malondialdehyde (MDA) levels compared to G2 (P < 0.05). Renal IR in diabetic rats (G1) resulted in a significant decrease in renal tissue glutathione (GSH) (P < 0.05) when compared to laser-treated rats (G2). A significant restoration was observed in the levels of superoxide dismutase (SOD) (P < 0.05) and catalase (CAT) (P < 0.05) in G2 as compared to G1. The levels of nitric oxide (NO) were increased in G1 in comparison to G2 (P < 0.05). The myeloperoxidase (MPO) activity was significantly higher in the renal tissue of G1 than that of G2 (P < 0.05). In addition, specimens from the G1 had a significantly greater histological injury than those from the G2 (P < 0.05). The results of present investigation revealed that PBM attenuated kidney damage induced by renal IR in diabetic rats.

  16. Glucosamine hydrochloride exerts a protective effect against unilateral ureteral obstruction-induced renal fibrosis by attenuating TGF-β signaling.

    PubMed

    Park, Jinah; Lee, So-Young; Ooshima, Akira; Yang, Kyung-Min; Kang, Jin Muk; Kim, Young-Woong; Kim, Seong-Jin

    2013-11-01

    Renal fibrosis is a common consequence of unilateral ureteral obstruction, which provides a useful model to investigate the pathogenesis of obstructive nephropathy and progressive renal fibrosis. Transforming growth factor (TGF-β1) has been recognized as a key mediator in renal fibrosis by stimulating matrix-producing fibrogenic cells and promoting extracellular matrix deposition. Therefore, considerable efforts have been made to regulate TGF-β signaling for antifibrotic therapy. Here, we investigated the mode of action of glucosamine hydrochloride (GS-HCl) on TGF-β1-induced renal fibrosis. In the obstructed kidneys and TGF-β1-treated renal cells, GS-HCl significantly decreased renal expression of α-smooth muscle actin, collagen I, and fibronectin. By investigating the inhibitory mechanism of GS-HCl on renal fibrosis, we found that GS-HCl suppressed TGF-β signaling by inhibiting N-linked glycosylation of the type II TGF-β receptor (TβRII), leading to an inefficient trafficking of TβRII to the membrane surface. Defective N-glycosylation of TβRII further suppressed the TGF-β1-binding to TβRII, thereby decreasing TGF-β signaling. Notably, GS-HCl treatment significantly reduced TGF-β1-induced up-regulation of Smad2/3 phosphorylation and transcriptional activity in vivo and in vitro. Taken together, GS-HCl-mediated regulation of TGF-β signaling exerted an antifibrotic effect, thereby ameliorating renal fibrosis. Our study suggests that GS-HCl would be a promising agent for therapeutic intervention for preventing TGF-β1-induced renal fibrosis in kidney diseases. Glucosamine-mediated attenuation of TGF-β signaling ameliorates renal fibrosis in vivo TGF-β1-induced fibrogenic action is reduced by glucosamine in vitro N-glycosylation of the type II TGF-β receptor is suppressed by glucosamine Glucosamine-induced defective N-glycosylation of TβRII decreases TGF-β signaling.

  17. Maternal fructose-intake-induced renal programming in adult male offspring.

    PubMed

    Tain, You-Lin; Wu, Kay L H; Lee, Wei-Chia; Leu, Steve; Chan, Julie Y H

    2015-06-01

    Nutrition in pregnancy can elicit long-term effects on the health of offspring. Although fructose consumption has increased globally and is linked to metabolic syndrome, little is known about the long-term effects of maternal high-fructose (HF) exposure during gestation and lactation, especially on renal programming. We examined potential key genes and pathways that are associated with HF-induced renal programming using whole-genome RNA next-generation sequencing (NGS) to quantify the abundance of RNA transcripts in kidneys from 1-day-, 3-week-, and 3-month-old male offspring. Pregnant Sprague-Dawley rats received regular chow or chow supplemented with HF (60% diet by weight) during the entire period of pregnancy and lactation. Male offspring exhibited programmed hypertension at 3 months of age. Maternal HF intake modified over 200 renal transcripts from nephrogenesis stage to adulthood. We observed that 20 differentially expressed genes identified in 1-day-old kidney are related to regulation of blood pressure. Among them, Hmox1, Bdkrb2, Adra2b, Ptgs2, Col1a2 and Tbxa2r are associated with endothelium-derived hyperpolarizing factor (EDHF). NGS also identified genes in arachidonic acid metabolism (Cyp2c23, Hpgds, Ptgds and Ptges) that may be potential key genes/pathways contributing to renal programming and hypertension. Collectively, our NGS data suggest that maternal HF intake elicits a defective adaptation of interrelated EDHFs during nephrogenesis which may lead to renal programming and hypertension in later life. Moreover, our results highlight genes and pathways involved in renal programming as potential targets for therapeutic approaches to prevent metabolic-syndrome-related comorbidities in children with HF exposure in early life. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Evaluation of renoprotective effect of Aphanizomenon flos-aquae on cisplatin-induced renal dysfunction in rats.

    PubMed

    Kuriakose, Gini C; Kurup, Muraleedhara G

    2008-01-01

    Cisplatin is an effective chemotherapeutic agent used in the treatment of a wide array of both pediatric and adult malignancies. Dose-dependent and cumulative nephrotoxicity is the major toxicity of this compound, sometimes requiring a reduction in dose or discontinuation of treatment. Recent evidence has implicated oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Aphanizomenon flos-aquae (AFA), blue-green algae, is claimed to be a potential antioxidant. The present study was designed to explore the renoprotective potential of AFA against cisplatin-induced oxidative stress and renal dysfunction. The ethanolic extract of Aphanizomenon flos-aquae (EEAFA) (25, 50, 100 mg/kg(-1) p.o.) was administered two days before through three days after cisplatin challenge (5 mg/kg(-1) i.p.). Renal injury was assessed by measuring serum creatinine, blood urea nitrogen, creatinine and urea clearance, and serum nitrite levels. Renal oxidative stress was determined by renal TBARS levels, reduced glutathione levels, and enzymatic activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione transferase (GST). A single dose of cisplatin produced marked renal oxidative and nitrosative stress and significantly deranged renal functions. Chronic EEAFA treatment significantly and dose-dependently restored renal functions, reduced lipid peroxidation, and enhanced reduced glutathione levels, superoxide dismutase, and catalase activities. The results of the present study clearly demonstrate the pivotal role of reactive oxygen species and their relation to renal dysfunction and point to the therapeutic potential of AFA in cisplatin-induced nephrotoxicity.

  19. Pre-stimulation of the kallikrein system in cisplatin-induced acute renal injury: An approach to renoprotection

    SciTech Connect

    Aburto, Andrés; Barría, Agustín; Cárdenas, Areli; Carpio, Daniel; Figueroa, Carlos D.; Burgos, Maria E.; Ardiles, Leopoldo

    2014-10-15

    Antineoplastic treatment with cisplatin is frequently complicated by nephrotoxicity. Although oxidative stress may be involved, the pathogenic mechanisms responsible for renal damage have not been completely clarified. In order to investigate the role of the renal kinin system in this condition, a group of rats was submitted to high potassium diet to stimulate the synthesis and excretion of tissue kallikrein 1 (rKLK1) previous to an intraperitoneal injection of 7 mg/kg cisplatin. A significant reduction in lipoperoxidation, evidenced by urinary excretion of malondialdehyde and renal immunostaining of hidroxy-nonenal, was accompanied by a decline in apoptosis. Coincident with these findings we observed a reduction in the expression of renal KIM-1 suggesting that renoprotection may be occurring. Stimulation or indemnity of the renal kinin system deserves to be evaluated as a complementary pharmacological measure to diminish cisplatin nephrotoxicity. - Highlights: • Mechanisms of cisplatin-induced-renal damage have not been completely clarified. • Cisplatin induces oxidative stress and apoptosis. • The renal kallikrein-kinin system is protective in experimental acute renal damage. • Kallikrein stimulation reduces oxidative stress and apoptosis induced by cisplatin. • Protection of the kallikrein-kinin system may reduce cisplatin toxicity.

  20. Ertapenem-Induced Encephalopathy in a Patient With Normal Renal Function

    PubMed Central

    Sutton, S. Scott; Jumper, Mark; Cook, Sean; Edun, Babatunde; Wyatt, Michael D.

    2017-01-01

    Drug-induced neurotoxicity is a rare adverse reaction associated with ertapenem. Encephalopathy is a type of neurotoxicity that is defined as a diffuse disease of the brain that alters brain function or structure. We report a patient with normal renal function who developed ertapenem-induced encephalopathy manifesting as altered mental status, hallucinations, and dystonic symptoms. The patient’s symptoms improved dramatically following ertapenem discontinuation, consistent with case reports describing ertapenem neurotoxicity in renal dysfunction. Since clinical evidence strongly suggested ertapenem causality, we utilized the Naranjo Scale to estimate the probability of an adverse drug reaction to ertapenem. Our patient received a Naranjo Scale score of 7, suggesting a probable adverse drug reaction, with a reasonable temporal sequence to support our conclusion. PMID:28203577

  1. Chemical inducers of differentiation in a long-term renal cell line.

    PubMed Central

    Lever, J E

    1989-01-01

    The long-term renal epithelial cell line LLC-PK1 expresses at confluence several differentiated characteristics of renal proximal tubule including Na/glucose cotransport and several brush border membrane hydrolases. The differentiation-inducing chemical hexamethylene bisacetamide (HMBA) triggers a dramatic induction of Na+/glucose symport, trehalase and maltase, expressed as an increase in the number of cells in the culture that express the differentiated phenotype. Characteristics of the induction response are reviewed in terms of proposed mechanisms of inducer action. New evidence suggests that in addition to elevation of intracellular Na levels mediated by partial inhibition of the sodium pump, HMBA treatment also alters polyamine levels via effects on ornithine decarboxylase. These responses may be mediated by HMBA effects on protein kinase C activity. The possible role of polyamine fluctuations and DNA demethylation in mediating HMBA effects on differentiated gene expression is currently being investigated. Images FIGURE 2. FIGURE 3. PMID:2647478

  2. Oral erdosteine administration attenuates cisplatin-induced renal tubular damage in rats.

    PubMed

    Yildirim, Zeki; Sogut, Sadik; Odaci, Ersan; Iraz, Mustafa; Ozyurt, Huseyin; Kotuk, Mahir; Akyol, Omer

    2003-02-01

    The effect of oral erdosteine on tissue malondialdehyde (MDA) and nitric oxide (NO) levels, and catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities are investigated in the cisplatin model of acute renal failure in rats. A single dose of cisplatin caused kidney damage manifested by kidney histology as well as increases in plasma creatinine and blood urea nitrogen (BUN) levels. Treatment with free radical scavenger erdosteine attenuated increases in plasma creatinine and BUN, and tissue MDA and NO levels, and provided a histologically-proven protection against cisplatin-induced acute renal failure. Erdosteine also reduced depletion in the tissue CAT, GSH-Px, and SOD activities. These results show that erdosteine may be a promising drug for protection against cisplatin-induced nephrotoxicity. However, further studies with different doses of erdosteine are warranted for clarifying the issue.

  3. Renal Ultrafiltration Changes Induced by Focused US1

    PubMed Central

    Fischer, Krisztina; McDannold, Nathan J.; Zhang, Yongzhi; Kardos, Magdolna; Szabo, Andras; Szabo, Antal; Reusz, Gyorgy S.; Jolesz, Ferenc A.

    2009-01-01

    microbubbles. This method could offer new opportunities for treatment of renal disease. © RSNA, 2009 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.2532082100/-/DC1 PMID:19703861

  4. Electronegative low density lipoprotein induces renal apoptosis and fibrosis: STRA6 signaling involved[S

    PubMed Central

    Chen, Chao-Hung; Ke, Liang-Yin; Chan, Hua-Chen; Lee, An-Sheng; Lin, Kun-Der; Chu, Chih-Sheng; Lee, Mei-Yueh; Hsiao, Pi-Jung; Hsu, Chin; Chen, Chu-Huang; Shin, Shyi-Jang

    2016-01-01

    Dyslipidemia has been proven to capably develop and aggravate chronic kidney disease. We also report that electronegative LDL (L5) is the most atherogenic LDL. On the other hand, retinoic acid (RA) and RA receptor (RAR) agonist are reported to be beneficial in some kidney diseases. “Stimulated by retinoic acid 6” (STRA6), one retinol-binding protein 4 receptor, was recently identified to regulate retinoid homeostasis. Here, we observed that L5 suppressed STRA6 cascades [STRA6, cellular retinol-binding protein 1 (CRBP1), RARs, retinoid X receptor α, and retinol, RA], but L5 simultaneously induced apoptosis and fibrosis (TGFβ1, Smad2, collagen 1, hydroxyproline, and trichrome) in kidneys of L5-injected mice and L5-treated renal tubular cells. These L5-induced changes of STRA6 cascades, renal apoptosis, and fibrosis were reversed in kidneys of LOX1−/− mice. LOX1 RNA silencing and inhibitor of c-Jun N-terminal kinase and p38MAPK rescued the suppression of STRA6 cascades and apoptosis and fibrosis in L5-treated renal tubular cells. Furthermore, crbp1 gene transfection reversed downregulation of STRA6 cascades, apoptosis, and fibrosis in L5-treated renal tubular cells. For mimicking STRA6 deficiency, efficient silencing of STRA6 RNA was performed and was found to repress STRA6 cascades and caused apoptosis and fibrosis in L1-treated renal tubular cells. In summary, this study reveals that electronegative L5 can cause kidney apoptosis and fibrosis via the suppression of STRA6 cascades, and implicates that STRA6 signaling may be involved in dyslipidemia-mediated kidney disease. PMID:27256691

  5. Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative stress in acetaminophen-induced hepato-renal injury.

    PubMed

    Naguib, Yahya M; Azmy, Rania M; Samaka, Rehab M; Salem, Mohamed F

    2014-12-15

    Acetaminophen (APAP)-induced toxicity is a predominant cause of acute hepatic and renal failure. In both humans and rodents toxicity begins with a reactive metabolite that binds to proteins. This leads to mitochondrial dysfunction and nuclear DNA fragmentation resulting in necrotic cell death. Pleurotus ostreatus (an edible oyster mushroom) is well recognized as a flavourful food, as well as a medicinal supplement. In the present study, we evaluated the role of Pleurotus ostreatus in the protection against APAP-induced hepato-renal toxicity. We also explored the mechanism by which Pleurotus ostreatus exerts its effects. Ninety adult male Swiss albino mice were divided into three groups (30 mice/group). Mice were offered normal diet (control and APAP groups), or diet supplemented with 10% Pleurotus ostreatus (APAP + Pleurotus ostreatus) for 10 days. Mice were either treated with vehicle (control group, single intra-peritoneal injection.), or APAP (APAP and APAP + Pleurotus ostreatus groups, single intra-peritoneal injection, 500 mg/kg), 24 hours after the last meal. APAP increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) glutamate dehydrogenase (GDH), creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (KIM-1), and hepatic and renal malondialdehyde (MDA) content. APAP decreased hepatic and renal glutathione (GSH) content, as well as glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. Supplementation with Pleurotus ostreatus significantly reduced APAP-induced elevated levels of ALT, AST, GDH, creatinine, BUN, KIM-1and MDA, while GSH level, and GSH-Px and SOD activities were significantly increased. Our findings were further validated by histopathology; treatment with Pleurotus ostreatus significantly decreased APAP-induced cell necrosis in liver and kidney tissues. We report here that the antioxidant effect of Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative

  6. Thymoquinone and curcumin attenuate gentamicin-induced renal oxidative stress, inflammation and apoptosis in rats

    PubMed Central

    Mahmoud, Ayman M; Ahmed, Osama M; Galaly, Sanaa R

    2014-01-01

    The present study was aimed to investigate the possible protective effects of thymoquinone (TQ) and curcumin (Cur) on gentamicin (GM)-induced nephrotoxicity in rats. Rats were divided into four groups as follows: group 1 received normal saline and served as normal controls, group 2 received GM only, group 3 concurrently received GM and TQ and group 4 concurrently received GM and Cur. At day 21, rats were sacrificed and samples were collected for assaying serum tumor necrosis factor alpha (TNF-α), urea and creatinine levels, and renal lipid peroxidaion, glutathione (GSH) content as well as glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities. In addition, kidneys were collected for histopathological examination and immunohistochemical determination of the antiapoptotic protein, B-cell lymphoma 2 (Bcl-2). The biochemical results showed that GM-induced nephrotoxicity was associated with a significant increase in serum TNF-α, urea and creatinine as well as renal lipid peroxidation. On the other hand, renal GSH content and GPx and SOD activities were significantly declined. Concomitant administration of either TQ or Cur efficiently alleviated the altered biochemical and histopathological features. In conclusion, both TQ and Cur showed more or less similar marked renoprotective effect against GM-induced nephrotoxicity through their antioxidant, anti-inflammatory and anti-apoptotic efficacies. PMID:26417245

  7. The effect of activated charcoal on adenine-induced chronic renal failure in rats.

    PubMed

    Ali, Badreldin H; Alza'abi, Mohamed; Ramkumar, Aishwarya; Al-Lawati, Intisar; Waly, Mostafa I; Beegam, Sumaya; Nemmar, Abderrahim; Brand, Susanne; Schupp, Nicole

    2014-03-01

    Activated charcoal (AC) is a sorbent that has been shown to remove urinary toxins like urea and indoxyl sulfate. Here, the influence of AC on kidney function of rats with experimental chronic renal failure (CRF) is investigated. CRF was induced in rats by feeding adenine (0.75%) for four weeks. As an intervention, AC was added to the feed at concentrations of 10%, 15% or 20%. Adenine treatment impaired kidney function: it lowered creatinine clearance and increased plasma concentrations of creatinine, urea, neutrophil gelatinase-associated lipocalin and vanin-1. Furthermore, it raised plasma concentrations of the uremic toxins indoxyl sulfate, phosphate and uric acid. Renal morphology was severely damaged and histopathological markers of inflammation and fibrosis were especially increased. In renal homogenates, antioxidant indices, including superoxide dismutase and catalase activity, total antioxidant capacity and reduced glutathione were adversely affected. Most of these changes were significantly ameliorated by dietary administration of AC at a concentration of 20%, while effects induced by lower doses of dietary AC on adenine nephrotoxicity were not statistically significant. The results suggest that charcoal is a useful sorbent agent in dietary adenine-induced CRF in rats and that its usability as a nephroprotective agent in human kidney disease should be studied.

  8. Nephroprotective Effect of Ursolic Acid in a Murine Model of Gentamicin-Induced Renal Damage

    PubMed Central

    Pai, Preethi G.; Chamari Nawarathna, Savindika; Kulkarni, Avdhooth; Habeeba, Umma; Reddy C., Sudarshan; Teerthanath, Srinivas; Shenoy, Jnaneshwara P.

    2012-01-01

    The present study evaluates the nephroprotective effects of ursolic acid in a murine model of gentamicin induced renal damage. Wistar albino rats of either sex, weighing 150–200 g were divided into 5 groups; normal saline, gentamicin 80 mg/kg, intraperitoneally for 8 days, ursolic acid at 2, 5, and 10 mg/kg, per oral for 8 days, ursolic acid administered 3 days prior and concurrently with gentamicin for 5 days. Blood urea, serum creatinine, uric acid and blood urea nitrogen analyses and microscopic examination of kidney were performed. Gentamicin treatment caused nephrotoxicity as evidenced by marked elevation in serum urea, serum uric acid, serum creatinine and blood urea nitrogen (162.33 ± 9.92 mg/dL, 3.13 ± 0.12 mg/dL, 6.85 ± 0.35 mg/dL and 75.86 ± 4.64 mg/dL; resp.) when compared to the saline treated groups. Co-administration of ursolic acid with gentamicin decreased the rise in these parameters in a dose dependent manner. Histopathological analysis revealed epithelial loss with intense granular degeneration in gentamicin treated rats, whereas ursolic acid mitigated the severity of gentamicin-induced renal damage. To conclude, our data suggest that ursolic acid exhibits renoprotective effect in gentamicin induced renal damage and further studies on its mechanis of action are warranted. PMID:22811930

  9. Renal assist device and treatment of sepsis-induced acute kidney injury in intensive care units.

    PubMed

    Issa, Naim; Messer, Jennifer; Paganini, Emil P

    2007-01-01

    Acute kidney injury (AKI) is a frequent and serious complication of sepsis in ICU patients and is associated with a very high mortality. Despite the advent of sophisticated renal replacement therapies (RRT) employing high-dose hemofiltration and high-flux membranes, mortality and morbidity from sepsis-induced AKI remained high. Moreover, these dialytic modalities could not substitute for the important functions of renal tubular cells in decreasing sepsis-induced AKI biological dysregulations. The results from the in vitro and preclinical animal model studies were very intriguing and led to the development of a bioartificial kidney consisting of a renal tubule assist device containing human proximal tubular cells (RAD) added in tandem to a continuous venovenous hemofiltration circuit. The results from the phase I safety trial and the recent phase II clinical trial showed that the RAD not only can replace many of the indispensable biological kidney functions, but also modify the natural history of sepsis-induced AKI by ameliorating patient survival.

  10. Evaluation of anti-urolithiatic activity of Pashanabhedadi Ghrita against experimentally induced renal calculi in rats

    PubMed Central

    Gupta, Sanjay Kumar; Baghel, Madhav Singh; Bhuyan, Chaturbhuja; Ravishankar, B.; Ashok, B. K.; Patil, Panchakshari D.

    2012-01-01

    Population in an industrialized world is afflicted by urinary stone disease. Kidney stones are common in all kinds of urolithiasis. One distinguished formulation mentioned by Sushruta for management of Ashmari (urolithiasis) is Pashanabhedadi Ghrita (PBG), which is in clinical practice since centuries. Validation of drug is the requirement of time through the experimental study. In this study, trial of PBG has been made against ammonium oxalate rich diet and gentamicin injection induced renal calculi in albino rats. The calculi were induced by gentamicin injection and ammonium oxalate rich diet. Test drug was administered concomitantly in the dose of 900 mg/kg for 15 consecutive days. Rats were sacrificed on the 16th day. Parameters like kidney weight, serum biochemical, kidney tissue and histopathology of kidney were studied. Concomitant treatment of PBG attenuates blood biochemical parameters non-significantly, where as it significantly attenuated lipid peroxidation and enhanced glutathione and glutathione peroxidase activities. It also decreased crystal deposition markedly into the renal tubules in number as well as size and prevented damage to the renal tubules. The findings showed that PBG is having significant anti-urolithiatic activities against ammonium oxalate rich diet plus gentamicine injection induced urolithiasis in rats. PMID:23723654

  11. Protein and calorie effects on progression of induced chronic renal failure in cats.

    PubMed

    Finco, D R; Brown, S A; Brown, C A; Crowell, W A; Sunvold, G; Cooper, T L

    1998-05-01

    To determine effects of dietary protein and calories on progression of induced chronic renal failure in cats. 28 young adult female cats. Renal mass was reduced surgically, and glomerular filtration rate (GFR) was determined. Cats were alloted to 4 groups of 7 with similar mean GFR (1.52 to 1.55 ml/min/kg of body weight). Diets were formulated to provide: low protein and calorie (diet A), low protein and high calorie (diet B), high protein and low calorie (diet C), and high protein and calorie (diet D) intakes. Cats were fed their prescribed diet for 12 months, then blood and urine biochemical variables were measured, after which kidney specimens were examined microscopically. Protein intake by cats of groups C and D (9.0 g/d/kg) was substantially greater than that by cats of groups A and B (5.3 and 5.2 g/d/kg, respectively). Caloric intake by cats of groups B and D (73 and 71 calories/d/kg, respectively) was greater than that by cats of groups A and C (58 and 55 calories/d/kg, respectively). Renal glomerular lesions were mild and not affected by protein, calories or their interactions. Nonglomerular lesions, though mild, were significantly influenced by calorie intake, but not by protein or calorie-protein interactions. The GFR did not decrease in any group. Urine protein-to-creatinine ratio increased significantly in all groups after reduction of renal mass, but values from all groups remained within the reference range (0 to 0.3). Diets replete in protein were not associated with increased severity of glomerular or nonglomerular renal lesions, increased proteinuria, or decreased GFR. Diets replete in calories were not associated with increased severity of glomerular lesions, but were associated with mild increase of nonglomerular lesions. Factors other than protein and calorie intake must be considered potential causes of progression of renal failure in cats. Results raise questions about the practice of restricting quantity of protein in the diet of cats with

  12. MicroRNA-328 inhibits renal tubular cell epithelial-to-mesenchymal transition by targeting the CD44 in pressure-induced renal fibrosis.

    PubMed

    Chen, Cheng-Hsien; Cheng, Chung-Yi; Chen, Yen-Cheng; Sue, Yuh-Mou; Liu, Chung-Te; Cheng, Tzu-Hurng; Hsu, Yung-Ho; Chen, Tso-Hsiao

    2014-01-01

    Epithelial-mesenchymal transition (EMT) occurs in stressed tubular epithelial cells, contributing to renal fibrosis. Initial mechanisms promoting EMT are unknown. Pressure force is an important mechanism contributing to the induction and progression of renal fibrogenesis in ureteric obstruction. In our study of cultured rat renal tubular cells (NRK-52E) under 60 mmHg of pressure, we found that the epithelial marker E-cadherin decreased and mesenchymal markers, e.g., α-smooth muscle actin, fibronectin and Snail, increased. Pressure also induced the expression of connective tissue growth factor and transforming growth factor-β. MicroRNA array assays showed that pressure reduced miR-328 at the initial stage of pressurization. We identified a potential target sequence of miR-328 in rat CD44 3'-untranslated regions. In contrast with the miR-328 expression, CD44 expression was up-regulated at the initial pressurization stage. We also found that miR-328 expression decreased and CD44 increased in ureteric obstruction kidneys in the animal study. CD44 siRNA transfection significantly increased E-cadherin expression and inhibited pressure-induced EMT. Both hyaluronan binding peptide pep-1 and osteopontin neutralizing antibody inhibited pressure-induced EMT. Our results suggest that miR-328-mediated CD44 transient upregulation is an important trigger of the pressure-induced EMT in renal fibrosis.

  13. Cinnabar-Induced Subchronic Renal Injury Is Associated with Increased Apoptosis in Rats

    PubMed Central

    Wang, Ying; Wang, Dapeng; Wu, Jie; Wang, Bohan; Gao, Xianhui; Wang, Liangjun; Ma, Honglin

    2015-01-01

    The aim of this study was to explore the role of apoptosis in cinnabar-induced renal injury in rats. To test this role, rats were dosed orally with cinnabar (1 g/kg/day) for 8 weeks or 12 weeks, and the control rats were treated with 5% carboxymethylcellulose solution. Levels of urinary mercury (UHg), renal mercury (RHg), serum creatinine (SCr), and urine kidney injury molecule 1 (KIM-1) were assessed, and renal pathology was analyzed. Apoptotic cells were identified and the apoptotic index was calculated. A rat antibody array was used to analyze expression of cytokines associated with apoptosis. Results from these analyses showed that UHg, RHg, and urine KIM-1, but not SCr, levels were significantly increased in cinnabar-treated rats. Renal pathological changes in cinnabar-treated rats included vacuolization of tubular cells, formation of protein casts, infiltration of inflammatory cells, and increase in the number of apoptotic tubular cells. In comparison to the control group, expression of FasL, Fas, TNF-α, TRAIL, activin A, and adiponectin was upregulated in the cinnabar-treated group. Collectively, our results suggest that prolonged use of cinnabar results in kidney damage due to accumulation of mercury and that the underlying mechanism involves apoptosis of tubular cells via a death receptor-mediated pathway. PMID:25629042

  14. Prevention of Renal Complications Induced by Non- Steroidal Anti-Inflammatory Drugs.

    PubMed

    Ković, Sonja Vuč; Vujović, Katarina Savić; Srebro, Dragana; Medić, Branislava; Ilic-Mostic, Tatjana

    2016-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for the treatment of pain, inflamation and fever. They are usually well tolerated in healthy persons, but in patients with risk factors (advanced age, renal impairment, heart failure, liver disease, concurrent medications with antihypertensive drugs), NSAIDs can induce serious renal adverse effects. They include sodium and water retention with edema, worsening of heart failure, hypertension, hyponatremia, hyperkalemia, acute kidney injury, chronic kidney disease, renal papillary necrosis and acute interstitial nephritis. The majority of these adverse effects are due to the inhibition of prostaglandins synthesis and they are dose and duration-dependent. Acute forms of kidney injuries are transient and often reversible upon drug withdrawal. Chronic use of NSAIDs in some patients may result in chronic kidney disease. It is recommended that patients at risk should have preventative strategies in place, including the use of the "lowest effective dose" of NSAID for the "shortest possible time" and monitoring renal function, fluid retention and electrolyte abnormalities. Patients who are taking antihypertensive medications should be monitored for high blood pressure and the doses of antihypertensive medications should be adjusted if needed. In general, the combination of NSAIDs and angiotensin inhibitors should be avoided. Some other preventive measures are dietary salt restriction, use of topical NSAIDs/non-pharmacological therapies and use of calcium channel blockers for treating hypertension.

  15. Renal function impairment induced by change in posture in patients with cirrhosis and ascites.

    PubMed Central

    Bernardi, M; Santini, C; Trevisani, F; Baraldini, M; Ligabue, A; Gasbarrini, G

    1985-01-01

    The assumption of upright posture by patients with liver cirrhosis leads to striking activation of adrenergic and renin-angiotensin systems. The tilting-induced modifications in renal function of eight healthy controls and 14 untreated patients with liver cirrhosis and ascites were related to plasma concentrations of noradrenaline, renin activity and aldosterone. All patients had preserved renal blood perfusion. All parameters were evaluated during bed rest for two hours and in the sitting posture for one hour. Basal plasma renin activity (0.1 greater than p greater than 0.05), aldosterone and noradrenaline concentrations (p less than or equal to 0.01) were raised in cirrhotics. The renal function tests (creatinine clearance, filtered sodium, tubular rejection fraction, urinary sodium excretion) were significantly reduced in cirrhosis. Under basal conditions, in cirrhotic patients tubular rejection fraction and urinary sodium excretion were inversely related to both noradrenaline and aldosterone concentrations. After tilting, the noradrenaline and aldosterone integrated outputs (sigma delta) were significantly greater in cirrhosis. All renal function tests significantly decreased in cirrhotics, whereas creatinine clearance only significantly decreased in controls. Patient's tubular rejection fraction of sodium and sodium excretion were related to sigma delta aldosteronaemia (r = -0.72; p less than 0.01), but no longer to sigma delta plasma noradrenaline. PMID:3891534

  16. Phosphate–Induced Renal Fibrosis Requires the Prolyl Isomerase Pin1

    PubMed Central

    Shiizaki, Kazuhiro; Kuro-o, Makoto; Malter, James S.

    2016-01-01

    Tubulo-interstitial fibrosis is a common, destructive endpoint for a variety of kidney diseases. Fibrosis is well correlated with the loss of kidney function in both humans and rodents. The identification of modulators of fibrosis could provide novel therapeutic approaches to reducing disease progression or severity. Here, we show that the peptidyl-prolyl isomerase Pin1 is an important molecular contributor that facilitates renal fibrosis in a well-characterized animal model. While wild-type mice fed a high phosphate diet (HPD) for 8–12 weeks developed calcium deposition, macrophage infiltration and extracellular matrix (ECM) accumulation in the kidney interstitium, Pin1 null mice showed significantly less pathology. The serum Pi in both WT and KO mice were significantly increased by the HPD, but the serum Ca was slightly decreased in KO compared to WT. In addition, both WT and KO HPD mice had less weight gain but exhibited normal organ mass (kidney, lung, spleen, liver and heart). Unexpectedly, renal function was not initially impaired in either genotype irrespective of the HPD. Our results suggest that diet containing high Pi induces rapid renal fibrosis before a significant impact on renal function and that Pin1 plays an important role in the fibrotic process. PMID:26914452

  17. The impact of modern treatment principles may have eliminated lithium-induced renal failure.

    PubMed

    Aiff, Harald; Attman, Per-Ola; Aurell, Mattias; Bendz, Hans; Schön, Staffan; Svedlund, Jan

    2014-02-01

    We have previously shown that lithium can cause end-stage renal disease (ESRD): however, this serious side-effect of lithium in prophylactic treatment of mood disorders may reflect the treatment regime of the 1960s and 1970s. Today's modern treatment routines, intended to reduce or eliminate lithium-induced ESRD (Li-ESRD), were introduced in Sweden in the early 1980s. The aim of the present study was to test the hypothesis that these routines have eliminated the risk of Li-ESRD. We used the Swedish Renal Registry to identify patients on renal replacement therapy (RRT), treated with dialysis or renal transplantation, with suspected Li-ESRD in two regions of Sweden with altogether about three million inhabitants. We reviewed their medical records to verify the exposure to lithium treatment, the diagnosis of Li-ESRD and the date of starting the lithium treatment. We found 32 RRT patients in whom lithium treatment was the sole or main contributing cause of ESRD. The starting year of their lithium treatment was between 1965-1980 in all patients. No patient started lithium treatment later than 1980. Modern lithium treatment may have eliminated the risk of Li-ESRD. Our findings support the continued use of lithium as a safe drug for the long-term treatment of mood disorders.

  18. Multiple Mechanisms are Involved in Salt-Sensitive Hypertension-Induced Renal Injury and Interstitial Fibrosis

    PubMed Central

    Wei, Shi-Yao; Wang, Yu-Xiao; Zhang, Qing-Fang; Zhao, Shi-Lei; Diao, Tian-Tian; Li, Jian-Si; Qi, Wen-Rui; He, Yi-Xin; Guo, Xin-Yu; Zhang, Man-Zhu; Chen, Jian-Yu; Wang, Xiao-Ting; Wei, Qiu-Ju; Wang, Yu; Li, Bing

    2017-01-01

    Salt-sensitive hypertension (SSHT) leads to kidney interstitial fibrosis. However, the potential mechanisms leading to renal fibrosis have not been well investigated. In present study, Dahl salt-sensitive (DS) rats were divided into three groups: normal salt diet (DSN), high salt diet (DSH) and high salt diet treated with hydrochlorothiazide (HCTZ) (DSH + HCTZ). A significant increase in systolic blood pressure (SBP) was observed 3 weeks after initiating the high salt diet, and marked histological alterations were observed in DSH rats. DSH rats showed obvious podocyte injury, peritubular capillary (PTC) loss, macrophage infiltration, and changes in apoptosis and cell proliferation. Moreover, Wnt/β-catenin signaling was significantly activated in DSH rats. However, HCTZ administration attenuated these changes with decreased SBP. In addition, increased renal and urinary Wnt4 expression was detected with time in DSH rats and was closely correlated with histopathological alterations. Furthermore, these alterations were also confirmed by clinical study. In conclusion, the present study provides novel insight into the mechanisms related to PTC loss, macrophage infiltration and Wnt/β-catenin signaling in SSHT-induced renal injury and fibrosis. Therefore, multi-target therapeutic strategies may be the most effective in preventing these pathological processes. Moreover, urinary Wnt4 may be a noninvasive biomarker for monitoring renal injury after hypertension. PMID:28383024

  19. Epigallocatechin-3-gallate attenuates unilateral ureteral obstruction-induced renal interstitial fibrosis in mice.

    PubMed

    Wang, Yanqiu; Wang, Bowen; Du, Feng; Su, Xuesong; Sun, Guangping; Zhou, Guangyu; Bian, Xiaohui; Liu, Na

    2015-04-01

    The severity of tubulointerstitial fibrosis is regarded as an important determinant of renal prognosis. Therapeutic strategies targeting tubulointerstitial fibrosis have been considered to have potential in the treatment of chronic kidney disease. This study aims to evaluate the protective effects of (-)-epigallocatechin-3-gallate (EGCG), a green tea polyphenol, against renal interstitial fibrosis in mice. EGCG was administrated intraperitoneally for 14 days in a mouse model of unilateral ureteral obstruction (UUO). The results of our histological examination showed that EGCG alleviated glomerular and tubular injury and attenuated renal interstitial fibrosis in UUO mice. Furthermore, the inflammatory responses induced by UUO were inhibited, as represented by decreased macrophage infiltration and inflammatory cytokine production. Additionally, the expression of type I and III collagen in the kidney were reduced by EGCG, which indicated an inhibition of extracellular matrix accumulation. EGCG also caused an up-regulation in α-smooth muscle actin expression and a down-regulation in E-cadherin expression, indicating the inhibition of epithelial-to-mesenchymal transition. These changes were found to be in parallel with the decreased level of TGF-β1 and phosphorylated Smad. In conclusion, the present study demonstrates that EGCG could attenuate renal interstitial fibrosis in UUO mice, and this renoprotective effect might be associated with its effects of inflammatory responses alleviation and TGF-β/Smad signaling pathway inhibition.

  20. Nox2 and Cyclosporine-Induced Renal Hypoxia.

    PubMed

    Djamali, Arjang; Wilson, Nancy A; Sadowski, Elizabeth A; Zha, Wei; Niles, David; Hafez, Omeed; Dorn, Justin R; Mehner, Thomas R; Grimm, Paul C; Hoffmann, F Michael; Zhong, Weixiong; Fain, Sean B; Reese, Shannon R

    2016-06-01

    We hypothesized that nicotinamide adenosine diphosphate oxidase 2 (Nox2) plays an important role in cyclosporine A (CsA)-induced chronic hypoxia. We tested this hypothesis in Fisher 344 rats, C57BL/6 J wild type and Nox2-/- mice, and in liver transplant recipients with chronic CsA nephrotoxicity. We used noninvasive molecular imaging (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging) and molecular diagnostic tools to assess intrarenal oxygenation and perfusion, and the molecular phenotype of CsA nephrotoxicity. We observed that chemical and genetic inhibition of Nox2 in rats and mice resulted in the prevention of CsA-induced hypoxia independent of regional perfusion (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging, pimonidazole, HIF-1α). Nicotinamide adenosine diphosphate oxidase 2 knockout was also associated with decreased oxidative stress (Nox2, HIF-1α, hydrogen peroxide, hydroxynonenal), and fibrogenesis (α-smooth muscle actin, picrosirius red, trichrome, vimentin). The molecular signature of chronic CsA nephrotoxicity using transcriptomic analyses demonstrated significant changes in 40 genes involved in injury repair, metabolism, and oxidative stress in Nox2-/- mice. Immunohistochemical analyses of kidney biopsies from liver transplant recipients with chronic CsA nephrotoxicity showed significantly greater Nox2, α-smooth muscle actin and picrosirius levels compared with controls. These studies suggest that Nox2 is a modulator of CsA-induced hypoxia upstream of HIF-1α and define the molecular characteristics that could be used for the diagnosis and monitoring of chronic calcineurin inhibitor nephrotoxicity.

  1. Cyclosporine-A induced neurotoxicity after renal transplantation.

    PubMed

    Derici, U; Arinsoy, T; Sindel, S; Tali, T; Leventoglu, A; Sert, S

    2001-06-01

    Cyclosporine-A is a highly potent immunosuppressive agent for solid organ transplantation, but has many side effects including nephrotoxicity, hypertension, gum hyperplasia, hepatotoxicity, and neurotoxicity. Neurotoxicity is a less known toxic effect. The pathogenesis of this effect is unclear. However, it has been postulated that hypomagnesemia, hypocholesterolemia, corticosteroids, and/or neurotoxic substances can induce this syndrome. Also, it has been suggested that the endothelial damage caused by Cyclosporine-A may contribute to neuropeptide-mediated ischemia in the brain and lead to the development of neurological symptoms. In this report, we present a case with reversible neurologic deficits whose symptoms returned to normal after the cessation of cyclosporine-A.

  2. Thalidomide ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in an experimental model.

    PubMed

    Amirshahrokhi, Keyvan; Khalili, Ali-Reza

    2015-04-01

    Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.

  3. Efficacy and Safety of Renal Sympathetic Denervation on Dogs with Pressure Overload-Induced Heart Failure.

    PubMed

    Chen, Pingan; Leng, Shuilong; Luo, Yishan; Li, Shaonan; Huang, Zicheng; Liu, Zhenxi; Liu, Zhen; Wang, Jie; Lei, Xiaoming

    2017-02-01

    In dogs with heart failure (HF) induced by overload pressure, the role of renal sympathetic denervation (RSD) on heart failure and in the renal artery is unclear. Therefore, we investigated the efficacy and safety of RSD in dogs with pressure overload-induced heart failure. Twenty mongrel dogs were divided into a sham-operated group, an HF group and an HF + RSD group. In the sham-operated group, the abdominal aorta was located but was not constricted, in the HF group, the abdominal aorta was constricted without RSD, and the HF+RSD group underwent RSD with constriction of the abdominal aorta after 10 weeks. Blood sampling assays, echocardiography, intravascular ultrasound (IVUS) measurement and histopathological examination were performed. Renal sympathetic denervation caused a significant reduction in the levels of noradrenaline (166.62±6.84 vs. 183.48±13.66 pg/ml, P<0.05), plasma renin activity (1.93±0.12 vs. 2.10±0.13 ng/mlh, P<0.05) and B-type natriuretic peptide (71.14±3.86 vs. 83.15±5.73 pg/ml, P<0.05) at eight weeks after RSD in the HF+RSD group. Compared with the HF group at eight weeks, the left ventricular internal dimension at end-diastole and end-systole were lower and the left ventricular ejection fraction was higher (all P<0.05) at eight weeks after RSD in the HF+RSD group. Intravenous ultrasound images showed no changes in the renal artery lumen, and intimal hyperplasia and vascular lumen stenosis were not observed after RSD. Renal sympathetic denervation could improve cardiac function in dogs with HF induced by pressure overload; RSD had no adverse influence on the renal artery. Copyright © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

  4. Responsiveness of renal glomeruli to adenosine in streptozotocin-induced diabetic rats dependent on hyperglycaemia level.

    PubMed

    Szczepańska-Konkel, M; Jankowski, M; Stiepanow-Trzeciak, A; Rudzik, A; Pawełczyk, T; Angielski, S

    2003-03-01

    Glomerular filtration rate (GFR) in response to adenosine precursor, NAD, and glomeruli contractility in response to adenosine were evaluated in streptozotocin-induced diabetic rats with severe (blood glucose 27.8 +/- 1.2 mmol/L) and moderate hyperglycaemia (18.2 +/- 0.9 mmol/L) compared with nondiabetic (ND)-rats. In anaesthetised rats, basal GFR was greater in moderately diabetic rats compared with severely diabetic rats (p < 0.05) and ND-rats (p < 0.02). Intravenous infusion of 5 nmol x min(-1) x kg(-1) NAD reduced GFR and renal plasma flow (RPF) in diabetic rats but had no effect on these parameters in ND-rats. Moreover, NAD-induced reduction of GFR and RPF was greater in rats with severe diabetes (41% and 30%, respectively) than in with moderate diabetes (25% and 26%, respectively). Theophylline (0.2 micromol x min(-1) x kg(-1) ) abolished renal response to NAD. Isolated glomeruli contraction in response to adenosine, assessed by glomerular 3H-inulin space reduction, was lowered in moderately diabetic-group and enhanced in severely diabetic-group. compared with ND-group (p < 0.05). Adenosine A1-receptor antagonist DPCPX inhibited adenosine-induced glomeruli contraction. This differential response of diabetic renal glomeruli to adenosine suggests that impaired glomerular contractility in response to adenosine could be responsible for hyperfiltration in moderate diabets, whereas, the increased adenosine-dependent contractility of glomeruli in severe diabetes may increase the risk of acute renal failure in this condition.

  5. A two-hit mechanism for sepsis-induced impairment of renal tubule function

    PubMed Central

    Watts, Bruns A.; George, Thampi; Sherwood, Edward R.

    2013-01-01

    Renal insufficiency is a common and severe complication of sepsis, and the development of kidney dysfunction increases morbidity and mortality in septic patients. Sepsis is associated with a variety of defects in renal tubule function, but the underlying mechanisms are incompletely understood. We used a cecal ligation and puncture (CLP) model to examine mechanisms by which sepsis influences the transport function of the medullary thick ascending limb (MTAL). MTALs from sham and CLP mice were studied in vitro 18 h after surgery. The results show that sepsis impairs the ability of the MTAL to absorb HCO3− through two distinct mechanisms. First, sepsis induces an adaptive decrease in the intrinsic capacity of the tubules to absorb HCO3−. This effect is associated with an increase in ERK phosphorylation in MTAL cells and is prevented by pretreatment of CLP mice with a MEK/ERK inhibitor. The CLP-induced reduction in intrinsic HCO3− absorption rate appears to involve loss of function of basolateral Na+/H+ exchange. Second, sepsis enhances the ability of LPS to inhibit HCO3− absorption, mediated through upregulation of Toll-like receptor 4 (TLR4)-ERK signaling in the basolateral membrane. The two inhibitory mechanisms are additive and thus can function in a two-hit capacity to impair renal tubule function in sepsis. Both effects depend on ERK and are eliminated by interventions that prevent ERK activation. Thus the TLR4 and ERK signaling pathways represent potential therapeutic targets to treat or prevent sepsis-induced renal tubule dysfunction. PMID:23324175

  6. Renal ischemia/reperfusion-induced cardiac hypertrophy in mice: Cardiac morphological and morphometric characterization

    PubMed Central

    Cirino-Silva, Rogério; Kmit, Fernanda V; Trentin-Sonoda, Mayra; Nakama, Karina K; Panico, Karine; Alvim, Juliana M; Dreyer, Thiago R; Martinho-Silva, Herculano

    2017-01-01

    Background Tissue remodeling is usually dependent on the deposition of extracellular matrix that may result in tissue stiffness and impaired myocardium contraction. Objectives We had previously demonstrated that renal ischemia/reperfusion (I/R) is able to induce development of cardiac hypertrophy in mice. Therefore, we aimed to characterize renal I/R-induced cardiac hypertrophy. Design C57BL/6 J mice were subjected to 60 minutes’ unilateral renal pedicle occlusion, followed by reperfusion (I/R) for 5, 8, 12 or 15 days. Gene expression, protein abundance and morphometric analyses were performed in all time points. Results Left ventricle wall thickening was increased after eight days of reperfusion (p < 0.05). An increase in the number of heart ventricle capillaries and diameter after 12 days of reperfusion (p < 0.05) was observed; an increase in the density of capillaries starting at 5 days of reperfusion (p < 0.05) was also observed. Analyses of MMP2 protein levels showed an increase at 15 days compared to sham (p < 0.05). Moreover, TGF-β gene expression was downregulated at 12 days as well TIMP 1 and 2 (p < 0.05). The Fourier-transform infrared spectroscopy analysis showed that collagen content was altered only in the internal section of the heart (p < 0.05); such data were supported by collagen mRNA levels. Conclusions Renal I/R leads to impactful changes in heart morphology, accompanied by an increase in microvasculature. Although it is clear that I/R is able to induce cardiac remodeling, such morphological changes is present in only a section of the heart tissue. PMID:28228941

  7. Ochratoxin A induces rat renal carcinogenicity with limited induction of oxidative stress responses

    SciTech Connect

    Qi, Xiaozhe; Yu, Tao; Zhu, Liye; Gao, Jing; He, Xiaoyun; Huang, Kunlun; Luo, Yunbo; Xu, Wentao

    2014-11-01

    Ochratoxin A (OTA) has displayed nephrotoxicity and renal carcinogenicity in mammals, however, no clear mechanisms have been identified detailing the relationship between oxidative stress and these toxicities. This study was performed to clarify the relationship between oxidative stress and the renal carcinogenicity induced by OTA. Rats were treated with 70 or 210 μg/kg b.w. OTA for 4 or 13 weeks. In the rats administrated with OTA for 13 weeks, the kidney was damaged seriously. Cytoplasmic vacuolization was observed in the outer stripe of the outer medulla. Karyomegaly was prominent in the tubular epithelium. Kidney injury molecule-1 (Kim-1) was detected in the outer stripe of the outer medulla in both low- and high-dose groups. OTA increased the mRNA levels of clusterin in rat kidneys. Interestingly, OTA did not significantly alter the oxidative stress level in rat liver and kidney. Yet, some indications related to proliferation and carcinogenicity were observed. A dose-related increase in proliferating cell nuclear antigen (PCNA) was observed at 4 weeks in both liver and kidney, but at 13 weeks, only in the kidney. OTA down-regulated reactive oxygen species (ROS) and up-regulated vimentin and lipocalin 2 in rat kidney at 13 weeks. The p53 gene was decreased in both liver and kidney at 13 weeks. These results suggest that OTA caused apparent kidney damage within 13 weeks but exerted limited effect on oxidative stress parameters. It implies that cell proliferation is the proposed mode of action for OTA-induced renal carcinogenicity. - Highlights: • We studied OTA toxicities in both the rat liver and kidney for 13 weeks. • OTA exerts limited effects on oxidative stress in the rat liver and kidney. • OTA induced renal carcinogenicity resulting from cell proliferation.

  8. 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.

  9. Increased Dietary Sodium Induces COX2 Expression by activating NFκB in Renal Medullary Interstitial Cells

    PubMed Central

    Zhao, Min; Davis, Linda S.; Blackwell, Timothy S.; Yull, Fiona; Breyer, Matthew D.; Hao, Chuan-Ming

    2013-01-01

    High salt diet induces renal medullary COX2 expression. Selective blockade of renal medullary COX2 activity in rats causes salt sensitive hypertension, suggesting a role for renal medullary COX2 in maintaining systemic sodium balance. The present study characterized the cellular location of COX2 induction in the kidney of mice following high salt diet and examined the role of NFκB in mediating this COX2 induction in response to increased dietary salt. High salt diet (8% NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6J mice. Co-immunofluorescence using a COX2 antibody and antibodies against AQP2, ClC-K, AQP1 and CD31 showed that high salt diet-induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a 7 fold increase of luciferase activity in the renal medulla of the NFκB-luciferase reporter mice following high salt diet, and a robust induction of EGFP expression mainly in renal medullary interstitial cells of the NFκB-EGFP reporter mice following high salt diet. Treating high salt diet fed C57Bl/6J mice with selective IκB kinase inhibitor IMD-0354 (8mg/kg bw) substantially suppressed COX2 induction in renal medulla, and also significantly reduced urinary PGE2. These data therefore suggest that renal medullary interstitial cell NFκB plays an important role in mediating renal medullary COX2 expression and promoting renal PGE2 synthesis in response to increased dietary sodium. PMID:23900806

  10. Increased dietary sodium induces COX2 expression by activating NFκB in renal medullary interstitial cells.

    PubMed

    He, Wenjuan; Zhang, Min; Zhao, Min; Davis, Linda S; Blackwell, Timothy S; Yull, Fiona; Breyer, Matthew D; Hao, Chuan-Ming

    2014-02-01

    High salt diet induces renal medullary cyclooxygenase 2 (COX2) expression. Selective blockade of renal medullary COX2 activity in rats causes salt-sensitive hypertension, suggesting a role for renal medullary COX2 in maintaining systemic sodium balance. The present study characterized the cellular location of COX2 induction in the kidney of mice following high salt diet and examined the role of NFκB in mediating this COX2 induction in response to increased dietary salt. High salt diet (8 % NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6 J mice. Co-immunofluorescence using a COX2 antibody and antibodies against aquaporin-2, ClC-K, aquaporin-1, and CD31 showed that high salt diet-induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a sevenfold increase of luciferase activity in the renal medulla of the NFκB-luciferase reporter mice following high salt diet, and a robust induction of enhanced green fluorescent protein (EGFP) expression mainly in renal medullary interstitial cells of the NFκB-EGFP reporter mice following high salt diet. Treating high salt diet-fed C57Bl/6 J mice with selective IκB kinase inhibitor IMD-0354 (8 mg/kg bw) substantially suppressed COX2 induction in renal medulla, and also significantly reduced urinary prostaglandin E2 (PGE2). These data therefore suggest that renal medullary interstitial cell NFκB plays an important role in mediating renal medullary COX2 expression and promoting renal PGE2 synthesis in response to increased dietary sodium.

  11. Central Diabetes Insipidus and Cisplatin-Induced Renal Salt Wasting Syndrome: A Challenging Combination.

    PubMed

    Cortina, Gerard; Hansford, Jordan R; Duke, Trevor

    2016-05-01

    We describe a 2-year-old female with a suprasellar primitive neuroectodermal tumor and central diabetes insipidus (DI) who developed polyuria with natriuresis and subsequent hyponatremia 36 hr after cisplatin administration. The marked urinary losses of sodium in combination with a negative sodium balance led to the diagnosis of cisplatin-induced renal salt wasting syndrome (RSWS). The subsequent clinical management is very challenging. Four weeks later she was discharged from ICU without neurological sequela. The combination of cisplatin-induced RSWS with DI can be confusing and needs careful clinical assessment as inaccurate diagnosis and management can result in increased neurological injury.

  12. Colchicine-induced myoneuropathy in a cyclosporine-treated renal transplant recipient.

    PubMed

    Huh, Kyungmin; Joung, Ji Young; Jeong, Hyemin; Je, Dongmo; Cho, Yoon Young; Jang, Hye Ryoun; Huh, Wooseong

    2013-06-01

    Colchicine is a relatively safe medication that is widely used for both prevention and treatment of gout attack. However, serious adverse events, including myoneuropathy and multiorgan failure, have been reported. We report a case of colchicine-induced myoneuropathy in a female kidney transplant recipient who had been taking cyclosporine. She developed gastrointestinal discomfort and paresthesia 5 days after the initiation of colchicine. She showed signs of myoneuropathy, and hepatic and renal injury. Colchicine toxicity was suspected, and colchicine was discontinued. Her symptoms and laboratory findings improved gradually. Literature was reviewed for previous reports of colchicine-induced myoneuropathy in solid organ transplant recipients.

  13. Colchicine-induced myoneuropathy in a cyclosporine-treated renal transplant recipient

    PubMed Central

    Huh, Kyungmin; Joung, Ji Young; Jeong, Hyemin; Je, Dongmo; Cho, Yoon Young; Jang, Hye Ryoun; Huh, Wooseong

    2013-01-01

    Colchicine is a relatively safe medication that is widely used for both prevention and treatment of gout attack. However, serious adverse events, including myoneuropathy and multiorgan failure, have been reported. We report a case of colchicine-induced myoneuropathy in a female kidney transplant recipient who had been taking cyclosporine. She developed gastrointestinal discomfort and paresthesia 5 days after the initiation of colchicine. She showed signs of myoneuropathy, and hepatic and renal injury. Colchicine toxicity was suspected, and colchicine was discontinued. Her symptoms and laboratory findings improved gradually. Literature was reviewed for previous reports of colchicine-induced myoneuropathy in solid organ transplant recipients. PMID:26877917

  14. A2 Noradrenergic Lesions Prevent Renal Sympathoinhibition Induced by Hypernatremia in Rats

    PubMed Central

    Pedrino, Gustavo Rodrigues; Freiria-Oliveira, André Henrique; Almeida Colombari, Débora Simões; Rosa, Daniel Alves; Cravo, Sergio Luiz

    2012-01-01

    Renal vasodilation and sympathoinhibition are recognized responses induced by hypernatremia, but the central neural pathways underlying such responses are not yet entirely understood. Several findings suggest that A2 noradrenergic neurons, which are found in the nucleus of the solitary tract (NTS), play a role in the pathways that contribute to body fluid homeostasis and cardiovascular regulation. The purpose of this study was to determine the effects of selective lesions of A2 neurons on the renal vasodilation and sympathoinhibition induced by hypertonic saline (HS) infusion. Male Wistar rats (280–350 g) received an injection into the NTS of anti-dopamine-beta-hydroxylase-saporin (A2 lesion; 6.3 ng in 60 nl; n = 6) or free saporin (sham; 1.3 ng in 60 nl; n = 7). Two weeks later, the rats were anesthetized (urethane 1.2 g⋅kg−1 b.wt., i.v.) and the blood pressure, renal blood flow (RBF), renal vascular conductance (RVC) and renal sympathetic nerve activity (RSNA) were recorded. In sham rats, the HS infusion (3 M NaCl, 1.8 ml⋅kg−1 b.wt., i.v.) induced transient hypertension (peak at 10 min after HS; 9±2.7 mmHg) and increases in the RBF and RVC (141±7.9% and 140±7.9% of baseline at 60 min after HS, respectively). HS infusion also decreased the RSNA (−45±5.0% at 10 min after HS) throughout the experimental period. In the A2-lesioned rats, the HS infusion induced transient hypertension (6±1.4 mmHg at 10 min after HS), as well as increased RBF and RVC (133±5.2% and 134±6.9% of baseline at 60 min after HS, respectively). However, in these rats, the HS failed to reduce the RSNA (115±3.1% at 10 min after HS). The extent of the catecholaminergic lesions was confirmed by immunocytochemistry. These results suggest that A2 noradrenergic neurons are components of the neural pathways regulating the composition of the extracellular fluid compartment and are selectively involved in hypernatremia-induced sympathoinhibition. PMID:22629424

  15. Renal Alterations in Feline Immunodeficiency Virus (FIV)-Infected Cats: A Natural Model of Lentivirus-Induced Renal Disease Changes

    PubMed Central

    Poli, Alessandro; Tozon, Natasa; Guidi, Grazia; Pistello, Mauro

    2012-01-01

    Human immunodeficiency virus (HIV) is associated with several renal syndromes including acute and chronic renal failures, but the underlying pathogenic mechanisms are unclear. HIV and feline immunodeficiency virus (FIV) share numerous biological and pathological features, including renal alterations. We investigated and compared the morphological changes of renal tissue of 51 experimentally and 21 naturally infected cats. Compared to the latter, the experimentally infected cats exhibited some mesangial widening and glomerulonephritis, milder proteinuria, and lower tubular and interstitial alterations. The numbers of giant protein tubular casts and tubular microcysts were also lower. In contrast, diffuse interstitial infiltrates and glomerular and interstitial amyloidosis were detected only in naturally infected cats. Similar alterations are found in HIV infected patients, thus supporting the idea of a causative role of FIV infection in renal disease, and underlining the relevance of the FIV and its natural host as an animal model for investigating lentivirus-associated nephropathy. PMID:23170163

  16. The role of indomethacin and tezosentan on renal effects induced by Bothrops moojeni Lys49 myotoxin I.

    PubMed

    Barbosa, P S F; Martins, A M C; Alves, R S; Amora, D N; Martins, R D; Toyama, Marcos H; Havt, A; Nascimento, N R F; Rocha, V L C; Menezes, D B; Fonteles, M C; Monteiro, H S A

    2006-06-15

    Renal changes determined by Lys49 myotoxin I (BmTx I), isolated from Bothrops moojeni are well known. The scope of the present study was to investigate the possible mechanisms involved in the production of these effects by using indomethacin (10 microg/mL), a non-selective inhibitor of cyclooxygenase, and tezosentan (10 microg/mL), an endothelin antagonist. By means of the method of mesenteric vascular bed, it has been observed that B. moojeni myotoxin (5 microg/mL) affects neither basal perfusion pressure nor phenylephrine-preconstricted vessels. This fact suggests that the increase in renal perfusion pressure and in renal vascular resistance did not occur by a direct effect on renal vasculature. Isolated kidneys from Wistar rats, weighing 240-280 g, were perfused with Krebs-Henseleit solution. The infusion of BmTx-I increased perfusion pressure, renal vascular resistance, urinary flow and glomerular filtration rate. Sodium, potassium and chloride tubular transport was reduced after addition of BmTx-I. Indomethacin blocked the effects induced by BmTx-I on perfusion pressure and renal vascular resistance, however, it did not revert the effect on urinary flow and sodium, potassium and chloride tubular transport. The alterations of glomerular filtration rate were inhibited only at 90 min of perfusion. The partial blockade exerted by indomethacin treatment showed that prostaglandins could have been important mediators of BmTx-I renal effects, but the participation of other substances cannot be excluded. The blockage of all renal alterations observed after tezosentan treatment support the hypothesis that endothelin is the major substance involved in the renal pathophysiologic alterations promoted by the Lys49 PLA(2) myotoxin I, isolated from B. moojeni. In conclusion, the rather intense renal effects promoted by B. moojeni myotoxin-I were probably caused by the release of renal endothelin, interfering with the renal parameters studied.

  17. c-Myc promotes renal fibrosis by inducing integrin αv-mediated transforming growth factor-β signaling.

    PubMed

    Shen, Yang; Miao, Naijun; Wang, Bao; Xu, Jinlan; Gan, Xinxin; Xu, Dan; Zhou, Li; Xue, Hong; Zhang, Wei; Yang, Li; Lu, Limin

    2017-10-01

    Fibrogenesis involves the activation of renal fibroblasts upon kidney injury. However, the mechanisms underlying renal fibroblast activation are poorly characterized. c-Myc is a predominant oncogene encoding a pleiotropic transcription factor that participates in the regulation of various genes, including genes vital for regulating the cell cycle, cell proliferation, and apoptosis. Here we tested whether renal fibrosis in unilateral ureteral obstruction and folic acid-induced renal fibrosis mouse models are associated with the overexpression of c-Myc. Transforming growth factor-β (TGF-β) has been identified as a key mediator of renal fibrosis, and it is secreted in an inactive form as a complex with latency-associated peptide and latent TGF-β-binding proteins. Five αv-containing integrins with different β -subunits can activate TGF-β, and consistent with this we found that c-Myc bound directly to the promoter of integrin αv in renal fibroblasts activating its transcription. This, in turn, induced activation of TGF-β signaling. Pharmacological blockade of c-Myc attenuated renal fibrosis in vivo in the ureteral obstruction and folic acid-treated mouse models and inhibited the proliferation and activation of renal fibroblasts in vitro. Thus, c-Myc overexpression stimulated proliferation and activation of renal fibroblasts by inducing integrin αv -mediated TGF-β signaling. Hence, targeting c-Myc may have clinical utility in the treatment of renal fibrosis. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  18. Renal denervation attenuates aldosterone expression and associated cardiovascular pathophysiology in angiotensin II-induced hypertension

    PubMed Central

    Chen, Dong-Rui; Ruan, Cheng-Chao; Xu, Jian-Zhong; Chen, Jing; Wu, Yong-Jie; Ma, Yu; Zhu, Ding-Liang; Gao, Ping-Jin

    2016-01-01

    The sympathetic nervous system interacts with the renin-angiotensin-aldosterone system (RAAS) contributing to cardiovascular diseases. In this study, we sought to determine if renal denervation (RDN) inhibits aldosterone expression and associated cardiovascular pathophysiological changes in angiotensin II (Ang II)-induced hypertension. Bilateral RDN or SHAM operation was performed before chronic 14-day Ang II subcutaneous infusion (200ng/kg/min) in male Sprague-Dawley rats. Bilateral RDN blunted Ang II-induced hypertension and ameliorated the mesenteric vascular dysfunction. Cardiovascular hypertrophy in response to Ang II was significantly attenuated by RDN as shown by histopathology and transthoracic echocardiography. Moreover, Ang II-induced vascular and myocardial inflammation and fibrosis were suppressed by RDN with concurrent decrease in fibronectin and collagen deposition, macrophage infiltration, and MCP-1 expression. Interestingly, RDN also inhibited Ang II-induced aldosterone expression in the plasma, kidney and heart. This was associated with the reduction of calcitonin gene-related peptide (CGRP) in the adrenal gland. Ang II promoted aldosterone secretion which was partly attenuated by CGRP in the adrenocortical cell line, suggesting a protective role of CGRP in this model. Activation of transforming growth factor-β (TGF-β)/Smad and mitogen-activated protein kinases (MAPKs) signaling pathway was both inhibited by RDN especially in the heart. These results suggest that the regulation of the renal sympathetic nerve in Ang II-induced hypertension and associated cardiovascular pathophysiological changes is likely mediated by aldosterone, with CGRP involvement. PMID:27661131

  19. Renoprotection of Kolaviron against benzo (A) pyrene-induced renal toxicity in rats.

    PubMed

    Adedara, Isaac A; Daramola, Yetunde M; Dagunduro, Joshua O; Aiyegbusi, Motunrayo A; Farombi, Ebenezer O

    2015-04-01

    Benzo(a)pyrene (B[a]P), a polycyclic aromatic hydrocarbon generally formed from incomplete combustion of organic matter, reportedly causes renal injury and elicits a nephropathic response. The present study investigated the modulatory effect of Kolaviron, an isolated bioflavonoid from the seed of Garcinia kola, on renal toxicity induced by B[a]P in Wistar rats. Benzo[a]pyrene was administered at a dose of 10 mg/kg alone or in combination with Kolaviron at 100 and 200 mg/kg for 15 d. Administration of B[a]P alone resulted in significant increase in plasma levels of urea and creatinine in the treated rats. Moreover, B[a]P exposure significantly decreased the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-s-transferase (GST) as well as glutathione (GSH) level in the kidneys of treated rats. Conversely, myeloperoxidase (MPO) activity, hydrogen peroxide (H2O2) and malondialdehyde (MDA) levels were markedly elevated in kidneys of B[a]P-treated rats compared with control. Further, B[a]P exposure significantly decreased the circulatory concentrations of triiodothyronine (T3) and T3/T4 ratio without affecting thyroxine (T4) in the treated rats. Light microscopy revealed tubular lumen with numerous protein casts in kidneys of rats exposed to B[a]P alone. Kolaviron co-treatment significantly improved the renal antioxidant status, thyroid gland function and restored the renal histology, thus demonstrating the protective effect of Kolaviron in B[a]P-treated rats. Dietary inclusion of Kolaviron could exert protective effects against renal toxicity resulting from B[a]P exposure.

  20. Role of renal metabolism and excretion in 5-nitrofuran-induced uroepithelial cancer in the rat.

    PubMed Central

    Spry, L A; Zenser, T V; Cohen, S M; Davis, B B

    1985-01-01

    5-Nitrofurans have been used in the study of chemical carcinogenesis. There is substantial evidence that N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) is deformylated to 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) in the process of FANFT-induced bladder cancer. Paradoxically, ANFT is less potent as a uroepithelial carcinogen than FANFT when fed to rats. Feeding aspirin with FANFT to rats decreases the incidence of bladder cancer. Isolated kidneys were perfused with 5-nitrofurans to determine renal clearances and whether aspirin acts to decrease urinary excretion of the carcinogen. In FANFT-perfused kidneys, FANFT was deformylated to ANFT and excreted (1.06 +/- 0.22 nmol/min) at a rate eightfold higher than excretion of FANFT. In kidneys perfused with equimolar ANFT, excretion of ANFT was 0.25 +/- 0.05 nmol/min, which suggests a coupling of renal deformylation of FANFT to excretion of ANFT in FANFT-perfused kidneys. Neither aspirin nor probenecid altered the urinary excretion or half-life of FANFT or ANFT. In rats fed 0.2% FANFT as part of their diet, coadministration of aspirin (0.5%) increased urinary excretion of ANFT during a 12-wk feeding study, which suggests decreased tissue binding or metabolism of ANFT. Kidney perfusion with acetylated ANFT (NFTA), a much less potent uroepithelial carcinogen, resulted in no ANFT excretion or accumulation, which indicates the specificity of renal deformylase. Renal deformylase activity was found in broken cell preparations of rat and human kidney. These data describe a unique renal metabolic/excretory coupling for these compounds that appears to explain the differential carcinogenic potential of the 5-nitrofurans tested. These results are consistent with the hypothesis that aspirin decreases activation of ANFT by inhibiting prostaglandin H synthase. PMID:4044826

  1. Antioxidant Activity of Tocotrienol Rich Fraction Prevents Fenitrothion-induced Renal Damage in Rats

    PubMed Central

    Budin, Siti Balkis; Han, Kim Jit; Jayusman, Putri Ayu; Taib, Izatus Shima; Ghazali, Ahmad Rohi; Mohamed, Jamaludin

    2013-01-01

    Fenitrothion (FNT) is an organophosphate compound widely used as pesticide in Malaysia. The present study aims to investigate effects of palm oil tocotrienol rich fraction (TRF) on the renal damage of FNT-treated rats. A total of 40 male Sprague Dawley rats were divided into 4 groups randomly, the control, TRF, FNT and FNT+TRF groups. FNT (20 mg/kg b.w.) and TRF (200 mg/kg b.w.) were given orally for 28 days continuously. Rats from the FNT+TRF group were supplemented with TRF 30 minutes prior to administration of FNT. Rats were sacrificed after 28 days, and the kidneys were removed for determination of oxidative stress and histological analysis. Plasma was collected for determination of blood creatinine and urea level. Statistical analysis showed that palm oil TRF has a protective effect against renal oxidative damage induced by FNT. In the FNT+TRF group, malondialdehyde and protein carbonyl levels were significantly lower, while the glutathione level as well as superoxide dismutase and catalase activities were significantly higher compared with the FNT-treated group (p<0.05). As for renal function, there was a markedly lower urea level (p<0.05) in the FNT+TRF group compared with the FNT-treated group, but there was no significant difference in creatinine level. Besides, total protein also showed no significant difference for all groups of rats (p>0.05). Histological evaluation also revealed that the FNT+TRF group had less glomerulus and renal tubule damage than the FNT-treated group. In conclusion, palm oil TRF was able to reduce oxidative stress and renal damage in FNT-treated rats. PMID:23914053

  2. Resveratrol as a therapeutic agent for renal fibrosis induced by unilateral ureteral obstruction.

    PubMed

    Liang, Jin; Tian, Shoufu; Han, Junxia; Xiong, Peihua

    2014-03-01

    Renal fibrosis is a common outcome of chronic kidney disease. This study was designed to examine the protective effects of resveratrol (RSV) against renal fibrosis induced by unilateral ureteral obstruction (UUO). We also attempted to elucidate the potential mechanism involved. Mice were randomly divided into three groups: sham-operated, UUO, and UUO/RSV (20 mg·kg(-1)·day(-1)). Histological changes were examined using periodic acid-Schiff and Masson's trichrome staining after 14 days. Superoxide dismutase (SOD), malondialdehyde (MDA), and 8-OHdG levels were determined using a commercially available kit. ICAM-1, TNF-α, and TGF-β levels were measured using real-time PCR. Fibronectin levels were measured by western blot, and the Smad3 acetylation and Sirt1 were examined by immunoprecipitation and western blot. Our study showed that RSV treatment significantly attenuated renal injury including extracellular matrix deposition and tubulointerstitium damage. Renal cortical mRNA levels of ICAM-1, TNF-α, and TGF-β, protein expression of fibronectin and Smad3 acetylation were significantly upregulated in the UUO group. However, treatment with RSV significantly decreased the expression of these proteins. Furthermore, RSV also decreased the levels of reactive oxygen species (ROS) including MDA and 8-OHdG, and increased the level of SOD, which protects cells against ROS damage. Our findings suggest that RSV treatment inhibits oxidative stress, Smad3 acetylation, and renal interstitial fibrosis. Therefore, RSV may have potential as a therapeutic target for the treatment of chronic kidney disease.

  3. Morphometric analysis of renal cortex changes induced by diethylstilbestrol (DES) in Syrian hamsters.

    PubMed

    Chang, C J; Lin, Y C; Brueggemeier, R W; Rikihisa, Y

    1992-12-01

    Estrogen-induced renal adenocarcinoma usually can be readily detected in castrated hamsters after 9 to 12 months of DES treatment. In the present study, we examined the morphological characteristics of the renal cortices of castrated hamsters that had received 3 months of DES treatment in order to describe early histological evidence of carcinogenesis induction. Twelve Syrian Golden hamsters, 8 to 9 weeks of age, were first castrated and then subjected to either subpannicular implantation of a 20 mg DES pellet (experiment group), or sham operation (controls). Morphological and 2-D morphometric evaluations were conducted sequentially on kidney histological sections. Numbers (N's) or area fractions (AF's) of renal components in the juxta-medullary junction of each kidney section were processed for morphometric evaluation. The DES treatment caused a 15% increase in kidney weight, but not body weight. Dysplastic foci associated with hyperplastic tubules were present in 67% of the left kidneys or 17% of the right kidneys of hamsters in the test group, but were absent in kidneys of controls. DES treatment decreased glomeruli N by 33% and increased the vasculature AF by 169% per examination field. DES also increased AF's of glomeruli, proximal tubules, distal tubules, and vasculature by 17, 81, 53 and 346% per nephron, respectively. Our results showed that, after the first three months of DES-treatment, hamster kidneys developed dysplastic foci and their masses were greater than controls. Increased renal components in the juxta-medullary junction region included glomeruli, tubules, and vasculature. The dysplastic foci may be sites of subsequent malignancies, whereas the increased renal mass might be a result of functional adaptation/expression to exogenous estrogen which might contribute to the carcinogenic process.

  4. 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

  5. Glutamate dehydrogenase requirement for apoptosis induced by aristolochic acid in renal tubular epithelial cells.

    PubMed

    Romanov, Victor; Whyard, Terry; Bonala, Radha; Johnson, Francis; Grollman, Arthur

    2011-12-01

    Ingestion of aristolochic acids (AA) contained in herbal remedies results in a renal disease and, frequently, urothelial malignancy. The genotoxicity of AA in renal cells, including mutagenic DNA adduct formation, is well-documented. However, the mechanisms of AA-induced tubular atrophy and renal fibrosis are largely unknown. Epithelial cell death is a critical characteristic of these pathological conditions. To elucidate the mechanisms of AA-induced cytotoxicity, we explored AA-interacting proteins in tubular epithelial cells (TEC). We found that AA interacts with a mitochondrial enzyme glutamate dehydrogenase (GDH) and moderately inhibits its activity. We report that AA induces cell death in GDH-knockdown TEC preferentially via non-apoptotic means, whereas in GDH-positive cells, death was executed by both the non-apoptotic and apoptotic mechanisms. Apoptosis is an energy-reliant process and demands higher adenosine 5'-triphosphate (ATP) consumption than does the non-apoptotic cell death. We found that, after AAI treatment, the ATP depletion is more pronounced in GDH-knockdown cells. When we reduced ATP in TEC cells by inhibition of glycolysis and mitochondrial respiration, cell death mode switched from apoptosis and necrosis to necrosis only. In addition, in cells incubated at low glucose and no glutamine conditions, oxaloacetate and pyruvate reduced AAI-induced apoptosis our data suggest that AAI-GDH interactions in TEC are critical for the induction of apoptosis by direct inhibition of GDH activity. AA binding may also induce changes in GDH conformation and promote interactions with other molecules or impair signaling by GDH metabolic products, leading to apoptosis.

  6. Proteomic analysis reveals alterations in the renal kallikrein pathway during hypoxia-induced hypertension.

    PubMed

    Thongboonkerd, Visith; Gozal, Evelyne; Sachleben, Leroy R; Arthur, John M; Pierce, William M; Cai, Jian; Chao, Julie; Bader, Michael; Pesquero, Joao B; Gozal, David; Klein, Jon B

    2002-09-20

    Obstructive sleep apnea syndrome (OSAS), a disorder characterized by episodic hypoxia (EH) during sleep, is associated with systemic hypertension. We used proteomic analysis to examine differences in rat kidney protein expression during EH, and their potential relationship to EH-induced hypertension. Young male Sprague-Dawley rats were exposed to either EH or sustained hypoxia (SH) for 14 (EH14/SH14) and 30 (EH30/SH30) days. Mean arterial blood pressure was significantly increased only in EH30 (p < 0.0002). Kidney proteins were resolved by two-dimensional-PAGE and were identified by MALDI-MS. Renal expression of kallistatin, a potent vasodilator, was down-regulated in all animals. Expression of alpha-1-antitrypsin, an inhibitor of kallikrein activation, was up-regulated in EH but down-regulated in SH. Western blotting showed significant elevation of B(2)-bradykinin receptor expression in all normotensive animals but remained unchanged in hypertensive animals. Proteins relevant to vascular hypertrophy, such as smooth muscle myosin and protein-disulfide isomerase were up-regulated in EH30 but were down-regulated in SH30. These data indicate that EH induces changes in renal protein expression consistent with impairment of vasodilation mediated by the kallikrein-kallistatin pathway and vascular hypertrophy. In contrast, SH-induced changes suggest the kallikrein- and bradykinin-mediated compensatory mechanisms for prevention of hypertension and vascular remodeling. To test the hypothesis suggested by the proteomic data, we measured the effect of EH on blood pressure in transgenic hKLK1 rats that overexpress human kallikrein. Transgenic hKLK1 animals were protected from EH-induced hypertension. We conclude that EH-induced hypertension may result, at least in part, from altered regulation of the renal kallikrein system.

  7. Antioxidant biofactor, a processed grain food, inhibits iron nitrilotriacetate-induced renal tumorigenesis, hyperproliferative response, and oxidative damage.

    PubMed

    Mizote, A; Okazaki, Y; Iqbal, M; Okada, S

    2008-03-01

    We have evaluated the effect of dietary antioxidant, antioxidant biofactor (a processed grain food), on iron nitrilotriacetate-induced renal tumorigenesis, hyperproliferative response, and oxidative damage. In tumorigenesis studies, iron nitrilotriacetate alone treatment resulted in a development of 75% renal cell tumor incidence, whereas, in the group of animals fed with antioxidant biofactor diet and treated with iron nitrilotriacetate, only 43% of renal cell tumor incidence was observed. In oxidative damage studies, the decrease in the level of renal glutathione and antioxidant enzymes induced by iron nitrilotriacetate was significantly reversed by antioxidant biofactor diet pretreatment in a dose-dependent manner (18-71% recovery, P < 0.05). Antioxidant biofactor diet pretreatment also resulted in a dose-dependent inhibition (35-49% inhibition, P < 0.05) of iron nitrilotriacetate-induced lipid peroxidation as measured by thiobarbituric acid reactive substances formation in renal tissues. Similarly, in hyperproliferation studies, antioxidant biofactor diet pretreatment showed a strong inhibition of iron nitrilotriacetate-induced renal ornithine decarboxylase activity (18-54% inhibition, P < 0.05). In addition, antioxidant biofactor fed diet pretreatment also protected the kidney tissues against observed histopathological alterations. From this data, it can be concluded that antioxidant biofactor diet can abrogate the toxic and tumor promoting effects of iron nitrilotriacetate and can serve as a potent chemopreventive agent to suppress oxidant-induced tissue injury and tumorigenesis.

  8. Cymbopogon citratus Protects against the Renal Injury Induced by Toxic Doses of Aminoglycosides in Rabbits.

    PubMed

    Ullah, N; Khan, M A; Khan, T; Ahmad, W

    2013-03-01

    Renal injury is the most common side-effect of aminoglycosides. These antimicrobial drugs are particularly effective against Gram-negative microorganisms. The present study was conducted to investigate the renal protective activity of Cymbopogon citratus in gentamicin-induced nephrotoxicity. Male rabbits were divided into four groups (n=6) including group 1 (0.9% saline treated), group 2 (80 mg/kg/day gentamicin-treated), group 3 (200 mg/kg/day Cymbopogon citratus treated) and group 4 (80 mg/kg/day gentamicin and 200 mg/kg/day Cymbopogon citratus treated). Biochemical kidney functioning parameters, urinary enzymes and histopathological examination were performed. The results of the present study showed that simultaneous administration of Cymbopogon citrates and gentamicin significantly protected alteration in body weight, blood urea nitrogen, serum creatinine, creatinine clearance, serum uric acid, serum electrolytes, urinary volume, urinary protein, urinary lactate dehydrogenase and urinary alkaline phosphatase induced by gentamicin. Histological examination of the kidney also suggested the same. It is concluded from the current study that co-administration of Cymbopogon citratus with gentamicin for 3 weeks successfully prevented renal damage associated with aminoglycosides.

  9. Betulinic acid protects against ischemia/reperfusion-induced renal damage and inhibits leukocyte apoptosis.

    PubMed

    Ekşioğlu-Demiralp, Emel; Kardaş, E Riza; Ozgül, Seçkin; Yağci, Tayfur; Bilgin, Hüseyin; Sehirli, Ozer; Ercan, Feriha; Sener, Göksel

    2010-03-01

    The possible protective effect of betulinic acid on renal ischemia/reperfusion (I/R) injury was studied. Wistar Albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 6 h of reperfusion. Betulinic acid (250 mg/kg, i.p.) or saline was administered at 30 min prior to ischemia and immediately before the reperfusion. Creatinine, blood urea nitrogen (BUN), lactate dehydrogenase (LDH) and TNF-alpha as well as the oxidative burst of neutrophil and leukocyte apoptosis were assayed in blood samples. Malondialdehyde (MDA), glutathione (GSH) levels, Na(+), K(+)-ATPase and myeloperoxidase (MPO) activities were determined in kidney tissue which was also analysed microscopically. I/R caused significant increases in blood creatinine, BUN, LDH and TNF-alpha. In the kidney samples of the I/R group, MDA levels and MPO activity were increased significantly, however, GSH levels and Na(+), K(+)-ATPase activity were decreased. Betulinic acid ameliorated the oxidative burst response to both formyl-methionyl-leucyl-phenylalanine (fMLP) and phorbol 12-myristate 13-acetate (PMA) stimuli, normalized the apoptotic response and most of the biochemical indices as well as histopathological alterations induced by I/R. In conclusion, these data suggest that betulinic acid attenuates I/R-induced oxidant responses, improved microscopic damage and renal function by regulating the apoptotic function of leukocytes and inhibiting neutrophil infiltration.

  10. Effect of metformin against cisplatin induced acute renal injury in rats: a biochemical and histoarchitectural evaluation.

    PubMed

    Sahu, Bidya Dhar; Kuncha, Madhusudana; Putcha, Uday Kumar; Sistla, Ramakrishna

    2013-09-01

    Although cisplatin has been a mainstay for cancer therapy, its use is limited mainly because of nephrotoxicity. Accumulating literature suggest the antioxidant and cytoprotective effect of metformin, a first line antidiabetic drug. With this background, we investigated the effect of metformin on the cisplatin induced nephrotoxicity in rats. A single injection of cisplatin (7.5 mg/kg, i.p.) caused marked renal damage, characterized by a significant increase in blood urea nitrogen (BUN), serum creatinine (Cr) and abnormal histo-architecture of kidney. These were accompanied by significant elevation of malondialdehyde (MDA), total reactive oxygen species (tROS) and caspase-3 levels and decreased antioxidant levels. Metformin treatment significantly attenuated the increase in malondialdehyde and tROS generation and restores the decrease in both enzymatic and non-enzymatic antioxidants. However metformin treatment did not prevent the cisplatin induced renal injury as there was no significant difference of renal function parameters (BUN and Cr), kidney histopathology as well as caspase-3 activity between cisplatin per se and metformin plus cisplatin treated rats. Histopathology studies revealed that similar glomerular and tubular pathological architecture in both cisplatin per se and cisplatin plus metformin group. In conclusion, the present study demonstrated that metformin is not an adjuvant drug to treat nephrotoxicity associated with cisplatin therapy.

  11. Environmental enrichment and abstinence attenuate ketamine-induced cardiac and renal toxicity

    PubMed Central

    Li, Xingxing; Li, Shuangyan; Zheng, Wenhui; Pan, Jian; Huang, Kunyu; Chen, Rong; Pan, Tonghe; Liao, Guorong; Chen, Zhongming; Zhou, Dongsheng; Shen, Wenwen; Zhou, Wenhua; Liu, Yu

    2015-01-01

    The current study was designed to investigate the effect of abstinence in combination with environmental enrichment (EE) on cardiac and renal toxicity induced by 2 weeks of ketamine self-administration (SA) in rodents. In Experiment 1, one group of rats underwent ketamine SA for 14 days. In Experiment 2, the animals completed 2 weeks of ketamine SA followed by 2 and 4 weeks of abstinence. In Experiment 3, animals underwent 14 days of ketamine SA and 4 weeks of abstinence in which isolated environment (IE) and EE was introduced. The corresponding control groups were included for each experiment. Two weeks of ketamine SA caused significant increases in organ weight, Apoptosis Stimulating Fragment/Kidney Injury Molecule-1, and apoptotic level of heart and kidney. The extended length of withdrawal from ketamine SA partially reduced toxicity on the heart and kidney. Finally, introduction of EE during the period of abstinence greatly promoted the effect of abstinence on ketamine-induced cardiac and renal toxicity. The interactive effect of EE and abstinence was promising to promote the recovery of cardiac and renal toxicity of ketamine. PMID:26112338

  12. Expression of Renal Aquaporins in Aristolochic Acid I and Aristolactam I-Induced Nephrotoxicity.

    PubMed

    Li, Ji; Zhang, Liang; Jiang, ZhenZhou; He, XiuQin; Zhang, LuYong; Xu, Ming

    2016-01-01

    Exposure to aristolochic acid (AA) can cause AA nephropathy, which is characterized by extensive proximal tubular damage and polyuria. To test the hypothesis that polyuria might be induced by altered regulation of aquaporins (AQPs) in the kidney, different doses of AA-I or aristolactam I (AL-I) were administered intraperitoneally to Sprague-Dawley rats, and urine, blood, and kidney samples were analyzed. In addition, AQP1, AQP2, AQP4 and AQP6 expression in the kidney were determined. The results showed dose-dependent proximal tubular damage and polyuria in the AA-I- and AL-I-treated groups, and the nephrotoxicity of AL-I was higher than that of AA-I. The expression of renal AQP1, AQP2 and AQP4, but not AQP6 were significantly inhibited by AA-I and AL-I. Comparison of the inhibition potencies of AA-I and AL-I showed that AL-I was a stronger inhibitor of AQP1 expression than AA-I, while there was no difference in their effects on AQP2 and AQP4. These results suggested that AA induced renal damage and polyuria were associated with a specific decrease in the expression of renal AQP1 AQP2 and AQP4, and AL-I showed higher nephrotoxicity than AA-I, which might be attributable to the differences in their inhibition of AQP1. © 2016 S. Karger AG, Basel.

  13. Urinary excretion of furosemide in rats with HgCl sub 2 -induced acute renal damage

    SciTech Connect

    Fujimura, Akio; Sudoh, Toshiaki; Ohashi, Kyoichi; Ebihara, Akio )

    1992-01-01

    To examine the influence of mercuric chloride (HgCl{sub 2})-induced acute renal damage on urinary excretion of furosemide, HgCl{sub 2} or its vehicle along was given intraperitoneally to Wistar rats. The following two experiments were done. Study 1: three percent body weight (b.w.) of 1% NaCl solution or furosemide in 3% b.w. of 1% NaCl solution was given orally before and after HgCl{sub 2} treatment, and an 8-hour urine was collected. Study 2: furosemide was given orally, and blood samples were obtained at 1, 2, 3, 4, 6 and 8 hours after administration. Urinary excretion of N-acetyl-{beta}-D-glucosaminidase increased, and urine volume and urinary excretions of furosemide and sodium decreased in the HgCl{sub 2}-treated rats. There were significant correlations between the urinary furosemide and its diuretic effects. Regression lines after HgCl{sub 2} were significantly different from those before treatment. The values of absorption as well as elimination rate constant were smaller, while the time to maximum concentration and the elimination half-life were longer in the HgCl{sub 2}-treated rats compared to vehicle-treated animals. These results suggest that the urinary excretion of furosemide and the responsiveness of renal tubular cells to this agent are impaired in rats with HgCl{sub 2}-induced acute renal damage.

  14. BAG3 regulates ECM accumulation in renal proximal tubular cells induced by TGF-β1.

    PubMed

    Du, Feng; Li, Si; Wang, Tian; Zhang, Hai-Yan; Li, De-Tian; Du, Zhen-Xian; Wang, Hua-Qin; Wang, Yan-Qiu

    2015-01-01

    Previously we have demonstrated that Bcl-2-associated athanogene 3 (BAG3) is increased in renal fibrosis using a rat unilateral ureteral obstruction model. The current study investigated the role of BAG3 in renal fibrosis using transforming growth factor (TGF)-β1-treated human proximal tubular epithelial (HK-2) cells. An upregulation of BAG3 in vitro models was observed, which correlated with the increased synthesis of extracellular matrix (ECM) proteins and expression of tissue-type plasminogen activator inhibitor (PAI)-1. Blockade of BAG3 induction by shorting hairpin RNA suppressed the expression of ECM proteins but had no effect on PAI-1 expression induced by TGF-β1. Forced overexpression of BAG3 selectively increased collagens. TGF-β1-induced BAG3 expression in HK-2 cells was attenuated by ERK1/2 and JNK MAPK inhibitors. In addition, forced BAG3 overexpression blocked attenuation of collagens expression by ERK1/2 and JNK inhibitors. These data suggest that ERK1/2 and JNK signaling events are involved in modulating the expression of BAG3, which would ultimately contribute to renal fibrosis by enhancing the synthesis and deposition of ECM proteins.

  15. Cymbopogon citratus Protects against the Renal Injury Induced by Toxic Doses of Aminoglycosides in Rabbits

    PubMed Central

    Ullah, N.; Khan, M. A.; Khan, T.; Ahmad, W.

    2013-01-01

    Renal injury is the most common side-effect of aminoglycosides. These antimicrobial drugs are particularly effective against Gram-negative microorganisms. The present study was conducted to investigate the renal protective activity of Cymbopogon citratus in gentamicin-induced nephrotoxicity. Male rabbits were divided into four groups (n=6) including group 1 (0.9% saline treated), group 2 (80 mg/kg/day gentamicin-treated), group 3 (200 mg/kg/day Cymbopogon citratus treated) and group 4 (80 mg/kg/day gentamicin and 200 mg/kg/day Cymbopogon citratus treated). Biochemical kidney functioning parameters, urinary enzymes and histopathological examination were performed. The results of the present study showed that simultaneous administration of Cymbopogon citrates and gentamicin significantly protected alteration in body weight, blood urea nitrogen, serum creatinine, creatinine clearance, serum uric acid, serum electrolytes, urinary volume, urinary protein, urinary lactate dehydrogenase and urinary alkaline phosphatase induced by gentamicin. Histological examination of the kidney also suggested the same. It is concluded from the current study that co-administration of Cymbopogon citratus with gentamicin for 3 weeks successfully prevented renal damage associated with aminoglycosides. PMID:24019578

  16. Fucan-coated silver nanoparticles synthesized by a green method induce human renal adenocarcinoma cell death.

    PubMed

    Rocha Amorim, Monica Oliveira; Lopes Gomes, Dayanne; Dantas, Larisse Araujo; Silva Viana, Rony Lucas; Chiquetti, Samanta Cristina; Almeida-Lima, Jailma; Silva Costa, Leandro; Oliveira Rocha, Hugo Alexandre

    2016-12-01

    Polysaccharides containing sulfated L-fucose are often called fucans. The seaweed Spatoglossum schröederi synthesizes three fucans, among which fucan A is the most abundant. This polymer is not cytotoxic against various normal cell lines and is non-toxic to rats when administered at high doses. In addition, it exhibits low toxicity against tumor cells. With the aim of increasing the toxicity of fucan A, silver nanoparticles containing this polysaccharide were synthesized using a green chemistry method. The mean size of these nanoparticles was 210nm. They exhibited a spherical shape and negative surface charge and were stable for 14 months. When incubated with cells, these nanoparticles did not show any toxic effects against various normal cell lines; however, they decreased the viability of various tumor cells, especially renal adenocarcinoma cells 786-0. Flow cytometry analyses showed that the nanoparticles induced cell death responses of 786-0 cells through necrosis. Assays performed with several renal cell lines (HEK, VERO, MDCK) showed that these nanoparticles only induce death of 786-0 cells. The data obtained herein leads to the conclusion that fucan A nanoparticles are promising agents against renal adenocarcinoma. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Pioglitazone protects against cisplatin induced nephrotoxicity in rats and potentiates its anticancer activity against human renal adenocarcinoma cell lines.

    PubMed

    Mahmoud, Mona F; El Shazly, Shimaa M

    2013-01-01

    Cisplatin-induced nephrotoxicity is a serious problem that limits its use in cancer treatment. The present study aimed to investigate the renal protective capacity of pioglitazone to reduce the cisplatin- induced nephrotoxicity. The underlying suggested mechanism(s) and whether this nephroprotective effect (if any) interferes with the cytotoxic effect of cisplatin on cancer cells were also investigated. Pioglitazone, Bisphenol A diglycidyl ether, BADGE, IP injected (Peroxisome proliferator- activated receptor gamma (PPAR-γ) antagonist), or their combination were administered to rats one hour before cisplatin injection. Moreover, their effects on the cell viability of human renal adenocarcinoma cell models (ACHN) were studied. The obtained results showed that pioglitazone improved the renal function, structural changes, renal malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB) genes expression in cisplatin injected rats. It increased both renal reduced glutathione (GSH) content and PPAR-γ gene expression. In contrast to the data obtained by prior administration of BADGE. Pioglitazone also potentiated the cytotoxic effect of cisplatin on human renal adenocarcinoma cells and this effect was abolished by BADGE co administration. In conclusion, these results suggested that pioglitazone protected against cisplatin- induced nephrotoxicity through its interaction with PPAR-γ receptors and antioxidant effects. Furthermore, pioglitazone did not interfere but rather potentiated the cytotoxic effects of cisplatin on human renal adenocarcinoma cells.

  18. Lipid droplet accumulation is associated with an increase in hyperglycemia-induced renal damage: prevention by liver X receptors.

    PubMed

    Kiss, Eva; Kränzlin, Bettina; Wagenblaβ, Katja; Bonrouhi, Mahnaz; Thiery, Joachim; Gröne, Elisabeth; Nordström, Viola; Teupser, Daniel; Gretz, Norbert; Malle, Ernst; Gröne, Hermann-Josef

    2013-03-01

    Dyslipidemia is a frequent component of the metabolic disorder of diabetic patients contributing to organ damage. Herein, in low-density lipoprotein receptor-deficient hyperlipidemic and streptozotozin-induced diabetic mice, hyperglycemia and hyperlipidemia acted reciprocally, accentuating renal injury and altering renal function. In hyperglycemic-hyperlipidemic kidneys, the accumulation of Tip47-positive lipid droplets in glomeruli, tubular epithelia, and macrophages was accompanied by the concomitant presence of the oxidative stress markers xanthine oxidoreductase and nitrotyrosine, findings that could also be evidenced in renal biopsy samples of diabetic patients. As liver X receptors (LXRα,β) regulate genes linked to lipid and carbohydrate homeostasis and inhibit inflammatory gene expression in macrophages, the effects of systemic and macrophage-specific LXR activation were analyzed on renal damage in hyperlipidemic-hyperglycemic mice. LXR stimulation by GW3965 up-regulated genes involved in cholesterol efflux and down-regulated proinflammatory/profibrotic cytokines, inhibiting the pathomorphology of diabetic nephropathy, renal lipid accumulation, and improving renal function. Xanthine oxidoreductase and nitrotyrosine levels were reduced. In macrophages, GW3965 or LXRα overexpression significantly suppressed glycated or acetylated low-density lipoprotein-induced cytokines and reactive oxygen species. Specifically, in mice, transgenic expression of LXRα in macrophages significantly ameliorated hyperlipidemic-hyperglycemic nephropathy. The results demonstrate the presence of lipid droplet-induced oxidative mechanisms and the pathophysiologic role of macrophages in diabetic kidneys and indicate the potent regulatory role of LXRs in preventing renal damage in diabetes.

  19. Forced diuresis with the RenalGuard system: impact on contrast induced acute kidney injury.

    PubMed

    Solomon, Richard

    2014-01-01

    Kidney injury following the administration of iodinated contrast media occurs particularly in patients with reduced kidney and cardiac function and when large doses of contrast are used. There is little compelling evidence that vasodilators and anti-oxidants prevent this injury. Most prevention trials have employed intravenous volume loading as a central strategy. However, the success of this approach depends upon maintaining euvolemia while producing a vigorous diuresis. A novel strategy for maintaining euvolemia and inducing a vigorous diuresis has been developed using the RenalGuard system. In this review; the mechanism of protective action is reviewed. The trials of the RenalGuard device are reviewed and future uses of the device are discussed.

  20. Dysregulation of renal aquaporins and epithelial sodium channel in lithium-induced nephrogenic diabetes insipidus.

    PubMed

    Nielsen, Jakob; Kwon, Tae-Hwan; Christensen, Birgitte Mønster; Frøkiaer, Jørgen; Nielsen, Søren

    2008-05-01

    Lithium is used commonly to treat bipolar mood disorders. In addition to its primary therapeutic effects in the central nervous system lithium has a number of side effects in the kidney. The side effects include nephrogenic diabetes insipidus with polyuria, mild sodium wasting, and changes in acid/base balance. These functional changes are associated with marked structural changes in collecting duct cell composition and morphology, likely contributing to the functional changes. Over the past few years, investigations of lithium-induced renal changes have provided novel insight into the molecular mechanisms that are responsible for the disturbances in water, sodium, and acid/base metabolism. This includes dysregulation of renal aquaporins, epithelial sodium channel, and acid/base transporters. This review focuses on these issues with the aim to present this in context with clinically relevant features.

  1. Intravesical foreign body–induced bladder calculi resulting in obstructive renal failure

    PubMed Central

    Kamal, Fadi; Clark, Aaron T.D.; Lavallée, Luke Thomas; Roberts, Matthew; Watterson, James

    2008-01-01

    We report the case of a 30-year-old man who presented with obstructive renal failure and urosepsis due to bladder outlet–obstructing bladder calculi that formed around 3 copper wires that were self-inserted into his urinary bladder 15 years previously. We present the evaluation, imaging and management of the unique complications resulting from the self-insertion of an intra-vesical foreign body. Our patient’s case was unique for 2 reasons. First, the length of time (15 yr) from foreign body insertion to presentation is the longest interval reported in the literature. Second, this is the first report of bladder calculi induced by the insertion of a foreign body that resulted in obstructive renal failure. PMID:18953457

  2. Mineralocorticoid-induced sodium appetite and renal salt retention: Evidence for common signaling and effector mechanisms

    PubMed Central

    Fu, Yiling; Vallon, Volker

    2014-01-01

    An increase in renal sodium chloride (salt) retention and an increase in sodium appetite is the body's response to salt restriction or depletion in order to restore salt balance. Renal salt retention and increased sodium appetite can also be maladaptive and sustain the pathophysiology in conditions like salt-sensitive hypertension and chronic heart failure. Here we review the central role of the mineralocorticoid aldosterone in both the increase in renal salt reabsorption and sodium appetite. We discuss the working hypothesis that aldosterone activates similar signaling and effector mechanisms in the kidney and brain, including the mineralocorticoid receptor, the serum-and-glucocorticoid-induced kinase SGK1, the ubiquitin ligase NEDD4-2, and the epithelial sodium channel ENaC. The latter also mediates the gustatory salt sensing in the tongue, which is required for the manifestation of increased salt intake. Effects of aldosterone on both brain and kidney synergize with the effects of angiotensin II. Thus, mineralocorticoids appear to induce similar molecular pathways in the kidney, brain, and possibly tongue, which could provide opportunities for more effective therapeutic interventions. Inhibition of renal salt reabsorption is compensated by stimulation of salt appetite and vice versa; targeting both mechanisms should be more effective. Inhibiting the arousal to consume salty food may improve a patient's compliance to reducing salt intake. While a better understanding of the molecular mechanisms is needed and will provide new options, current pharmacological interventions that target both salt retention and sodium appetite include mineralocorticoid receptor antagonists and potentially inhibitors of angiotensin II and ENaC. PMID:25376899

  3. Increased Klk9 Urinary Excretion Is Associated to Hypertension-Induced Cardiovascular Damage and Renal Alterations

    PubMed Central

    Blázquez-Medela, Ana M.; García-Sánchez, Omar; Quirós, Yaremi; Blanco-Gozalo, Victor; Prieto-García, Laura; Sancho-Martínez, Sandra M.; Romero, Miguel; Duarte, Juan M.; López-Hernández, Francisco J.; López-Novoa, José M.; Martínez-Salgado, Carlos

    2015-01-01

    Abstract Early detection of hypertensive end-organ damage and secondary diseases are key determinants of cardiovascular prognosis in patients suffering from arterial hypertension. Presently, there are no biomarkers for the detection of hypertensive target organ damage, most outstandingly including blood vessels, the heart, and the kidneys. We aimed to validate the usefulness of the urinary excretion of the serine protease kallikrein-related peptidase 9 (KLK9) as a biomarker of hypertension-induced target organ damage. Urinary, plasma, and renal tissue levels of KLK9 were measured by the Western blot in different rat models of hypertension, including angiotensin-II infusion, DOCA-salt, L-NAME administration, and spontaneous hypertension. Urinary levels were associated to cardiovascular and renal injury, assessed by histopathology. The origin of urinary KLK9 was investigated through in situ renal perfusion experiments. The urinary excretion of KLK9 is increased in different experimental models of hypertension in rats. The ACE inhibitor trandolapril significantly reduced arterial pressure and the urinary level of KLK9. Hypertension did not increase kidney, heart, liver, lung, or plasma KLK9 levels. Hypertension-induced increased urinary excretion of KLK9 results from specific alterations in its tubular reabsorption, even in the absence of overt nephropathy. KLK9 urinary excretion strongly correlates with cardiac hypertrophy and aortic wall thickening. KLK9 appears in the urine in the presence of hypertension as a result of subtle renal handling alterations. Urinary KLK9 might be potentially used as an indicator of hypertensive cardiac and vascular damage. PMID:26469898

  4. Differentiation of murine embryonic stem and induced pluripotent stem cells to renal lineage in vitro

    SciTech Connect

    Morizane, Ryuji; Monkawa, Toshiaki; Itoh, Hiroshi

    2009-12-25

    Embryonic stem (ES) cells which have the unlimited proliferative capacity and extensive differentiation potency can be an attractive source for kidney regeneration therapies. Recent breakthroughs in the generation of induced pluripotent stem (iPS) cells have provided with another potential source for the artificially-generated kidney. The purpose of this study is to know how to differentiate mouse ES and iPS cells into renal lineage. We used iPS cells from mouse fibroblasts by transfection of four transcription factors, namely Oct4, Sox2, c-Myc and Klf4. Real-time PCR showed that renal lineage markers were expressed in both ES and iPS cells after the induction of differentiation. It also showed that a tubular specific marker, KSP progressively increased to day 18, although the differentiation of iPS cells was slower than ES cells. The results indicated that renal lineage cells can be differentiated from both murine ES and iPS cells. Several inducing factors were tested whether they influenced on cell differentiation. In ES cells, both of GDNF and BMP7 enhanced the differentiation to metanephric mesenchyme, and Activin enhanced the differentiation of ES cells to tubular cells. Activin also enhanced the differentiation of iPS cells to tubular cells, although the enhancement was lower than in ES cells. ES and iPS cells have a potential to differentiate to renal lineage cells, and they will be an attractive resource of kidney regeneration therapy. This differentiation is enhanced by Activin in both ES and iPS cells.

  5. Increased renal tubular sodium reabsorption during exercise-induced hypervolemia in humans

    NASA Technical Reports Server (NTRS)

    Nagashima, K.; Wu, J.; Kavouras, S. A.; Mack, G. W.

    2001-01-01

    We tested the hypothesis that renal tubular Na(+) reabsorption increased during the first 24 h of exercise-induced plasma volume expansion. Renal function was assessed 1 day after no-exercise control (C) or intermittent cycle ergometer exercise (Ex, 85% of peak O(2) uptake) for 2 h before and 3 h after saline loading (12.5 ml/kg over 30 min) in seven subjects. Ex reduced renal blood flow (p-aminohippurate clearance) compared with C (0.83 +/- 0.12 vs. 1.49 +/- 0.24 l/min, P < 0.05) but did not influence glomerular filtration rates (97 +/- 10 ml/min, inulin clearance). Fractional tubular reabsorption of Na(+) in the proximal tubules was higher in Ex than in C (P < 0.05). Saline loading decreased fractional tubular reabsorption of Na(+) from 99.1 +/- 0.1 to 98.7 +/- 0.1% (P < 0.05) in C but not in Ex (99.3 +/- 0.1 to 99.4 +/- 0.1%). Saline loading reduced plasma renin activity and plasma arginine vasopressin levels in C and Ex, although the magnitude of decrease was greater in C (P < 0.05). These results indicate that, during the acute phase of exercise-induced plasma volume expansion, increased tubular Na(+) reabsorption is directed primarily to the proximal tubules and is associated with a decrease in renal blood flow. In addition, saline infusion caused a smaller reduction in fluid-regulating hormones in Ex. The attenuated volume-regulatory response acts to preserve distal tubular Na(+) reabsorption during saline infusion 24 h after exercise.

  6. Health significance of cadmium induced renal dysfunction: a five year follow up.

    PubMed Central

    Roels, H A; Lauwerys, R R; Buchet, J P; Bernard, A M; Vos, A; Oversteyns, M

    1989-01-01

    To assess the health significance of the early renal changes after chronic exposure to cadmium, 23 workers removed from exposure because of the discovery of an increased urinary excretion of beta 2-microglobulin or retinol binding protein, or both, have been examined once a year for five years. Eight of these workers had also an increased albuminuria. These workers had been exposed to cadmium for six to 41.7 years (mean 25 years) and their first follow up examination took place when they had been removed from exposure for six years on average. At that time, their mean age was 58.6 years (range: 45.5-68.1). It has been confirmed that the proteinuria induced by cadmium is irreversible. The most important finding, however, is a significant increase of creatinine and beta 2-microglobulin concentrations in serum with time, indicating a progressive reduction of the glomerular filtration rate despite removal from exposure. It is estimated that on average this rate has decreased by 31 ml/min/1.73 m2 during the five year follow up study. This decrease is significantly greater (about five times) than that accounted for by aging and is not more pronounced in workers with impaired renal function at the start of the study than in those presenting only with subclinical signs of renal damage. Serum alkaline phosphatase activity also increases significantly with time. In conclusion, the present study indicates that the early renal changes induced by cadmium should be regarded as adverse effects; they are predictive of an exacerbation of the age related decline of the glomerular filtration rate. PMID:2686749

  7. Citrus bergamia Risso & Poiteau juice protects against renal injury of diet-induced hypercholesterolemia in rats.

    PubMed

    Trovato, Ada; Taviano, Maria F; Pergolizzi, Simona; Campolo, Loredana; De Pasquale, Rita; Miceli, Natalizia

    2010-04-01

    The present study was designed to evaluate the protective effect of treatment with Citrus bergamia juice (1 mL/day, for 30 days) against hypercholesterolemic diet-induced renal injury in rat.C. bergamia juice provoked a significant reduction in the plasma levels of cholesterol, triglycerides and LDL, and an increase in HDL levels, versus hyperlipidemic controls (p < 0.05). Plasma creatinine levels, measured to assess renal glomerular function, did not change compared with hyperlipidemic controls (0.37 +/- 0.11 mg/dL and 0.32 +/- 0.10 mg/dL, respectively). Moreover, in vivo lipid peroxidation was measured in kidney homogenate; C. bergamia juice administration significantly decreased MDA levels elevations compared with hyperlipidemic controls (4.10 +/- 0.10 nmol/mg protein and 4.78 +/- 0.15 nmol/mg protein, respectively).Histological observations of the kidney supported the biochemical data and indicated a protective effect of C. bergamia juice on the development of renal damage in hypercholesterolemic rats.The antioxidant potential of C. bergamia juice was examined in two in vitro systems: in the DPPH test the juice showed a noticeable effect on scavenging free radicals (IC(50) = 25.01 +/- 0.70 +/-L); in the reducing power assay it showed a strong activity, too (1.44 +/- 0.01 ASE/mL).These findings suggest that C. bergamia juice has a protective role in hypercholesterolemic diet-induced renal damage, which may be attributed to its antioxidant properties. Copyright (c) 2009 John Wiley & Sons, Ltd.

  8. The cardiotonic steroid hormone marinobufagenin induces renal fibrosis: implication of epithelial-to-mesenchymal transition.

    PubMed

    Fedorova, Larisa V; Raju, Vanamala; El-Okdi, Nasser; Shidyak, Amjad; Kennedy, David J; Vetteth, Sandeep; Giovannucci, David R; Bagrov, Alexei Y; Fedorova, Olga V; Shapiro, Joseph I; Malhotra, Deepak

    2009-04-01

    We recently demonstrated that the cardiotonic steroid marinobufagenin (MBG) induced fibrosis in rat hearts through direct stimulation of collagen I secretion by cardiac fibroblasts. This stimulation was also responsible for the cardiac fibrosis seen in experimental renal failure. In this study, the effect of MBG on the development of renal fibrosis in rats was investigated. Four weeks of MBG infusion triggered mild periglomerular and peritubular fibrosis in the cortex and the appearance of fibrotic scars in the corticomedullary junction of the kidney. MBG also significantly increased the protein levels and nuclear localization of the transcription factor Snail in the tubular epithelia. It is known that activation of Snail is associated with epithelial-to-mesenchymal transition (EMT) during renal fibrosis. To examine whether MBG alone can trigger EMT, we used the porcine proximal tubular cell line LLC-PK1. MBG (100 nM) caused LLC-PK1 cells grown to confluence to acquire a fibroblast-like shape and have an invasive motility. The expressions of the mesenchymal proteins collagen I, fibronectin, and vimentin were increased twofold. However, the total level of E-cadherin remained unchanged. These alterations in LLC-PK1 cells in the presence of MBG were accompanied by elevated expression and nuclear translocation of Snail. During the time course of EMT, MBG did not have measurable inhibitory effects on the ion pumping activity of its natural ligand, Na(+)-K(+)-ATPase. Our data suggest that the MBG may be an important factor in inducing EMT and, through this mechanism, elevated levels of MBG in chronic renal failure may play a role in the progressive fibrosis.

  9. Increased renal tubular sodium reabsorption during exercise-induced hypervolemia in humans

    NASA Technical Reports Server (NTRS)

    Nagashima, K.; Wu, J.; Kavouras, S. A.; Mack, G. W.

    2001-01-01

    We tested the hypothesis that renal tubular Na(+) reabsorption increased during the first 24 h of exercise-induced plasma volume expansion. Renal function was assessed 1 day after no-exercise control (C) or intermittent cycle ergometer exercise (Ex, 85% of peak O(2) uptake) for 2 h before and 3 h after saline loading (12.5 ml/kg over 30 min) in seven subjects. Ex reduced renal blood flow (p-aminohippurate clearance) compared with C (0.83 +/- 0.12 vs. 1.49 +/- 0.24 l/min, P < 0.05) but did not influence glomerular filtration rates (97 +/- 10 ml/min, inulin clearance). Fractional tubular reabsorption of Na(+) in the proximal tubules was higher in Ex than in C (P < 0.05). Saline loading decreased fractional tubular reabsorption of Na(+) from 99.1 +/- 0.1 to 98.7 +/- 0.1% (P < 0.05) in C but not in Ex (99.3 +/- 0.1 to 99.4 +/- 0.1%). Saline loading reduced plasma renin activity and plasma arginine vasopressin levels in C and Ex, although the magnitude of decrease was greater in C (P < 0.05). These results indicate that, during the acute phase of exercise-induced plasma volume expansion, increased tubular Na(+) reabsorption is directed primarily to the proximal tubules and is associated with a decrease in renal blood flow. In addition, saline infusion caused a smaller reduction in fluid-regulating hormones in Ex. The attenuated volume-regulatory response acts to preserve distal tubular Na(+) reabsorption during saline infusion 24 h after exercise.

  10. Piroxicam-induced hepatic and renal histopathological changes in mice

    PubMed Central

    Ebaid, Hossam; Dkhil, Mohamed A; Danfour, Mohamed A; Tohamy, Amany; Gabry, Mohamed S

    2007-01-01

    Piroxicam is a non-steroidal anti-inflammatory drug widely used in rheumatic diseases. The aim of this study was to investigate Piroxicam-induced histopathological changes in livers and kidneys of male albino mice. Methods Animals were classified into a control group and 4 treated groups. Piroxicam was injected intraperitoneally using 0.3 mg/kg every day for four weeks. Each week a group of mice was sacrificed. Liver and kidneys were obtained for histological and histochemical examination. Animals were classified into a control group and 4 treated groups. Piroxicam was injected intraperitoneally using 0.3 mg/kg every day for four weeks. Each week a group of mice was sacrificed. Liver and kidneys were obtained for histological and histochemical examination. Results Liver sections appeared with inflammatory cellular infiltration, vacuolated hepatocytes, dilated sinusoids, and increased number of Kupffer cells. Kidney sections appeared with some cellular inflammations. The glomeruli were shrunk resulting in widening of the urinary space. Oedema and vacuolations were noticed in the tubular cells. There was a positive correlation between these pathological changes and the increased treatment periods. Histochemical staining revealed that glycogen and protein contents had decreased in the hepatocytes. This depletion worsened gradually in liver cells after two, three, and four weeks. Similar depletion of the glycogen content was observed in kidney tissue. However, protein content appeared to be slightly decreased in the kidney tubules and glomeruli. Incensement of coarse chromatin in the nuclei of hepatocytes, Kupffer cells and most inflammatory cells were detected by Fuelgen method. Kidney tissues appeared with a severe decrease in coarse chromatin in the nuclei. Liver sections appeared with inflammatory cellular infiltration, vacuolated hepatocytes, dilated sinusoids, and increased number of Kupffer cells. Kidney sections appeared with some cellular inflammations. The

  11. Alpha1-Antitrypsin Attenuates Renal Fibrosis by Inhibiting TGF-β1-Induced Epithelial Mesenchymal Transition

    PubMed Central

    Cho, Jang-Hee; Ryu, Hye-Myung; Oh, Eun-Joo; Yook, Ju-Min; Ahn, Ji-Sun; Jung, Hee-Yeon; Choi, Ji-Young; Park, Sun-Hee; Kim, Yong-Lim; Kwak, Ihm Soo; Kim, Chan-Duck

    2016-01-01

    Alpha1-antitrypsin (AAT) exerts its anti-inflammatory effect through regulating the activity of serine proteinases. This study evaluated the inhibitory effects of AAT against the transforming growth factor (TGF)-β1 induced epithelial-to-mesenchymal transition (EMT) in unilateral ureter obstruction (UUO) mice and Madin-Darby canine kidney (MDCK) cells. C57BL/6 mice with induced UUO were injected intraperitoneally with AAT (80 mg/Kg) or vehicle for 7 days. MDCK cells were treated with TGF-β1 (2 ng/mL) for 48 hours to induce EMT, and co-treated with AAT (10 mg/mL) to inhibit the EMT. Masson’s trichrome and Sirius red staining was used to estimate the extent of renal fibrosis in UUO mice. The expression of alpha-smooth muscle actin (α-SMA), vimentin, fibronectin, collagen I, and E-cadherin in MDCK cells and kidney tissue were evaluated. Masson’s and Sirius red staining revealed that the area of renal fibrosis was significantly smaller in AAT treated UUO group compared with that of UUO and vehicle treated UUO groups. AAT treatment attenuated upregulation of Smad2/3 phosphorylation in UUO mouse model. Co-treatment of MDCK cells with TGF-β1 and AAT significantly attenuated the changes in the expression of α-SMA, vimentin, fibronectin, collagen I, and E-cadherin. AAT also decreased the phosphorylated Smad3 expression and the phosphorylated Smad3/Smad3 ratio in MDCK cells. AAT treatment inhibited EMT induced by TGF-β1 in MDCK cells and attenuated renal fibrosis in the UUO mouse model. The results of this work suggest that AAT could inhibit the process of EMT through the suppression of TGF-β/Smad3 signaling. PMID:27607429

  12. Alpha1-Antitrypsin Attenuates Renal Fibrosis by Inhibiting TGF-β1-Induced Epithelial Mesenchymal Transition.

    PubMed

    Cho, Jang-Hee; Ryu, Hye-Myung; Oh, Eun-Joo; Yook, Ju-Min; Ahn, Ji-Sun; Jung, Hee-Yeon; Choi, Ji-Young; Park, Sun-Hee; Kim, Yong-Lim; Kwak, Ihm Soo; Kim, Chan-Duck

    2016-01-01

    Alpha1-antitrypsin (AAT) exerts its anti-inflammatory effect through regulating the activity of serine proteinases. This study evaluated the inhibitory effects of AAT against the transforming growth factor (TGF)-β1 induced epithelial-to-mesenchymal transition (EMT) in unilateral ureter obstruction (UUO) mice and Madin-Darby canine kidney (MDCK) cells. C57BL/6 mice with induced UUO were injected intraperitoneally with AAT (80 mg/Kg) or vehicle for 7 days. MDCK cells were treated with TGF-β1 (2 ng/mL) for 48 hours to induce EMT, and co-treated with AAT (10 mg/mL) to inhibit the EMT. Masson's trichrome and Sirius red staining was used to estimate the extent of renal fibrosis in UUO mice. The expression of alpha-smooth muscle actin (α-SMA), vimentin, fibronectin, collagen I, and E-cadherin in MDCK cells and kidney tissue were evaluated. Masson's and Sirius red staining revealed that the area of renal fibrosis was significantly smaller in AAT treated UUO group compared with that of UUO and vehicle treated UUO groups. AAT treatment attenuated upregulation of Smad2/3 phosphorylation in UUO mouse model. Co-treatment of MDCK cells with TGF-β1 and AAT significantly attenuated the changes in the expression of α-SMA, vimentin, fibronectin, collagen I, and E-cadherin. AAT also decreased the phosphorylated Smad3 expression and the phosphorylated Smad3/Smad3 ratio in MDCK cells. AAT treatment inhibited EMT induced by TGF-β1 in MDCK cells and attenuated renal fibrosis in the UUO mouse model. The results of this work suggest that AAT could inhibit the process of EMT through the suppression of TGF-β/Smad3 signaling.

  13. CCR5 deficiency increased susceptibility to lipopolysaccharide-induced acute renal injury.

    PubMed

    Lee, Dong Hun; Park, Mi Hee; Hwang, Chul Ju; Hwang, Jae Yeon; Yoon, Hae Suk; Yoon, Do Young; Hong, Jin Tae

    2016-05-01

    C-C chemokine receptor 5 (CCR5) regulates leukocyte chemotaxis and activation, and its deficiency exacerbates development of nephritis. Therefore, we investigated the role of CCR5 during lipopolysaccharide (LPS)-induced acute kidney injury. CCR5-deficient (CCR5-/-) and wild-type (CCR5+/+) mice, both aged about 10 months, had acute renal injury induced by intraperitoneal injection of LPS (10 mg/kg). Compared with CCR5+/+ mice, CCR5-/- mice showed increased mortality and renal injury, including elevated creatinine and blood urea nitrogen levels, following LPS challenge. Compared to CCR5+/+ mice, CCR5-/- mice also exhibited greater increases in the serum concentrations of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β following LPS challenge. Furthermore, infiltration of macrophages and neutrophils, expression of intracellular adhesion molecule (ICAM)-1, and the number of apoptotic cells were more greatly increased by LPS treatment in CCR5-/- mice than in CCR5+/+ mice. The concentrations of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β were also significantly increased in the kidney of CCR5-/- mice after LPS challenge. Moreover, primary kidney cells from CCR5-/- mice showed greater increases in TNF-α production and p38 MAP kinase activation following treatment with LPS compared with that observed in the cells from CCR5+/+ mice. LPS-induced TNF-α production and apoptosis in the primary kidney cells from CCR5-/- mice were inhibited by treatment with p38 MAP kinase inhibitor. These results suggest that CCR5 deficiency increased the production of TNF-α following LPS treatment through increased activation of the p38 pathway in the kidney, resulting in renal apoptosis and leukocyte infiltration and led to exacerbation of LPS-induced acute kidney injury.

  14. Hydralazine-induced ANCA vasculitis with pulmonary renal syndrome: a rare clinical presentation.

    PubMed

    Marina, Vamsee Priya; Malhotra, Deepak; Kaw, Dinkar

    2012-12-01

    Hydralazine is a commonly used drug for treatment of hypertension and is known to cause drug-induced lupus erythematosus. It has rarely been reported to cause anti neutrophil cytoplasmic antibody positive vasculitis, a life-threatening complication. Presentation could be extremely variable delaying diagnosis. Although drug-induced vasculitis has been infrequently associated with rapidly progressing glomerulonephritis, pulmonary involvement presenting as pulmonary renal syndrome is extremely rare. We report a case of hydralazine-induced vasculitis presenting as pulmonary renal syndrome with fatal outcome even after aggressive treatment. Numerous antibodies are associated with hydralazine including anti myeloperoxidase antibody, anti-nuclear antibody, anti-histone antibody, and anti-elastase antibody. Additionally, we also report the presence of anti-phospholipid antibodies specific to anti-cardiolipin, anti-beta2 glycoprotein, and anti-phosphatid that have not been previously reported. We conclude that early diagnosis and prompt discontinuation of the drug is necessary for the treatment of hydralazine-induced anti neutrophil cytoplasmic antibody vasculitis.

  15. Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury.

    PubMed

    Estrela, Gabriel R; Wasinski, Frederick; Bacurau, Reury F; Malheiros, Denise M A C; Câmara, Niels O S; Araújo, Ronaldo C

    2014-09-01

    Cisplatin treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of creatinine and urea, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1β and TNF-α). The kinin B2 receptor has been associated with the inflammation process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the diabetic nephropathy status. To examine the role of the kinin B2 receptor in cisplatin-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with cisplatin. Additionally, WT mice were treated with a B2 receptor antagonist after cisplatin administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum creatinine and blood urea after cisplatin administration. Thus, our data suggest that the kinin B2 receptor is involved in cisplatin-induced acute kidney injury by mediating the necrotic process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by cisplatin therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. The protective effect of grape seed procyanidin extract against cadmium-induced renal oxidative damage in mice.

    PubMed

    Chen, Qing; Zhang, Rong; Li, Wei-min; Niu, Yu-jie; Guo, Hui-cai; Liu, Xue-hui; Hou, Yu-chun; Zhao, Li-juan

    2013-11-01

    As an important environmental pollutant, cadmium (Cd) can lead to serious renal damage. Grape seed procyanidins extract (GSPE), a biological active component of grape seed, has been shown to possess antioxidative effects. Here, we assessed the protective effect of GSPE on Cd-induced renal damage using animal experiment. After 30 days, the oxidative damage of kidney was evaluated through measurement of superoxide dismutase (SOD), glutathione peroxidation (GSH-Px) and malondialdehyde (MDA). Since, oxidative stress could lead to apoptosis, the renal apoptosis was measured using flow cytometer. Moreover, the expression of apoptosis-related protein Bax and Bcl-2 was analyzed by immunohistochemistry and Western blot. The results showed that Cd led to the decrease of SOD and GSH-Px activities, and the increase of MDA level, induced renal apoptosis. However, the coadministration of GSPE attenuated Cd-induced lipid peroxidation, and antagonized renal apoptosis, probably associated with the expression of Bax and Bcl-2. These data suggested that GSPE has protective effect against renal oxidative damage induced by Cd, which provide a potential natural chemopreventive agent against Cd-poisoning. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Involvement of caspase-12-dependent apoptotic pathway in ionic radiocontrast urografin-induced renal tubular cell injury

    SciTech Connect

    Wu, Cheng Tien; Weng, Te I.; Chen, Li Ping; Chiang, Chih Kang; Liu, Shing Hwa

    2013-01-01

    Contrast medium (CM) induces a direct toxic effect on renal tubular cells. This toxic effect subjects in the disorder of CM-induced nephropathy. Our previous work has demonstrated that CM shows to activate the endoplasmic reticulum (ER)-related adaptive unfolding protein response (UPR) activators. Glucose-regulated protein 78 (GRP78)/eukaryotic initiation factor 2α (eIF2α)-related pathways play a protective role during the urografin (an ionic CM)-induced renal tubular injury. However, the involvement of ER stress-related apoptotic signals in the urografin-induced renal tubular cell injury remains unclear. Here, we examined by the in vivo and in vitro experiments to explore whether ER stress-regulated pro-apoptotic activators participate in urografin-induced renal injury. Urografin induced renal tubular dilation, tubular cells detachment, and necrosis in the kidneys of rats. The tubular apoptosis, ER stress-related pro-apoptotic transcriptional factors, and kidney injury marker-1 (kim-1) were also conspicuously up-regulated in urografin-treated rats. Furthermore, treatment of normal rat kidney (NRK)-52E tubular cells with urografin augmented the expressions of activating transcription factor-6 (ATF-6), C/EBP homologous protein (CHOP), Bax, caspase-12, JNK, and inositol-requiring enzyme (IRE) 1 signals. Urografin-induced renal tubular cell apoptosis was not reversed by the inhibitors of ATF-6, JNK signals or CHOP siRNA transfection, but it could be partially reversed by the inhibitor of caspase-12. Taken together, the present results and our previous findings suggest that exposure of CM/urografin activates the ER stress-regulated survival- and apoptosis-related signaling pathways in renal tubular cells. Caspase-12-dependent apoptotic pathway may be partially involved in the urografin-induced nephropathy. -- Highlights: ► Ionic contrast medium-urografin induces renal tubular cell apoptosis. ► Urografin induces the ER stress-regulated survival and apoptosis

  18. Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension.

    PubMed

    Ling, Yeong Hann; Krishnan, Shalini M; Chan, Christopher T; Diep, Henry; Ferens, Dorota; Chin-Dusting, Jaye; Kemp-Harper, Barbara K; Samuel, Chrishan S; Hewitson, Timothy D; Latz, Eicke; Mansell, Ashley; Sobey, Christopher G; Drummond, Grant R

    2017-02-01

    To determine whether a clinically-utilised IL-1 receptor antagonist, anakinra, reduces renal inflammation, structural damage and blood pressure (BP) in mice with established hypertension. Hypertension was induced in male mice by uninephrectomy, deoxycorticosterone acetate (2.4mg/d,s.c.) and replacement of drinking water with saline (1K/DOCA/salt). Control mice received uninephrectomy, a placebo pellet and normal drinking water. 10days post-surgery, mice commenced treatment with anakinra (75mg/kg/d, i.p.) or vehicle (0.9% saline, i.p.) for 11days. Systolic BP was measured by tail cuff while qPCR, immunohistochemistry and flow cytometry were used to measure inflammatory markers, collagen and immune cell infiltration in the kidneys. By 10days post-surgery, 1K/DOCA/salt-treated mice displayed elevated systolic BP (148.3±2.4mmHg) compared to control mice (121.7±2.7mmHg; n=18, P<0.0001). The intervention with anakinra reduced BP in 1K/DOCA/salt-treated mice by ∼20mmHg (n=16, P<0.05), but had no effect in controls. In 1K/DOCA/salt-treated mice, anakinra modestly reduced (∼30%) renal expression of some (CCL5, CCL2; n=7-8; P<0.05) but not all (ICAM-1, IL-6) inflammatory markers, and had no effect on immune cell infiltration (n=7-8, P>0.05). Anakinra reduced renal collagen content (n=6, P<0.01) but paradoxically appeared to exacerbate the renal and glomerular hypertrophy (n=8-9, P<0.001) that accompanied 1K/DOCA/salt-induced hypertension. Despite its anti-hypertensive and renal anti-fibrotic actions, anakinra had minimal effects on inflammation and leukocyte infiltration in mice with 1K/DOCA/salt-induced hypertension. Future studies will assess whether the anti-hypertensive actions of anakinra are mediated by protective actions in other BP-regulating or salt-handling organs such as the arteries, skin and brain. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. Thromboxane-induced renal vasoconstriction is mediated by the ADP-ribosyl cyclase CD38 and superoxide anion.

    PubMed

    Moss, Nicholas G; Vogel, Paul A; Kopple, Tayler E; Arendshorst, William J

    2013-09-15

    The present renal hemodynamic study tested the hypothesis that CD38 and superoxide anion (O2(·-)) participate in the vasoconstriction produced by activation of thromboxane prostanoid (TP) receptors in the mouse kidney. CD38 is the major mammalian ADP-ribosyl cyclase contributing to vasomotor tone through the generation of cADP-ribose, a second messenger that activates ryanodine receptors to release Ca(2+) from the sarcoplasmic reticulum in vascular smooth muscle cells. We evaluated whether the stable thromboxane mimetic U-46619 causes less pronounced renal vasoconstriction in CD38-deficient mice and the involvement of O2(·-) in U-46619-induced renal vasoconstriction. Our results indicate that U-46619 activation of TP receptors causes renal vasoconstriction in part by activating cADP-ribose signaling in renal resistance arterioles. Based on maximal renal blood flow and renal vascular resistance responses to bolus injections of U-46619, CD38 contributes 30-40% of the TP receptor-induced vasoconstriction. We also found that the antioxidant SOD mimetic tempol attenuated the magnitude of vasoconstriction by U-46619 in both groups of mice, suggesting mediation by O2(·-). The degree of tempol blockage of U-46619-induced renal vasoconstriction was greater in wild-type mice, attenuating renal vasoconstriction by 40% compared with 30% in CD38-null mice. In other experiments, U-46619 rapidly stimulated O2(·-) production (dihydroethidium fluorescence) in isolated mouse afferent arterioles, an effect abolished by tempol. These observations provide the first in vivo demonstration of CD38 and O2(·-) involvement in the vasoconstrictor effects of TP receptor activation in the kidney and in vitro evidence for TP receptor stimulation of O2(·-) production by the afferent arteriole.

  20. Thromboxane-induced renal vasoconstriction is mediated by the ADP-ribosyl cyclase CD38 and superoxide anion

    PubMed Central

    Vogel, Paul A.; Kopple, Tayler E.; Arendshorst, William J.

    2013-01-01

    The present renal hemodynamic study tested the hypothesis that CD38 and superoxide anion (O2·−) participate in the vasoconstriction produced by activation of thromboxane prostanoid (TP) receptors in the mouse kidney. CD38 is the major mammalian ADP-ribosyl cyclase contributing to vasomotor tone through the generation of cADP-ribose, a second messenger that activates ryanodine receptors to release Ca2+ from the sarcoplasmic reticulum in vascular smooth muscle cells. We evaluated whether the stable thromboxane mimetic U-46619 causes less pronounced renal vasoconstriction in CD38-deficient mice and the involvement of O2·− in U-46619-induced renal vasoconstriction. Our results indicate that U-46619 activation of TP receptors causes renal vasoconstriction in part by activating cADP-ribose signaling in renal resistance arterioles. Based on maximal renal blood flow and renal vascular resistance responses to bolus injections of U-46619, CD38 contributes 30–40% of the TP receptor-induced vasoconstriction. We also found that the antioxidant SOD mimetic tempol attenuated the magnitude of vasoconstriction by U-46619 in both groups of mice, suggesting mediation by O2·−. The degree of tempol blockage of U-46619-induced renal vasoconstriction was greater in wild-type mice, attenuating renal vasoconstriction by 40% compared with 30% in CD38-null mice. In other experiments, U-46619 rapidly stimulated O2·− production (dihydroethidium fluorescence) in isolated mouse afferent arterioles, an effect abolished by tempol. These observations provide the first in vivo demonstration of CD38 and O2·− involvement in the vasoconstrictor effects of TP receptor activation in the kidney and in vitro evidence for TP receptor stimulation of O2·− production by the afferent arteriole. PMID:23884143

  1. Stem cell conditioned culture media attenuated albumin-induced epithelial-mesenchymal transition in renal tubular cells.

    PubMed

    Hu, Junping; Zhu, Qing; Li, Pin-Lan; Wang, Weili; Yi, Fan; Li, Ningjun

    2015-01-01

    Proteinuria-induced epithelial-mesenchymal transition (EMT) plays an important role in progressive renal tubulointerstitial fibrosis in chronic renal disease. Stem cell therapy has been used for different diseases. Stem cell conditioned culture media (SCM) exhibits similar beneficial effects as stem cell therapy. The present study tested the hypothesis that SCM inhibits albumin-induced EMT in cultured renal tubular cells. Rat renal tubular cells were treated with/without albumin (20 µmg/ml) plus SCM or control cell media (CCM). EMT markers and inflammatory factors were measured by Western blot and fluorescent images. Albumin induced EMT as shown by significant decreases in levels of epithelial marker E-cadherin, increases in mesenchymal markers fibroblast-specific protein 1 and α-smooth muscle actin, and elevations in collagen I. SCM inhibited all these changes. Meanwhile, albumin induced NF-κB translocation from cytosol into nucleus and that SCM blocked the nuclear translocation of NF-κB. Albumin also increased the levels of pro-inflammatory factor monocyte chemoattractant protein-1 (MCP)-1 by nearly 30 fold compared with control. SCM almost abolished albumin-induced increase of MCP-1. These results suggest that SCM attenuated albumin-induced EMT in renal tubular cells via inhibiting activation of inflammatory factors, which may serve as a new therapeutic approach for chronic kidney diseases. © 2015 S. Karger AG, Basel.

  2. Modulation by cyclic AMP and phorbol myristate acetate of cephaloridine-induced injury in rat renal cortical slices.

    PubMed

    Kohda, Y; Gemba, M

    2001-01-01

    Intracellular signaling pathways of cAMP and protein kinase C (PKC) have been suggested to modulate the generation of free radicals. We investigated the effects of cAMP and phorbol myristate acetate (PMA), a PKC activator, on cephaloridine (CER)-induced renal cell injury, which has been reported to be due to the generation of free radicals. Incubation of rat renal cortical slices with CER resulted in increases in lipid peroxidation and lactate dehydrogenase (LDH) release and in decreases in gluconeogenesis and p-aminohippurate (PAH) accumulation in rat renal cortical slices, suggesting free radical-induced injury in slices exposed to CER. A derivative of cAMP ameliorated not only the increase in lipid peroxidation but also the renal cell damage induced by CER. This amelioration by a cAMP derivative of lipid peroxidation and renal cell damage caused by CER was blocked by KT 5720, a protein kinase A (PKA) inhibitor. Lipid peroxidation and the indices of cell injury were increased by PMA. PMA also enhanced CER-induced lipid peroxidation and cell damage in the slices. This enhancement by PMA of CER-induced injury was blocked by H-7, a PKC inhibitor. These results indicated that intracellular signaling pathways of cAMP and PKC modulate free radical-mediated nephrotoxicity induced by CER.

  3. LPS-induced renal inflammation is prevented by (-)-epicatechin in rats.

    PubMed

    Prince, Paula Denise; Fischerman, Laura; Toblli, Jorge E; Fraga, Cesar G; Galleano, Monica

    2017-04-01

    This work investigated the capacity of (-)-epicatechin to prevent the renal damage induced by LPS administration in rats. Male Sprague Dawley rats were fed for 4 days a diet without or with supplementation with (-)-epicatechin (80mg/kg BW/d), and subsequently i.p. injected with lipopolysaccharide (LPS). Six hours after injection, LPS-treated rats exhibited increased plasma creatinine and urea levels as indicators of impaired renal function. The renal cortex of the LPS-treated rats showed: i) increased expression of inflammatory molecules (TNF-α, iNOS and IL-6); ii) activation of several steps of NF-κB pathway; iii) overexpression of TLR4, and iv) higher superoxide anion production and lipid peroxidation index in association with increased levels of gp91(phox) and p47(phox) (NOX2) and NOX4. Pretreatment with dietary (-)-epicatechin prevented the adverse effects of LPS challenge essentially by inhibiting TLR4 upregulation and NOX activation and the consequent downstream events, e.g. NF-kB activation.

  4. Protective effect of crocetin on hemorrhagic shock-induced acute renal failure in rats.

    PubMed

    Wang, Yunbo; Yan, Junling; Xi, Liang; Qian, Zhiyu; Wang, Zhenghong; Yang, Lina

    2012-07-01

    Multiple organ failure is a common outcome of hemorrhagic shock followed by resuscitation, and the kidney is one of the prime target organs involved. The main objective of the study was to evaluate whether crocetin, a natural product from Gardenia jasminoides Ellis, has beneficial effects on renal dysfunction caused by hemorrhagic shock and resuscitation in rats. Anesthetized rats were bled to reduce mean arterial blood pressure to 35 (SD, 5) mmHg for 60 min and then were resuscitated with their withdrawn shed blood and normal saline. Crocetin was administered via the duodenum at a dose of 50 mg/kg 40 min after hemorrhage. The increase in creatinine and blood urea nitrogen was significantly reduced at 2 h after hemorrhage and resuscitation in crocetin-treated rats. The increases in renal nitric oxide, tumor necrosis factor α, and interleukin 6 were also attenuated by crocetin. Hemorrhagic shock resulted in a significant elevation in malondialdehyde production and was accompanied by a reduction in total superoxide dismutase activity, activation of nuclear factor κB, and overexpression of inducible nitric oxide synthase. These changes were significantly attenuated by crocetin at 2 h after resuscitation. These results suggested that crocetin blocks inflammatory cascades by inhibiting production of reactive oxygen species and restoring superoxide dismutase activity to ameliorate renal dysfunction caused by hemorrhage shock and resuscitation.

  5. Inhibition of GSK-3 induces differentiation and impaired glucose metabolism in renal cancer

    PubMed Central

    Pal, Krishnendu; Cao, Ying; Gaisina, Irina N.; Bhattacharya, Santanu; Dutta, Shamit K.; Wang, Enfeng; Gunosewoyo, Hendra; Kozikowski, Alan P.; Billadeau, Daniel D.; Mukhopadhyay, Debabrata

    2014-01-01

    Glycogen synthase kinase-3 (GSK-3), a constitutively active serine/threonine kinase, is a key regulator of numerous cellular processes ranging from glycogen metabolism to cell cycle regulation and proliferation. Consistent with its involvement in many pathways, it has also been implicated in the pathogenesis of various human diseases including Type II diabetes, Alzheimer's disease, bipolar disorder, inflammation and cancer. Consequently it is recognized as an attractive target for the development of new drugs. In the present study, we investigated the effect of both pharmacological and genetic inhibition of GSK-3 in two different renal cancer cell lines. We have shown potent anti-proliferative activity of 9-ING-41, a maleimide-based GSK-3 inhibitor. The anti-proliferative activity is most likely caused by G0–G1 and G2-M phase arrest as evident from cell cycle analysis. We have established that inhibition of GSK-3 imparted a differentiated phenotype in renal cancer cells. We have also shown that GSK-3 inhibition induced autophagy, likely as a result of imbalanced energy homeostasis caused by impaired glucose metabolism. Additionally, we have demonstrated the antitumor activity of 9-ING-41 in two different subcutaneous xenograft RCC tumor models. To our knowledge, this is the first report describing autophagy induction due to GSK-3 inhibition in renal cancer cells. PMID:24327518

  6. Amla as an antihyperglycemic and hepato-renal protective agent in fluoride induced toxicity

    PubMed Central

    Vasant, Rupal A.; Narasimhacharya, A. V. R. L.

    2012-01-01

    Purpose of the study was to examine the antihyperglycemic and hepato-renal protective effects of Emblica officinalis (Eo) fruit as a food supplement in fluoride induced toxicity. Eo fruit powder was incorporated into the diet (2.5, 5 and 10 gm %) of fluoride exposed animals for a duration of 30 days. Fluoride exposure caused significant elevation in plasma glucose, serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), acid phosphatase (ACP), alkaline phosphatase (ALP) activities, hepatic glucose-6-phosphatase (G-6-Pase) and decreased hepatic glycogen content, hexokinase activity and antioxidant profiles (hepatic and renal). An inclusion of Eo fruit powder significantly reduced plasma glucose levels, SGOT, SGPT, ACP and ALP activities, hepatic G-6-Pase activity and increased hepatic glycogen content and hexokinase activity. Hepatic and renal antioxidant status of fluoride exposed animals improved upon feeding Eo fruit powder. We, therefore, conclude that E. officinalis fruit could be useful in regulating hyperglycemia and enhances antioxidant status of fluoride exposed animals. PMID:22923969

  7. The feasibility of using microwave-induced thermoacoustic tomography for detection and evaluation of renal calculi

    NASA Astrophysics Data System (ADS)

    Cao, Caijun; Nie, Liming; Lou, Cunguang; Xing, Da

    2010-09-01

    Imaging of renal calculi is important for patients who suffered a urinary calculus prior to treatment. The available imaging techniques include plain x-ray, ultrasound scan, intravenous urogram, computed tomography, etc. However, the visualization of a uric acid calculus (radiolucent calculi) is difficult and often impossible by the above imaging methods. In this paper, a new detection method based on microwave-induced thermoacoustic tomography was developed to detect the renal calculi. Thermoacoustic images of calcium oxalate and uric acid calculus were compared with their x-ray images. The microwave absorption differences among the calcium oxalate calculus, uric acid calculus and normal kidney tissue could be evaluated by the amplitude of the thermoacoustic signals. The calculi hidden in the swine kidney were clearly imaged with excellent contrast and resolution in the three orthogonal thermoacoustic images. The results indicate that thermoacoustic imaging may be developed as a complementary method for detecting renal calculi, and its low cost and effective feature shows high potential for clinical applications.

  8. Ameliorating activity of ginger (Zingiber officinale) extract against lead induced renal toxicity in male rats.

    PubMed

    Reddy, Y Amarnath; Chalamaiah, M; Ramesh, B; Balaji, G; Indira, P

    2014-05-01

    Lead poisoning has been known to be associated with structural and functional abnormalities of multiple organ systems of human body. The aim of this investigation was to study the renal protective effects of ginger (Zingiber officinale) extract in lead induced toxicity rats. In this study renal glutathione (GSH) level, glutathione peroxidase (GPX), glutathione-s-transferase (GST), and catalase enzymes were measured in lead nitrate (300 mg/kg BW), and lead nitrate plus ginger extract (150 mg/kg BW) treated rat groups for 1 week and 3 weeks respectively. The glutathione level and GSH dependent antioxidant enzymes such as glutathione peroxidase, glutathione-s-transferase, and catalase significantly (P < 0.05) increased in ginger extract treated rat groups. In addition, histological studies showed lesser renal changes in lead plus ginger extract treated rat groups than that of lead alone treated rat groups. These results indicate that ginger extract alleviated lead toxic effects by enhancing the levels of glutathione, glutathione peroxidase, glutathione-s-transferase and catalase.

  9. Protective effects of Ficus racemosa stem bark against doxorubucin-induced renal and testicular toxicity

    PubMed Central

    Ahmed, Faiyaz; Urooj, Asna; Karim, Alias A.

    2013-01-01

    Background: Ficus racemosa Linn. (Moraceae) bark is a rich source of phenolic compounds known to possess potential antioxidant activity offering numerous health benefits. Materials and Methods: The present study evaluated the protective effects of sequential acetone extract of Ficus racemosa bark at two doses (FR250; 250 mg kg-1 and FR500; 500 mg kg-1 p.o.) against doxorubicin-induced renal and testicular toxicity in rats. Results: Doxorubicin administration resulted in significant decrease (P ≤ 0.05) in total protein and glutathione concentrations, while increased (P ≤ 0.05) serum urea, creatinine and thiobarbituric acid reactive substances (TBARS). Extract pretreatment restored biochemical parameters toward normalization. FR250 and FR500 decreased serum creatinine levels by 22.5% and 44%, while serum urea levels were decreased by 30.4% and 58.8%, respectively. Extract pretreatment (500 mg kg-1) decreased TBARS and increased glutathione levels in the kidney and testis to control levels. These observations were substantiated by histopathological studies, wherein normal renal and testicular architecture was restored in FR500 group. Conclusion: Doxorubicin exposure results in pronounced oxidative stress, and administration of F. racemosa stem bark extract offers significant renal and testicular protection by inhibiting lipidperoxidation-mediated through scavenging free radicals. PMID:23772108

  10. Potential immunotoxic effects of trichloroethylene-induced IV allergic reaction in renal impairment

    PubMed Central

    Yu, Jun-Feng; Feng, Yan-Yan

    2017-01-01

    Trichloroethylene (TCE) is known to induce allergic contact dermatitis and subsequent occupational medicamentosa-like dermatitis (OMLD) with multi-system injuries, including liver, kidney, and skin injuries. However, the mechanisms underlying immune system dysfunction that result in organ injury have not yet been clearly elucidated. In the present study, we measured the levels of secreted cytokines by effect or T cells in TCE-treated guinea pigs to better understand the contribution of allergic disorders in renal injuries. We immunized guinea pigs with trichloroethylene using the Guinea Pig Maximization Test (GPMT) and scored the inflammation on the guinea pigs’ skin. The kidney function and ultra-structural changes in the kidneys were detected using biochemical methods and electron microscopy. The deposition of cytokines was determined using immunohistochemistry. The sensitization rate was 63.16% in the TCE-sensitized groups. The electron microscopy results showed tubular epithelial cell mitochondrial swelling, vacuolar degeneration, and atrophy of the microvillus in the sensitized groups. A high degree of cytokine deposition was observed in the renal tubular proximal epithelial cells in the TCE-sensitized groups. As observed in this study, the variation in the level of immune system activation not only indicates that TCE can largely magnify the immune reaction but also suggests a potential role of immune dysfunction in renal impairment. PMID:28867961

  11. The feasibility of using microwave-induced thermoacoustic tomography for detection and evaluation of renal calculi.

    PubMed

    Cao, Caijun; Nie, Liming; Lou, Cunguang; Xing, Da

    2010-09-07

    Imaging of renal calculi is important for patients who suffered a urinary calculus prior to treatment. The available imaging techniques include plain x-ray, ultrasound scan, intravenous urogram, computed tomography, etc. However, the visualization of a uric acid calculus (radiolucent calculi) is difficult and often impossible by the above imaging methods. In this paper, a new detection method based on microwave-induced thermoacoustic tomography was developed to detect the renal calculi. Thermoacoustic images of calcium oxalate and uric acid calculus were compared with their x-ray images. The microwave absorption differences among the calcium oxalate calculus, uric acid calculus and normal kidney tissue could be evaluated by the amplitude of the thermoacoustic signals. The calculi hidden in the swine kidney were clearly imaged with excellent contrast and resolution in the three orthogonal thermoacoustic images. The results indicate that thermoacoustic imaging may be developed as a complementary method for detecting renal calculi, and its low cost and effective feature shows high potential for clinical applications.

  12. Ceramide-Induced Apoptosis in Renal Tubular Cells: A Role of Mitochondria and Sphingosine-1-Phoshate

    PubMed Central

    Ueda, Norishi

    2015-01-01

    Ceramide is synthesized upon stimuli, and induces apoptosis in renal tubular cells (RTCs). Sphingosine-1 phosphate (S1P) functions as a survival factor. Thus, the balance of ceramide/S1P determines ceramide-induced apoptosis. Mitochondria play a key role for ceramide-induced apoptosis by altered mitochondrial outer membrane permeability (MOMP). Ceramide enhances oligomerization of pro-apoptotic Bcl-2 family proteins, ceramide channel, and reduces anti-apoptotic Bcl-2 proteins in the MOM. This process alters MOMP, resulting in generation of reactive oxygen species (ROS), cytochrome C release into the cytosol, caspase activation, and apoptosis. Ceramide regulates apoptosis through mitogen-activated protein kinases (MAPKs)-dependent and -independent pathways. Conversely, MAPKs alter ceramide generation by regulating the enzymes involving ceramide metabolism, affecting ceramide-induced apoptosis. Crosstalk between Bcl-2 family proteins, ROS, and many signaling pathways regulates ceramide-induced apoptosis. Growth factors rescue ceramide-induced apoptosis by regulating the enzymes involving ceramide metabolism, S1P, and signaling pathways including MAPKs. This article reviews evidence supporting a role of ceramide for apoptosis and discusses a role of mitochondria, including MOMP, Bcl-2 family proteins, ROS, and signaling pathways, and crosstalk between these factors in the regulation of ceramide-induced apoptosis of RTCs. A balancing role between ceramide and S1P and the strategy for preventing ceramide-induced apoptosis by growth factors are also discussed. PMID:25751724

  13. Contribution of K(+) channels to endothelium-derived hypolarization-induced renal vasodilation in rats in vivo and in vitro.

    PubMed

    Rasmussen, Kasper Moller Boje; Braunstein, Thomas Hartig; Salomonsson, Max; Brasen, Jens Christian; Sorensen, Charlotte Mehlin

    2016-07-01

    We investigated the mechanisms behind the endothelial-derived hyperpolarization (EDH)-induced renal vasodilation in vivo and in vitro in rats. We assessed the role of Ca(2+)-activated K(+) channels and whether K(+) released from the endothelial cells activates inward rectifier K(+) (Kir) channels and/or the Na(+)/K(+)-ATPase. Also, involvement of renal myoendothelial gap junctions was evaluated in vitro. Isometric tension in rat renal interlobar arteries was measured using a wire myograph. Renal blood flow was measured in isoflurane anesthetized rats. The EDH response was defined as the ACh-induced vasodilation assessed after inhibition of nitric oxide synthase and cyclooxygenase using L-NAME and indomethacin, respectively. After inhibition of small conductance Ca(2+)-activated K(+) channels (SKCa) and intermediate conductance Ca(2+)-activated K(+) channels (IKCa) (by apamin and TRAM-34, respectively), the EDH response in vitro was strongly attenuated whereas the EDH response in vivo was not significantly reduced. Inhibition of Kir channels and Na(+)/K(+)-ATPases (by ouabain and Ba(2+), respectively) significantly attenuated renal vasorelaxation in vitro but did not affect the response in vivo. Inhibition of gap junctions in vitro using carbenoxolone or 18α-glycyrrhetinic acid significantly reduced the endothelial-derived hyperpolarization-induced vasorelaxation. We conclude that SKCa and IKCa channels are important for EDH-induced renal vasorelaxation in vitro. Activation of Kir channels and Na(+)/K(+)-ATPases plays a significant role in the renal vascular EDH response in vitro but not in vivo. The renal EDH response in vivo is complex and may consist of several overlapping mechanisms some of which remain obscure.

  14. Clopidogrel attenuates lithium-induced alterations in renal water and sodium channels/transporters in mice.

    PubMed

    Zhang, Yue; Peti-Peterdi, János; Heiney, Kristina M; Riquier-Brison, Anne; Carlson, Noel G; Müller, Christa E; Ecelbarger, Carolyn M; Kishore, Bellamkonda K

    2015-12-01

    Lithium (Li) administration causes deranged expression and function of renal aquaporins and sodium channels/transporters resulting in nephrogenic diabetes insipidus (NDI). Extracellular nucleotides (ATP/ADP/UTP), via P2 receptors, regulate these transport functions. We tested whether clopidogrel bisulfate (CLPD), an antagonist of ADP-activated P2Y(12) receptor, would affect Li-induced alterations in renal aquaporins and sodium channels/transporters. Adult mice were treated for 14 days with CLPD and/or Li and euthanized. Urine and kidneys were collected for analysis. When administered with Li, CLPD ameliorated polyuria, attenuated the rise in urine prostaglandin E2 (PGE2), and resulted in significantly higher urinary arginine vasopressin (AVP) and aldosterone levels as compared to Li treatment alone. However, urine sodium excretion remained elevated. Semi-quantitative immunoblotting revealed that CLPD alone increased renal aquaporin 2 (AQP2), Na-K-2Cl cotransporter (NKCC2), Na-Cl cotransporter (NCC), and the subunits of the epithelial Na channel (ENaC) in medulla by 25-130 %. When combined with Li, CLPD prevented downregulation of AQP2, Na-K-ATPase, and NKCC2 but was less effective against downregulation of cortical α- or γ-ENaC (70 kDa band). Thus, CLPD primarily attenuated Li-induced downregulation of proteins involved in water conservation (AVP-sensitive), with modest effects on aldosterone-sensitive proteins potentially explaining sustained natriuresis. Confocal immunofluorescence microscopy revealed strong labeling for P2Y(12)-R in proximal tubule brush border and blood vessels in the cortex and less intense labeling in medullary thick ascending limb and the collecting ducts. Therefore, there is the potential for CLPD to be directly acting at the tubule sites to mediate these effects. In conclusion, P2Y(12)-R may represent a novel therapeutic target for Li-induced NDI.

  15. Immunohistochemical detection of hypoxia-inducible factor-1alpha in human renal allograft biopsies.

    PubMed

    Rosenberger, Christian; Pratschke, Johann; Rudolph, Birgit; Heyman, Samuel N; Schindler, Ralf; Babel, Nina; Eckardt, Kai-Uwe; Frei, Ulrich; Rosen, Seymour; Reinke, Petra

    2007-01-01

    Although it generally is accepted that renal hypoxia may occur in various situations after renal transplantation, direct evidence for such hypoxia is lacking, and possible implications on graft pathophysiology remain obscure. Hypoxia-inducible factors (HIF) are regulated at the protein level by oxygen-dependent enzymes and, hence, allow for tissue hypoxia detection. With the use of high-amplification HIF-1alpha immunohistochemistry in renal biopsies, hypoxia is shown at specific time points after transplantation with clinicohistologic correlations. Immediately after engraftment, in primarily functioning grafts, abundant HIF-1alpha is present and correlates with cold ischemic time >15 h and/or graft age >50 yr (P < 0.04). In contrast, a low HIF-1alpha score correlates with primary nonfunction, likely reflecting loss of oxygen consumption for tubular transport. Protocol biopsies at 2 wk show widespread HIF-1alpha induction, irrespective of histology. Beyond 3 mo, both protocol biopsies and indicated biopsies are virtually void of HIF-1alpha, with the only exception being clinical/subclinical rejection. HIF-derived transcriptional adaptation to hypoxia may counterbalance, at least partly, the negative impact of cold preservation and warm reflow injury. Transient hypoxia at 2 wk may be induced by hyperfiltration, hypertrophy, calcineurin inhibitor-induced toxicity, or a combination of these. Lack of detectable HIF-1alpha at 3 mo and beyond suggests that at this time point, graft oxygen homeostasis occurs. The strong correlation between hypoxia and clinical/subclinical rejection in long-term grafts suggests that hypoxia is involved in such graft dysfunction, and HIF-1alpha immunohistochemistry could enhance the specific diagnosis of acute rejection.

  16. Medical ozone therapy reduces shock wave therapy-induced renal injury.

    PubMed

    Uğuz, Sami; Demirer, Zafer; Uysal, Bulent; Alp, Bilal Firat; Malkoc, Ercan; Guragac, Ali; Turker, Turker; Ateş, Ferhat; Karademir, Kenan; Ozcan, Ayhan; Yildirim, Ibrahim; Korkmaz, Ahmet; Guven, Ahmet

    2016-07-01

    Extracorporeal shock wave (ESW) lithotripsy is the preferred treatment modality for uncomplicated kidney stones. More recently free oxygen radical production following ESW application has been considered to be crucial in shock wave-induced renal damage. It has been shown that ozone therapy (OT) has ameliorative and preventive effects against various pathological conditions due to increased nitro-oxidative stress. In current study, we aimed to evaluate the efficacy of OT against ESW-induced renal injury. Twenty-four male Sprague-Dawley rats were divided into three groups: sham-operated, ESW, and ESW + OT groups. All groups except sham-operated group were subjected to ESW procedure. ESW + OT group received 1 mg/kg/day of oxygen/ozone mixture intraperitoneally at 2 h before ESW, and OT was continued once a day for consecutive three days. The animals were killed at the 4th day, and kidney tissue and blood samples were harvested for biochemical and histopathologic analysis. Serum ALT and AST levels, serum neopterin, tissue nitrite/nitrate levels, and tissue oxidative stress parameters were increased in the ESW group and almost came close to control values in the treatment group (p < 0.05, ESW vs. ESW + OT). Histopathological injury scores were significantly lower in treatment group than the ESW group (p < 0.05, ESW vs. ESW + OT). Immunohistochemical iNOS staining scores in ESW group were higher than those of sham-operated group (p < 0.05, ESW vs. sham-operated), iNOS staining scores in OT group were significantly lower than the ESW group (p < 0.05, ESW + OT vs. ESW). OT ameliorates nitro-oxidative stress and reduces the severity of pathological changes in the experimental ESW-induced renal injury of rat model.

  17. Renal protection in chronic kidney disease: hypoxia-inducible factor activation vs. angiotensin II blockade

    PubMed Central

    Deng, Aihua; Arndt, Mary Ann K.; Satriano, Joseph; Singh, Prabhleen; Rieg, Timo; Thomson, Scott; Tang, Tong

    2010-01-01

    The 5/6th nephrectomy or ablation/infarction (A/I) preparation has been used as a classic model of chronic kidney disease (CKD). We observed increased kidney oxygen consumption (QO2) and altered renal hemodynamics in the A/I kidney that were normalized after combined angiotensin II (ANG II) blockade. Studies suggest hypoxia inducible factor as a protective influence in A/I. We induced hypoxia-inducible factor (HIF) and HIF target proteins by two different methods, cobalt chloride (CoCl2) and dimethyloxalyglycine (DMOG), for the first week after creation of A/I and compared the metabolic and renal hemodynamic outcomes to combined ANG II blockade. We also examined the HIF target proteins expressed by using Western blots and real-time PCR. Treatment with DMOG, CoCl2, and ANG II blockade normalized kidney oxygen consumption factored by Na reabsorption and increased both renal blood flow and glomerular filtration rate. At 1 wk, CoCl2 and DMOG increased kidney expression of HIF by Western blot. In the untreated A/I kidney, VEGF, heme oxygenase-1, and GLUT1 were all modestly increased. Both ANG II blockade and CoCl2 therapy increased VEGF and GLUT1 but the cobalt markedly so. ANG II blockade decreased heme oxygenase-1 expression while CoCl2 increased it. By real-time PCR, erythropoietin and GLUT1 were only increased by CoCl2 therapy. Cell proliferation was modestly increased by ANG II blockade but markedly after cobalt therapy. Metabolic and hemodynamic abnormalities were corrected equally by ANG II blockade and HIF therapies. However, the molecular patterns differed significantly between ANG II blockade and cobalt therapy. HIF induction may prove to be protective in this model of CKD. PMID:20881034

  18. Carbon tetrachloride-induced hepatic and renal damages in rat: inhibitory effects of cacao polyphenol.

    PubMed

    Suzuki, Koichiro; Nakagawa, Kiyotaka; Yamamoto, Takayuki; Miyazawa, Taiki; Kimura, Fumiko; Kamei, Masanori; Miyazawa, Teruo

    2015-01-01

    Here, we investigated the protective effect of cacao polyphenol extract (CPE) on carbon tetrachloride (CCl4)-induced hepato-renal oxidative stress in rats. Rats were administered CPE for 7 days and then received intraperitoneal injection of CCl4. Two hours after injection, we found that CCl4 treatment significantly increased biochemical injury markers, lipid peroxides (phosphatidylcholine hydroperoxide (PCOOH) and malondialdehyde (MDA)) and decreased glutathione peroxidase activity in kidney rather than liver, suggesting that kidney is more vulnerable to oxidative stress under the present experimental conditions. CPE supplementation significantly reduced these changes, indicating that this compound has antioxidant properties against CCl4-induced oxidative stress. An inhibitory effect of CPE on CCl4-induced CYP2E1 mRNA degradation may provide an explanation for CPE antioxidant property. Together, these results provide quantitative evidence of the in vivo antioxidant properties of CPE, especially in terms of PCOOH and MDA levels in the kidneys of CCl4-treated rats.

  19. Treatment of hypertension and renal injury induced by the angiogenesis inhibitor sunitinib: preclinical study.

    PubMed

    Lankhorst, Stephanie; Kappers, Mariëtte H W; van Esch, Joep H M; Smedts, Frank M M; Sleijfer, Stefan; Mathijssen, Ron H J; Baelde, Hans J; Danser, A H Jan; van den Meiracker, Anton H

    2014-12-01

    Common adverse effects of angiogenesis inhibition are hypertension and renal injury. To determine the most optimal way to prevent these adverse effects and to explore their interdependency, the following drugs were investigated in unrestrained Wistar Kyoto rats exposed to the angiogenesis inhibitor sunitinib: the dual endothelin receptor antagonist macitentan; the calcium channel blocker amlodipine; the angiotensin-converting enzyme inhibitor captopril; and the phosphodiesterase type 5 inhibitor sildenafil. Mean arterial pressure was monitored telemetrically. After 8 days, rats were euthanized and blood samples and kidneys were collected. In addition, 24-hour urine samples were collected. After sunitinib start, mean arterial pressure increased rapidly by ≈30 mm Hg. Coadministration of macitentan or amlodipine largely prevented this rise, whereas captopril or sildenafil did not. Macitentan, captopril, and sildenafil diminished the sunitinib-induced proteinuria and endothelinuria and glomerular intraepithelial protein deposition, whereas amlodipine did not. Changes in proteinuria and endothelinuria were unrelated. We conclude that in our experimental model, dual endothelin receptor antagonism and calcium channel blockade are suitable to prevent angiogenesis inhibition-induced hypertension, whereas dual endothelin receptor antagonism, angiotensin-converting enzyme inhibitor, and phosphodiesterase type 5 inhibition can prevent angiogenesis inhibition-induced proteinuria. Moreover, the variable response of hypertension and renal injury to different antihypertensive agents suggests that these side effects are, at least in part, unrelated.

  20. Carnosic acid attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity.

    PubMed

    Sahu, Bidya Dhar; Rentam, Kiran Kumar Reddy; Putcha, Uday Kumar; Kuncha, Madhusudana; Vegi, Ganga Modi Naidu; Sistla, Ramakrishna

    2011-12-01

    Nephrotoxicity is one of the serious dose limiting side effects of cisplatin when used in the treatment of various malignant conditions. Accumulating evidence suggests that oxidative stress caused by free radicals and apoptosis of renal cells contributes to the pathogenesis of cisplatin-induced nephrotoxicity. Present study was aimed to explore the effect of carnosic acid, a potent antioxidant, against cisplatin induced oxidative stress and nephrotoxicity in rats. A single dose of cisplatin (7.5mg/kg) caused marked renal damage, characterized by a significant (P<0.05) increase in serum creatinine, blood urea nitrogen (BUN) and relative weight of kidney with higher kidney MDA (malondialdehyde), tROS (total reactive oxygen species), caspase 3, GSH (reduced glutathione) levels and lowered tissue nitrite, SOD (superoxide dismutase), CAT (catalase), GSH-Px (glutathione peroxidase), GR (glutathione reductase) and GST (glutathione S-transferase) levels compared to normal control. Carnosic acid treatment significantly (P<0.05) attenuated the increase in lipid peroxidation, caspase-3 and ROS generation and enhanced the levels of reduced glutathione, tissue nitrite level and activities of SOD, CAT, GSH-Px, GR and GST compared to cisplatin control. The present study demonstrates that carnosic acid has a protective effect on cisplatin induced experimental nephrotoxicity and is attributed to its potent antioxidant and antiapoptotic properties. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. 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

  2. Febuxostat ameliorates diabetic renal injury in a streptozotocin-induced diabetic rat model.

    PubMed

    Lee, Hong-Joo; Jeong, Kyung Hwan; Kim, Yang Gyun; Moon, Joo Young; Lee, Sang Ho; Ihm, Chun Gyoo; Sung, Ji Youn; Lee, Tae Won

    2014-01-01

    Oxidative stress and inflammation are known to play central roles in the development of diabetic nephropathy (DN). Febuxostat is a novel non-purine xanthine oxidase (XO)-specific inhibitor developed to treat hyperuricemia. In this study, we investigated whether febuxostat could ameliorate DN via renoprotective mechanisms such as alleviation of oxidative stress and anti-inflammatory actions. Male Sprague-Dawley rats were divided into three groups: a normal group, a diabetes group (DM group), and a febuxostat-treated diabetes group (DM+Fx group). We administered 5 mg/kg of febuxostat to experimental rats for 7 weeks and evaluated clinical and biochemical parameters and XO and xanthine dehydrogenase (XDH) activity in hepatic tissue. The degree of oxidative stress and extent of inflammation were evaluated from urine samples and renal tissue collected from each group. Diabetic rats (DM and DM+Fx groups) had higher blood glucose and kidney weight relative to body weight than normal rats. Albuminuria was significantly reduced in febuxostat-treated diabetic rats compared with untreated diabetic rats. Quantitative analysis showed that hepatic XO and XDH activities were higher in the DM groups, but decreased after treatment with febuxostat. Urinary 8-OHdG concentrations and renal cortical nitrotyrosine also indicated reduced oxidative stress in the DM+Fx group relative to the DM group. The number of ED-1-stained cells in the glomerulus and tubule of diabetic renal tissue decreased in febuxostat-treated diabetic rats relative to that of non-treated diabetic rats. Diabetic rats also expressed higher transcript levels of inflammatory genes (E-selectin and VCAM-1), an inflammation-induced enzyme (COX-2), and inflammatory mediators (ED-1 and NF-κB) than control rats; expression of these genes was significantly reduced by treatment with febuxostat. Febuxostat prevents diabetic renal injury such as albuminuria. This renoprotective effect appears to be due to attenuation of the

  3. Potential Biomarkers for Radiation-Induced Renal Toxicity following 177Lu-Octreotate Administration in Mice

    PubMed Central

    Schüler, Emil; Larsson, Maria; Parris, Toshima Z.; Johansson, Martin E.; Helou, Khalil; Forssell-Aronsson, Eva

    2015-01-01

    The kidneys are one of the main dose-limiting organs in peptide receptor radionuclide therapy and due to large inter-individual variations in renal toxicity, biomarkers are urgently needed in order to optimize therapy and reduce renal tissue damage. The aim of this study was to investigate the transcriptional, functional, and morphological effects on renal tissue after 177Lu-octreotate administration in normal mice, and to identify biomarkers for radiation induced renal toxicity. Methods C57BL/6N mice were i.v. injected with 0, 30, 60, 90, 120, or 150 MBq 177Lu-octreotate (0, 16, 29, 40, 48, and 54 Gy to the kidneys). At 4, 8, and 12 months after administration, radiation-induced effects were evaluated in relation to (a) global transcriptional variations in kidney tissues, (b) morphological changes in the kidneys, (c) changes in white and red blood cell count as well as blood levels of urea, and (d) changes in renal function using 99mTc-DTPA/99mTc-DMSA scintigraphy. Results In general, the highest number of differentially regulated transcripts was observed at 12 months after administration. The Cdkn1a, C3, Dbp, Lcn2, and Per2 genes displayed a distinct dose-dependent regulation, with increased expression level with increasing absorbed dose. Ifng, Tnf, and Il1B were identified as primary up-stream regulators of the recurrently regulated transcripts. Furthermore, previously proposed biomarkers for kidney injury and radiation damage were also observed. The functional investigation revealed reduced excretion of 99mTc-DTPA after 150 MBq, an increased uptake of 99mTc-DMSA at all dose levels compared with the controls, and markedly increased urea level in blood after 150 MBq at 12 months. Conclusion Distinct dose-response relationships were found for several of the regulated transcripts. The Cdkn1a, Dbp, Lcn2, and Per2 genes are proposed as biomarkers for 177Lu-octreotate exposure of kidney. Correlations to functional and morphological effects further confirm

  4. Diquat induces renal proximal tubule injury in glutathione reductase-deficient mice.

    PubMed

    Rogers, Lynette K; Bates, Carlton M; Welty, Stephen E; Smith, Charles V

    2006-12-15

    Reactive oxygen species (ROS) have been associated with many human diseases, and glutathione (GSH)-dependent processes are pivotal in limiting tissue damage. To test the hypothesis that Gr1(a1Neu) (Neu) mice, which do not express glutathione reductase (GR), would be more susceptible than are wild-type mice to ROS-mediated injury, we studied the effects of diquat, a redox cycling toxicant. Neu mice exhibited modest, dose- and time-dependent elevations in plasma alanine aminotransferase (ALT) activities, 126+/-36 U/l at 2 h after 5 micromol/kg of diquat, but no ALT elevations were observed in diquat-treated C3H/HeN mice for up to 6 h after 50 micromol/kg of diquat. Histology indicated little or no hepatic necrosis in diquat-treated mice of either strain, but substantial renal injury was observed in diquat-treated Neu mice, characterized by brush border sloughing in the proximal tubules by 1 h and tubular necrosis by 2 h after doses of 7.5 micromol/kg. Decreases in renal GSH levels were observed in the Neu mice by 2 h post dose (3.4+/-0.4 vs 0.2+/-0.0 micromol/g tissue at 0 and 50 micromol/kg, respectively), and increases in renal GSSG levels were observed in the Neu mice as early as 0.5 h after 7.5 micromol/kg (105.5+/-44.1 vs 27.9+/-4.8 nmol/g tissue). Blood urea nitrogen levels were elevated by 2 h in Neu mice after doses of 7.5 micromol/kg (Neu vs C3H, 32.8+/-4.1 vs 17.9+/-0.3 mg/dl). Diquat-induced renal injury in the GR-deficient Neu mice offers a useful model for studies of ROS-induced renal necrosis and of the contributions of GR in defense against oxidant-mediated injuries in vivo.

  5. Diquat induces renal proximal tubule injury in glutathione reductase-deficient mice

    SciTech Connect

    Rogers, Lynette K. . E-mail: rogersl@ccri.net; Bates, Carlton M.; Welty, Stephen E.; Smith, Charles V.

    2006-12-15

    Reactive oxygen species (ROS) have been associated with many human diseases, and glutathione (GSH)-dependent processes are pivotal in limiting tissue damage. To test the hypothesis that Gr1{sup a1Neu} (Neu) mice, which do not express glutathione reductase (GR), would be more susceptible than are wild-type mice to ROS-mediated injury, we studied the effects of diquat, a redox cycling toxicant. Neu mice exhibited modest, dose- and time-dependent elevations in plasma alanine aminotransferase (ALT) activities, 126 {+-} 36 U/l at 2 h after 5 {mu}mol/kg of diquat, but no ALT elevations were observed in diquat-treated C3H/HeN mice for up to 6 h after 50 {mu}mol/kg of diquat. Histology indicated little or no hepatic necrosis in diquat-treated mice of either strain, but substantial renal injury was observed in diquat-treated Neu mice, characterized by brush border sloughing in the proximal tubules by 1 h and tubular necrosis by 2 h after doses of 7.5 {mu}mol/kg. Decreases in renal GSH levels were observed in the Neu mice by 2 h post dose (3.4 {+-} 0.4 vs 0.2 {+-} 0.0 {mu}mol/g tissue at 0 and 50 {mu}mol/kg, respectively), and increases in renal GSSG levels were observed in the Neu mice as early as 0.5 h after 7.5 {mu}mol/kg (105.5 {+-} 44.1 vs 27.9 {+-} 4.8 nmol/g tissue). Blood urea nitrogen levels were elevated by 2 h in Neu mice after doses of 7.5 {mu}mol/kg (Neu vs C3H, 32.8 {+-} 4.1 vs 17.9 {+-} 0.3 mg/dl). Diquat-induced renal injury in the GR-deficient Neu mice offers a useful model for studies of ROS-induced renal necrosis and of the contributions of GR in defense against oxidant-mediated injuries in vivo.

  6. Laser-induced thermotherapy of renal cell carcinoma in man: dosimetry, ultrasound, and histopathologic correlation

    NASA Astrophysics Data System (ADS)

    Williams, J. C.; Swischuk, Peter N.; Morrison, Patricia M.; Chiao, Joseph

    2000-05-01

    Laser-induced thermoterapy (LITT), is the interstitial application of laser energy to achieve tissue coagulation by a thermal process. This is achieved by implanting the laser delivery fiber directly into the target tissue and firing the laser. LITT is being investigated and evaluated clinically as a treatment for renal tumors. The objective of this study was to determine if ultrasound could be used as a real-time monitoring modality of LITT during the coagulation process. Ultrasound characterization was correlated with histopathologic changes and dosimetry. In addition, temperature was monitored and correlated as well.

  7. Antioxidant properties of repaglinide and its protections against cyclosporine A-induced renal tubular injury

    PubMed Central

    Li, Dao; Li, Jin; Li, Hui; Wu, Qiong; Li, Qi-Xiong

    2016-01-01

    Objective(s): Repaglinide (RG) is an antihyperglycemic agent used for the treatment of non-insulin-dependent diabetes mellitus. It has a good safety and efficacy profile in diabetic patients with complications in renal impairment and is an appropriate treatment choice, even for individuals with more severe degrees of renal malfunctions. The aim of the present study was to examine the protective effect of RG on cyclosporine A (CsA)-induced rat renal impairment and to evaluate the antioxidant mechanisms by which RG exerts its protective actions. Materials and Methods: Fifty male Sprague-Dawley rats weighing 250–300 g were randomly divided into five groups: administrations of olive oil (control, PO), RG (0.4 mg/kg, PO), CsA (30 mg/kg in olive oil, SC), RG (0.2 or 0.4 mg/kg, PO) plus CsA (30 mg/kg in olive oil SC) every day for 15 days. Results: SC administration of CsA (30 mg/kg) to rats produced marked elevations in the levels of renal impairment parameters such as urinary protein, N-acetyl-beta-D-glucosaminidase (NAG), serum creatinine (SCr), and blood urea nitrogen (BUN). It also caused histologic injury to the kidneys. Oral administration of RG (0.2 and 0.4 mg/kg) markedly decreased all the aforementioned changes. In addition, CsA caused increases in the levels of malondialdehyde (MDA) and decreases in superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GSR), glutathione-S-transferase (GST), and glutathione in kidney homogenate, which were reversed significantly by both doses of RG. Conclusion: The findings of our study indicate that RG may play an important role in protecting the kidney from oxidative insult. PMID:27635199

  8. Lithium-induced renal insufficiency: a longitudinal study of creatinine increases in intellectually disabled adults.

    PubMed

    Janowsky, David S; Buneviciute, Juste; Hu, Qiaoyan; Davis, John M

    2011-12-01

    Lithium has been shown to increase serum creatinine levels in a subgroup of patients. However, lithium-induced increases in serum creatinine have not been well studied with regard to timing, trajectory, or predictability. The medical records of 16 intellectually disabled individuals treated with lithium between 1980 and 2010 in whom serum creatinine levels peaked at 1.5 mg/100 mL or higher (ie, who developed renal insufficiency) were reviewed. These individuals were compared with a group of 36 similar lithium-treated individuals in whom serum creatinine did not reach 1.5 mg/100 mL. The 16 lithium-treated individuals who developed renal insufficiency had a mean peak serum creatinine level of 1.8 ± 0.3 mg/100 mL while on lithium. The mean time from institution of lithium until the 1.5 mg/100 mL serum creatinine level was first reached was 7.9 years. After lithium was discontinued, overall mean serum creatinine levels did not significantly change. Reaching a serum creatinine level of 1.3 or 1.4 mg/100 mL predicted reaching a 1.5 mg/100 mL level or higher. No significant differences in the age lithium was started, baseline serum creatinine levels, years receiving lithium, sex, or race differentiated those who developed renal insufficiency. Prescribing lithium led to elevated serum creatinine levels in some individuals. A serum creatinine level of 1.3 and/or 1.4 mg/100 mL predicted renal insufficiency. Clinical implications of this study are that if 1 serum creatinine result reaches 1.3 mg/100 mL or more, intensive monitoring for further increases is indicated.

  9. Shock wave induces biological renal damage by activating excessive inflammatory responses in rat model.

    PubMed

    Li, Xiang; Long, Qingzhi; Cheng, Xinfa; He, Dalin

    2014-08-01

    The study was aimed to investigate the potential mechanism of inflammatory renal damage induced by shock wave. A total of 48 rats, with the right kidney cut, are randomly assigned into control group, ESWL group and ESWL + PDTC group. Rats were treated with shock wave at the left kidney. At post-shock wave 3 and 105 days, all the animals were sacrificed for detecting the expression of tumor necrosis factor (TNF)-α, intercellular adhesion molecule (ICAM)-1, and monocyte chemoattractant protein (MCP)-1. The inflammatory responses were evaluated by detecting the level of myeloperoxidase (MPO) and ED-1. The histological renal injury was also examined. Before the animals were sacrificed, the urine samples were collected for measuring the values of malondialdehyde (MDA), β2-microglobulin, interleukin (IL)-6, and IL-18. At post-shock wave 3 days, the higher expression of ICAM-1 and TNF-α were observed in shock wave-treated kidneys. The level of urine TNF-α, IL-6, and IL-18 were also increased significantly. Using PDTC obviously decreased the expression of ICAM-1 and TNF-α. It also effectively inhibited the degree of oxidative stress and neutrophil infiltration. At post-shock wave 105 days, the expression of MCP-1 and the level of urine β2-microglobulin and IL-18 were increased significantly. The histological analysis also indicated more ED-1-positive cells and serious fibrosis in shock wave-treated kidneys. PDTC significantly suppressed MCP-1 and IL-18 expression, decreased monocyte infiltration, and alleviate the degree of interstitium fibrosis. Shock wave triggered excessive inflammatory responses and aggravated renal biological damage. Several inflammatory factors including ICAM-1, MCP-1, and TNF-α were considered to play important role in this type of renal damage.

  10. High-Fat Diet Increased Renal and Hepatic Oxidative Stress Induced by Vanadium of Wistar Rat.

    PubMed

    Wang, J P; Cui, R Y; Zhang, K Y; Ding, X M; Luo, Y H; Bai, S P; Zeng, Q F; Xuan, Y; Su, Z W

    2016-04-01

    The study was conducted to assess the effect of vanadium (V) in high-fat diet on the liver and kidney of rats in a 5-week trial. Seventy-two female Wistar rats (BW = 95 ± 5 g) were randomly allotted into eight groups. Groups I, II, III, and IV obtained low-fat diet containing 0, 3, 15, and 30 mg/kg V, and V, VI, VII, and VIII groups received the respective vanadium doses with high-fat diet, respectively. There were lesions in the liver and kidney of V, VI, VII, and VIII groups, granular degeneration and vacuolar degeneration were observed in the renal tubular and glomerulus epithelial cells, and hepatocytes showed granular degeneration and vacuolar degeneration. Supplemented high-fat diet with vanadium was shown to decrease (P < 0.05) activities of superoxide dismutase, total antioxidant capacity, glutathione-S transferase, and NAD(P)H/quinone oxidoreductase 1 (NQO1) and increase malondialdehyde content in the liver and kidney. The relative expression of hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) and NQO1 mRNA was downregulated by V addition and high-fat diet, and the effect of V was more pronounced in high-fat diet (interaction, P < 0.05), with VIII group having the lowest mRNA expression of Nrf-2 and NQO1 in the liver and kidney. In conclusion, it suggested that dietary vanadium ranging from 15 to 30 mg/kg could lead to oxidative damage and vanadium accumulation in the liver and kidney, which caused renal and hepatic toxicity. The high-fat diet enhanced vanadium-induced hepatic and renal damage, and the mechanism was related to the modulation of the hepatic and renal mRNA expression of Nrf-2 and NQO1.

  11. A signature of renal stress resistance induced by short-term dietary restriction, fasting, and protein restriction.

    PubMed

    Jongbloed, F; Saat, T C; Verweij, M; Payan-Gomez, C; Hoeijmakers, J H J; van den Engel, S; van Oostrom, C T; Ambagtsheer, G; Imholz, S; Pennings, J L A; van Steeg, H; IJzermans, J N M; Dollé, M E T; de Bruin, R W F

    2017-01-19

    During kidney transplantation, ischemia-reperfusion injury (IRI) induces oxidative stress. Short-term preoperative 30% dietary restriction (DR) and 3-day fasting protect against renal IRI. We investigated the contribution of macronutrients to this protection on both phenotypical and transcriptional levels. Male C57BL/6 mice were fed control food ad libitum, underwent two weeks of 30%DR, 3-day fasting, or received a protein-, carbohydrate- or fat-free diet for various periods of time. After completion of each diet, renal gene expression was investigated using microarrays. After induction of renal IRI by clamping the renal pedicles, animals were monitored seven days postoperatively for signs of IRI. In addition to 3-day fasting and two weeks 30%DR, three days of a protein-free diet protected against renal IRI as well, whereas the other diets did not. Gene expression patterns significantly overlapped between all diets except the fat-free diet. Detailed meta-analysis showed involvement of nuclear receptor signaling via transcription factors, including FOXO3, HNF4A and HMGA1. In conclusion, three days of a protein-free diet is sufficient to induce protection against renal IRI similar to 3-day fasting and two weeks of 30%DR. The elucidated network of common protective pathways and transcription factors further improves our mechanistic insight into the increased stress resistance induced by short-term DR.

  12. A signature of renal stress resistance induced by short-term dietary restriction, fasting, and protein restriction

    PubMed Central

    Jongbloed, F.; Saat, T. C.; Verweij, M.; Payan-Gomez, C.; Hoeijmakers, J. H. J.; van den Engel, S.; van Oostrom, C. T.; Ambagtsheer, G.; Imholz, S.; Pennings, J. L. A.; van Steeg, H.; IJzermans, J. N. M.; Dollé, M. E. T.; de Bruin, R. W. F.

    2017-01-01

    During kidney transplantation, ischemia-reperfusion injury (IRI) induces oxidative stress. Short-term preoperative 30% dietary restriction (DR) and 3-day fasting protect against renal IRI. We investigated the contribution of macronutrients to this protection on both phenotypical and transcriptional levels. Male C57BL/6 mice were fed control food ad libitum, underwent two weeks of 30%DR, 3-day fasting, or received a protein-, carbohydrate- or fat-free diet for various periods of time. After completion of each diet, renal gene expression was investigated using microarrays. After induction of renal IRI by clamping the renal pedicles, animals were monitored seven days postoperatively for signs of IRI. In addition to 3-day fasting and two weeks 30%DR, three days of a protein-free diet protected against renal IRI as well, whereas the other diets did not. Gene expression patterns significantly overlapped between all diets except the fat-free diet. Detailed meta-analysis showed involvement of nuclear receptor signaling via transcription factors, including FOXO3, HNF4A and HMGA1. In conclusion, three days of a protein-free diet is sufficient to induce protection against renal IRI similar to 3-day fasting and two weeks of 30%DR. The elucidated network of common protective pathways and transcription factors further improves our mechanistic insight into the increased stress resistance induced by short-term DR. PMID:28102354

  13. Naproxen-induced Ca2+ movement and death in MDCK canine renal tubular cells.

    PubMed

    Cheng, H-H; Chou, C-T; Sun, T-K; Liang, W-Z; Cheng, J-S; Chang, H-T; Tseng, H-W; Kuo, C-C; Chen, F-A; Kuo, D-H; Shieh, P; Jan, C-R

    2015-11-01

    Naproxen is an anti-inflammatory drug that affects cellular calcium ion (Ca(2+)) homeostasis and viability in different cells. This study explored the effect of naproxen on [Ca(2+)](i) and viability in Madin-Darby canine kidney cells (MDCK) canine renal tubular cells. At concentrations between 50 μM and 300 μM, naproxen induced [Ca(2+)](i) rises in a concentration-dependent manner. This Ca(2+) signal was reduced partly when extracellular Ca(2+) was removed. The Ca(2+) signal was inhibited by a Ca(2+) channel blocker nifedipine but not by store-operated Ca(2+) channel inhibitors (econazole and SKF96365), a protein kinase C (PKC) activator phorbol 12-myristate 13-acetate, and a PKC inhibitor GF109203X. In Ca(2+)-free medium, pretreatment with 2,5-di-tert-butylhydroquinone or thapsigargin, an inhibitor of endoplasmic reticulum Ca(2+) pumps, partly inhibited naproxen-induced Ca(2+) signal. Inhibition of phospholipase C with U73122 did not alter naproxen-evoked [Ca(2+)](i) rises. At concentrations between 15 μM and 30 μM, naproxen killed cells in a concentration-dependent manner, which was not reversed by prechelating cytosolic Ca(2+) with the acetoxymethyl ester of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl. Annexin V/propidium iodide staining data suggest that naproxen induced apoptosis. Together, in MDCK renal tubular cells, naproxen induced [Ca(2+)](i) rises by inducing Ca(2+) release from multiple stores that included the endoplasmic reticulum and Ca(2+) entry via nifedipine-sensitive Ca(2+) channels. Naproxen induced cell death that involved apoptosis. © The Author(s) 2015.

  14. Diuretic-induced renal impairment without volume depletion in cirrhosis: changes in the renin-angiotensin system and the effect of β-adrenergic blockade

    PubMed Central

    Wilkinson, S. P.; Bernardi, M.; Wheeler, P. G.; Smith, I. K.; Williams, R.

    1979-01-01

    In 4 patients with cirrhosis and ascites, diuretic therapy resulted in an impairment of renal function that was associated with a rise in plasma renin activity (PRA). In 3, this occurred in the absence of volume depletion. When diuretics were discontinued, renal function returned to normal. β-adrenergic blocking drugs were then given to suppress renin secretion and diurectics restarted. On this occasion, impairment of renal function did not occur. In 2 further patients, administration of β-adrenergic blockers during a period of diuretic-induced renal impairment resulted in an improvement in renal function. Although these findings may indicate that diuretic-induced renal impairment in cirrhosis is at least partly due to activation of the renin-angiotensin system, in another group of patients a diuretic-induced rise in PRA was not associated with a deterioration in renal function. PMID:44911

  15. 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.

  16. Ets-1 targeted by microrna-221 regulates angiotensin II-induced renal fibroblast activation and fibrosis.

    PubMed

    Di, Jia; Jiang, Lei; Zhou, Yang; Cao, Hongdi; Fang, Li; Wen, Ping; Li, Xiurong; Dai, Chunsun; Yang, Junwei

    2014-01-01

    Fibroblast activation is one of the most important mechanisms for Angiotensin II (Ang II) in promoting renal fibrosis. Transcription factor Ets-1 is recognized to play a key role in kidney diseases. However, the role and mechanisms of Ets-1 in Ang-II induced fibroblast activation and kidney fibrosis are not fully understood. Mice were treated with Ang II via osmotic mini-pumps or Ang II expression plasmid (pAng II). Cultured normal rat kidney interstitial fibroblast (NRK-49F) cells were incubated with Ang II. Role of Ets-1 in renal fibrosis and fibroblast activation were assessed by Western blot, Immunohistochemical staining'MTT, Boyden chamber and Immunofluorescence staining. Effects of miR-221 on Ets-1 and fibroblast activation were investigated by MTT, Boyden chamber, Western blot and Q-PCR. We found that Ets-1 was up-regulated in fibrotic kidneys. Similarly, Ang II could activate NRK-49F cells as demonstrated by up-regulated α-SMA and fibronectin(FN) expression and enhanced cell proliferation and migration. Ang II also induced Ets-1 expression in NRK-49F cells in a dose and time dependent manner. Knock-down of Ets-1 by RNA interference attenuated Ang II-induced activation of NRK-49F cells. Ets-1 was previously reported as a target of microRNA-221 (miR-221). In Ang II-induced fibrotic kidney, miR-221 was down-regulated. Similar results were observed in Ang II treated NRK-49F cells. Ectopic expression of miR-221 mimic attenuated the up-regulation of Ets-1 by Ang II in NRK-49F cells, which further prevented the activation of NRK-49F cells. However, the inhibitor of miR-221 aggravated Ang II induced Ets-1 expression and NRK-49F cells activation. Our study suggests that miR-221/Ets-1 axis takes an important role in mediating AngII induced interstitial fibroblast activation and renal fibrosis. © 2014 S. Karger AG, Basel.

  17. Dietary nitrite ameliorates renal injury in L-NAME-induced hypertensive rats.

    PubMed

    Tsuchiya, Koichiro; Tomita, Shuhei; Ishizawa, Keisuke; Abe, Shinji; Ikeda, Yasumasa; Kihira, Yoshitaka; Tamaki, Toshiaki

    2010-02-15

    Nitric oxide (NO) has numerous important functions in the kidney, and long-term blockage of nitric oxide synthases in rats by L-NAME results in severe hypertension and progressive kidney damage. On the other hand, NO production seems to be low in patients with chronic kidney disease (CKD), and NO deficiency may play a role in CKD progression. In this review, we summarized the mechanisms of amelioration of renal injury induced by L-NAME treated rats by treatment of nitrite. First, we demonstrate whether orally-administrated nitrite-derived NO can shift to the circulation. When 3mg/kg body weight Na(15)NO(2) was orally administered to rats, an apparent EPR signal derived from Hb(15)NO (A(z)=23.4 gauss) appeared in the blood, indicating that orally ingested nitrite can be a source of NO in vivo. Next, in order to clarify the capacity of nitrite to prevent renal disease, we administered low-dose nitrite (LDN: 0.1mg of sodium nitrite in 1L of drinking water), medium-dose nitrite (MDN: 1mg sodium nitrite/L, which corresponds to the amount of nitrite ingested by vegetarians), or high-dose nitrite (HDN: 10mg sodium nitrite/L) to rats simultaneously with L-NAME (1 g l-NAME/L) for 8 weeks, then examined the blood NO level as a hemoglobin-NO adduct (iron-nitrosyl-hemoglobin) using electron paramagnetic resonance spectroscopy, urinary protein excretion, and renal histological changes at the end of the experiment. It was found that oral administration of MDN and HDN but not LDN increased the blood iron-nitrosyl-hemoglobin concentration to the normal level, ameliorated the L-NAME-induced proteinuria, and reduced renal histological damage. The findings demonstrate that chronic administration of a mid-level dietary dose of nitrite restores the circulating iron-nitrosyl-hemoglobin levels reduced by L-NAME and that maintenance of the circulating iron-nitrosyl-hemoglobin level in a controlled range protects against L-NAME-induced renal injury. Taking these findings together, we

  18. Selective Rac1 inhibition protects renal tubular epithelial cells from oxalate-induced NADPH oxidase-mediated oxidative cell injury

    PubMed Central

    Thamilselvan, Vijayalakshmi; Menon, Mani

    2013-01-01

    Oxalate-induced oxidative cell injury is one of the major mechanisms implicated in calcium oxalate nucleation, aggregation and growth of kidney stones. We previously demonstrated that oxalate-induced NADPH oxidase-derived free radicals play a significant role in renal injury. Since NADPH oxidase activation requires several regulatory proteins, the primary goal of this study was to characterize the role of Rac GTPase in oxalate-induced NADPH oxidase-mediated oxidative injury in renal epithelial cells. Our results show that oxalate significantly increased membrane translocation of Rac1 and NADPH oxidase activity of renal epithelial cells in a time-dependent manner. We found that NSC23766, a selective inhibitor of Rac1, blocked oxalate-induced membrane translocation of Rac1 and NADPH oxidase activity. In the absence of Rac1 inhibitor, oxalate exposure significantly increased hydrogen peroxide formation and LDH release in renal epithelial cells. In contrast, Rac1 inhibitor pretreatment, significantly decreased oxalate-induced hydrogen peroxide production and LDH release. Furthermore, PKC α and δ inhibitor, oxalate exposure did not increase Rac1 protein translocation, suggesting that PKC resides upstream from Rac1 in the pathway that regulates NADPH oxidase. In conclusion, our data demonstrate for the first time that Rac1-dependent activation of NADPH oxidase might be a crucial mechanism responsible for oxalate-induced oxidative renal cell injury. These findings suggest that Rac1 signaling plays a key role in oxalate-induced renal injury, and may serve as a potential therapeutic target to prevent calcium oxalate crystal deposition in stone formers and reduce recurrence. PMID:21814770

  19. Ochratoxin A induces rat renal carcinogenicity with limited induction of oxidative stress responses.

    PubMed

    Qi, Xiaozhe; Yu, Tao; Zhu, Liye; Gao, Jing; He, Xiaoyun; Huang, Kunlun; Luo, Yunbo; Xu, Wentao

    2014-11-01

    Ochratoxin A (OTA) has displayed nephrotoxicity and renal carcinogenicity in mammals, however, no clear mechanisms have been identified detailing the relationship between oxidative stress and these toxicities. This study was performed to clarify the relationship between oxidative stress and the renal carcinogenicity induced by OTA. Rats were treated with 70 or 210 μg/kg b.w. OTA for 4 or 13 weeks. In the rats administrated with OTA for 13 weeks, the kidney was damaged seriously. Cytoplasmic vacuolization was observed in the outer stripe of the outer medulla. Karyomegaly was prominent in the tubular epithelium. Kidney injury molecule-1 (Kim-1) was detected in the outer stripe of the outer medulla in both low- and high-dose groups. OTA increased the mRNA levels of clusterin in rat kidneys. Interestingly, OTA did not significantly alter the oxidative stress level in rat liver and kidney. Yet, some indications related to proliferation and carcinogenicity were observed. A dose-related increase in proliferating cell nuclear antigen (PCNA) was observed at 4 weeks in both liver and kidney, but at 13 weeks, only in the kidney. OTA down-regulated reactive oxygen species (ROS) and up-regulated vimentin and lipocalin 2 in rat kidney at 13 weeks. The p53 gene was decreased in both liver and kidney at 13 weeks. These results suggest that OTA caused apparent kidney damage within 13 weeks but exerted limited effect on oxidative stress parameters. It implies that cell proliferation is the proposed mode of action for OTA-induced renal carcinogenicity.

  20. Reduction of paraquat-induced renal cytotoxicity by manganese and copper complexes of EGTA and EHPG.

    PubMed

    Samai, Mohamed; Hague, Theresa; Naughton, Declan P; Gard, Paul R; Chatterjee, Prabal K

    2008-02-15

    Superoxide anion generation plays an important role in the development of paraquat toxicity. Although superoxide dismutase mimetics (SODm) have provided protection against organ injury involving generation of superoxide anions, they often suffer problems, e.g., regarding their bioavailability or potential pro-oxidant activity. The aim here was to investigate and compare the therapeutic potential of two novel SODm, manganese(II) and copper(II) complexes of the calcium chelator ethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA) and of the contrast agent ethylenebis(hydroxyphenylglycine) (EHPG), against paraquat-induced renal toxicity in vitro. Incubation of renal NRK-52E cells with paraquat (1 mM) for 24 h produced submaximal, yet significant, reduction in cellular viability and cell death and produced significant increases in superoxide anion and hydroxyl radical generation. Manganese and copper complexes of EGTA (10-100 microM) and EHPG (30-100 microM) reduced paraquat-induced renal cell toxicity and reduced superoxide anion and hydroxyl radical generation significantly. Manganese complexes displayed greater efficacy than copper complexes and, at equivalent concentrations, manganese complexed with EHPG provided the greatest protection. Furthermore, these metal complexes did not interfere with the uptake of [methyl-(14)C]paraquat into NRK-52E cells, suggesting that they provided protection against paraquat cytotoxicity via intracellular mechanisms. These complexes did not display cytotoxicity at the concentrations examined. Together, these results suggest that manganese and copper complexes of EGTA and EHPG, and especially the manganese-EHPG complex, could provide benefit against paraquat nephrotoxicity.

  1. Anti-inflammatory effects of royal jelly on ethylene glycol induced renal inflammation in rats.

    PubMed

    Aslan, Zeyneb; Aksoy, Laçine

    2015-01-01

    In this study, anti-inflammatory effects of Royal Jelly were investigated by inducing renal inflammation in rats with the use of ethylene glycol. For this purpose, the calcium oxalate urolithiasis model was obtained by feeding rats with ethylene glycol in drinking water. The rats were divided in five study groups. The 1st group was determined as the control group. The rats in the 2nd group received ethylene glycol (1%) in drinking water. The rats in the 3rd group were daily fed with Royal Jelly by using oral gavage. The 4th group was determined as the preventive group and the rats were fed with ethylene glycol (1%) in drinking water while receiving Royal Jelly via oral gavage. The 5th group was determined as the therapeutic group and received ethylene glycol in drinking water during the first 2 weeks of the study and Royal Jelly via oral gavage during the last 2 weeks of the study. At the end of the study, proinflammatory/anti-inflammatory cytokines, TNF-a, IL-1ß and IL-18 levels in blood and renal tissue samples from the rats used in the application were measured. The results have shown that ethylene glycol does induce inflammation and renal damage. This can cause the formation of reactive oxygen species. Royal Jelly is also considered to have anti-inflammatory effects due to its possible antiradical and antioxidative effects. It can have positive effects on both the prevention of urolithiasis and possible inflammation during the existing urolithiasis and support the medical treatment.

  2. Effects of alpha adrenoceptor blockade on renal nerve stimulation-induced norepinephrine release and vasoconstriction in the dog kidney.

    PubMed

    Hisa, H; Araki, S; Tomura, Y; Hayashi, Y; Satoh, S

    1989-02-01

    Effects of alpha-antagonists on renal norepinephrine (NE) release and vasoconstriction induced by renal nerve stimulation (RNS) were examined in pentobarbital-anesthetized dogs. RNS at 1,2 and 3 Hz (1 msec duration, 10-20 V) for 1 min decreased renal blood flow (RBF) and increased both the renal venous NE concentration (NEC) and calculated renal NE efflux (NEE). The RBF responses to 2 and 3 Hz RNS and NEC responses to 1, 2 and 3 Hz RNS during intrarenal arterial infusion of yohimbine (1.0 micrograms/kg/min) were greater than those observed during the control period. The NEE responses to 1 and 2 Hz RNS, but not to 3 Hz RNS, were also potentiated by the yohimbine infusion. Prazosin treatment (0.2 mg/kg i.v.) attenuated the RBF responses. Subsequent infusion of yohimbine potentiated both the NEC and NEE responses to 1, 2 and 3 Hz RNS in this alpha-1 adrenoceptor-blocked state. These results suggest that an alpha-2 adrenoceptor-mediated inhibitory mechanism of neural NE release exists in the dog kidney, which can be activated by endogenously released catecholamines to modulate the neural control of renal hemodynamics. Alpha-1 adrenoceptor-mediated renal vasoconstriction may affect the evaluation of neural NE release by NEE when high-frequency RNS is applied during inhibition of the alpha-2 adrenoceptor-mediated mechanism.

  3. Protective Effect of Aqueous Crude Extract of Neem (Azadirachta indica) Leaves on Plasmodium berghei-Induced Renal Damage in Mice

    PubMed Central

    Somsak, Voravuth; Chachiyo, Sukanya; Jaihan, Ubonwan; Nakinchat, Somrudee

    2015-01-01

    Malaria is a major public health problem in the world because it can cause of death in patients. Malaria-associated renal injury is associated with 45% of mortality in adult patients hospitalized with severe form of the disease. Therefore, new plant extracts to protect against renal injury induced by malaria infection are urgently needed. In this study, we investigated the protective effect of aqueous crude extract of Azadirachta indica (neem) leaves on renal injury induced by Plasmodium berghei ANKA infection in mice. ICR mice were injected intraperitoneally with 1 × 107 parasitized erythrocytes of PbANKA, and neem extracts (500, 1,000, and 2,000 mg/kg) were given orally for 4 consecutive days. Plasma blood urea nitrogen (BUN) and creatinine levels were subsequently measured. Malaria-induced renal injury was evidenced as marked increases of BUN and creatinine levels. However, the oral administration of neem leaf extract to PbANKA infected mice for 4 days brought back BUN and creatinine levels to near normalcy, and the highest activity was observed at doses of 1,000 and 2,000 mg/kg. Additionally, no toxic effects were found in normal mice treated with this extract. Hence, neem leaf extract can be considered a potential candidate for protection against renal injury induced by malaria. PMID:26379714

  4. Protective Effect of Aqueous Crude Extract of Neem (Azadirachta indica) Leaves on Plasmodium berghei-Induced Renal Damage in Mice.

    PubMed

    Somsak, Voravuth; Chachiyo, Sukanya; Jaihan, Ubonwan; Nakinchat, Somrudee

    2015-01-01

    Malaria is a major public health problem in the world because it can cause of death in patients. Malaria-associated renal injury is associated with 45% of mortality in adult patients hospitalized with severe form of the disease. Therefore, new plant extracts to protect against renal injury induced by malaria infection are urgently needed. In this study, we investigated the protective effect of aqueous crude extract of Azadirachta indica (neem) leaves on renal injury induced by Plasmodium berghei ANKA infection in mice. ICR mice were injected intraperitoneally with 1 × 10(7) parasitized erythrocytes of PbANKA, and neem extracts (500, 1,000, and 2,000 mg/kg) were given orally for 4 consecutive days. Plasma blood urea nitrogen (BUN) and creatinine levels were subsequently measured. Malaria-induced renal injury was evidenced as marked increases of BUN and creatinine levels. However, the oral administration of neem leaf extract to PbANKA infected mice for 4 days brought back BUN and creatinine levels to near normalcy, and the highest activity was observed at doses of 1,000 and 2,000 mg/kg. Additionally, no toxic effects were found in normal mice treated with this extract. Hence, neem leaf extract can be considered a potential candidate for protection against renal injury induced by malaria.

  5. Tanshinone II Aattenuates renal damage in STZ-induced diabetic rats via inhibiting oxidative stress and inflammation

    PubMed Central

    Gao, Yu; Sun, Dandan; Liu, Qizhen; Dai, Dongjun; Lu, Zeyuan; Wang, Niansong; Ge, Sheng; Wang, Feng

    2017-01-01

    Oxidative stress and inflammation have been demonstrated to be involved in the onset and promotion of diabetic nephropathy (DN).Tanshinone IIA (Tan) possesses both antioxidant and anti-inflammatory properties. Here, the aim of the present study was to explore whether Tan could attenuate renal damage in the rats with streptozotocin (STZ)-induced diabetes and its potential mechanisms. Tan was gavaged to STZ-induced diabetic rats at the dose of 10mg/kg once a day for 12 weeks. Tan treatment significantly attenuated albuminuria and renal histopathology in diabetic rats. Besides, Tan treatment also effectively inhibited oxidative stress and inflammatory reaction in the kidneys of diabetic rats. Our study provided evidence that the protective effect of Tan on diabetes-induced renal injury is associated with inhibition of oxidative stress and inflammation. Tan may be a potential candidate for the treatment of DN. PMID:28404881

  6. Modification of spontaneous renal lesion of APA hamsters by streptozotocin-induced diabetes

    PubMed Central

    NISHIDA, ETSUKO; YAMANOUCHI, JUN; OGATA, SEIYA; DOI, KUNIO; ITAGAKI, SHIN-ICHI

    1997-01-01

    Syrian hamsters of the APA strain (APA hamsters) develop spontaneous mesangial thickening in the renal glomeruli from an early age. They also develop focal and segmental glomerulosclerosis (FSG) at and after 6 months of age. In this study, histopathological, immunohistochemical and lectin histochemical examinations were conducted to clarify the modification of the spontaneous renal lesions of APA hamsters by streptozotocin(SZ)-induced diabetes. Histopathological analysis revealed that the expansion of the mesangial region was more prominent and the thickening of the glomerular basement membrane (GBM) was weaker in SZ-treated animals than in non-treated ones. Immunohistochemical analysis suggested that type IV collagen and laminin were involved in the expansion of the mesangial region and thickening of the GBM. In lectin histochemical analysis, podocytes, capillary endothelial cells, GBM and a part of mesangial region of SZ-treated animals were positive for RCA120 and GSL-I with neuraminidase-pretreatment although they were negative for these lectins in non-treated animals. These results suggest that the spontaneous glomerular lesion of APA hamsters is modified qualitatively and quantitatively by SZ-induced diabetes. PMID:9306924

  7. Doppler sonography in experimentally induced acute renal failure in rabbits. Resistive index versus serum creatinine levels.

    PubMed

    Yoon, D Y; Kim, S H; Kim, H D; Na, D G; Goo, J M; Choi, H J; Yeon, K M; Han, M C

    1995-03-01

    The purpose of this study is to investigate the temporal relation between the change in the resistive index (RI) from renal Doppler sonography and that of serum creatinine values in the course of experimentally induced reversible acute renal failure (ARF) in rabbits. Reversible ARF was induced in 10 New Zealand white rabbits by injecting a glycerol solution (6.0 mL/kg) into the thigh muscle. Doppler sonography was performed before injection, and 6, 12, and 24 hours, and 3, 5, 7, and 14 days after injection of glycerol. Blood samples for measuring serum creatinine levels were obtained in the same time sequence. Three rabbits, which died during the course of the experiment, were excluded from the study group. The RI elevated rapidly after glycerol injection, peaked at 12 hours, and then decreased to normal values by 7 days. Conversely, serum creatinine values were elevated and peaked at 1 day and then decreased to normal by 14 days. The change in the RI preceded the change in serum creatinine levels in the course of reversible ARF. There was a weak linear correlation between RI and serum creatinine levels, with a correlation coefficient of 0.33. Doppler sonography with measurement of resistive index may be useful in predicting the course of ARF.

  8. Pharmacokinetic-pharmacodynamic analysis of sunitinib-induced thrombocytopenia in Japanese patients with renal cell carcinoma.

    PubMed

    Nagata, Masashi; Ishiwata, Yasuyoshi; Takahashi, Yutaka; Takahashi, Hiromitsu; Saito, Kazutaka; Fujii, Yasuhisa; Kihara, Kazunori; Yasuhara, Masato

    2015-01-01

    The aim of the present study was to clarify the therapeutic range and adequate dose of sunitinib in Japanese renal cell carcinoma patients by means of a pharmacokinetic-pharmacodynamic analysis of sunitinib-induced thrombocytopenia. Six patients with renal cell carcinoma were enrolled in this study. After starting the sunitinib treatment, between three and seven blood samples were obtained from each patient just before the administration of sunitinib. Serum concentrations of sunitinib and its active metabolite N-desethyl-sunitinib were fit to the 1-compartment model with first-order absorption. Changes in platelet counts were fit to the pharmacokinetic-pharmacodynamic model, in which the proliferation of platelet progenitor cells was assumed to be linearly inhibited by sunitinib and its metabolite. All patients using 50 mg as an initial dose of sunitinib developed grade 2 or 3 thrombocytopenia. The pharmacokinetic-pharmacodynamic model created successfully described the time course of sunitinib-induced thrombocytopenia and could predict changes in platelet counts after alterations to the dosage of sunitinib administered. The simulation results indicated that the total trough level of sunitinib to avoid severe thrombocytopenia should be <100 ng/mL, and also that the initial daily dose of sunitinib could be reduced to 37.5 mg or 25 mg in most Japanese patients. In addition to the pharmacokinetic-guided dosage adjustment, the careful monitoring of platelet counts is required for the safe use of sunitinib.

  9. Lead Induced Hepato-renal Damage in Male Albino Rats and Effects of Activated Charcoal

    PubMed Central

    Offor, Samuel J.; Mbagwu, Herbert O. C.; Orisakwe, Orish E.

    2017-01-01

    Lead is a multi-organ toxicant implicated in various cancers, diseases of the hepatic, renal, and reproductive systems etc. In search of cheap and readily available antidote this study has investigated the role of activated charcoal in chronic lead exposure in albino rats. Eighteen mature male albino rats were used, divided into three groups of six rats per group. Group 1 (control rats) received deionised water (10 ml/kg), group 2 was given lead acetate solution 60 mg/kg and group 3 rats were given lead acetate (60 mg/kg) followed by Activated charcoal, AC (1000 mg/kg) by oral gavage daily for 28 days. Rats in group 2 showed significant increases in serum Aspartate aminotransferase, Alkaline phosphatase, Alanine aminotransferase, urea, bilirubin, total cholesterol, triglycerides, Low Density Lipoprotein, Very Low Density Lipoproteins, Total White Blood Cell Counts, Malondialdehyde, Interleukin-6, and decreases in Packed Cell Volume, hemoglobin concentration, Red blood cell count, total proteins, albumins, superoxide dismutase, glutathione peroxidase and total glutathione. Co-administration of AC significantly decreased these biomarkers with the exception of the sperm parameters. Histopathology of liver and kidney also confirmed the protective effective of AC against lead induced hepato-renal damage. AC may be beneficial in chronic lead induced liver and kidney damage. PMID:28352230

  10. Ameliorating Effect of Gemigliptin on Renal Injury in Murine Adriamycin-Induced Nephropathy

    PubMed Central

    Lee, Shin Yeong; Kim, Jin Sug; Kim, Yang Gyun; Moon, Ju-Young; Lee, Tae Won; Ihm, Chun Gyoo

    2017-01-01

    Background. Previous studies have shown the antiapoptotic and anti-inflammatory potential of DPP-IV inhibitor in experimental models of renal injury. We tested whether DPP-IV inhibitor (gemigliptin) ameliorates renal injury by suppressing apoptosis, inflammation, and oxidative stress in mice with adriamycin nephropathy. Methods. Mice were treated with normal saline (control), gemigliptin (GM), adriamycin (ADR), or adriamycin combined with gemigliptin (ADR+GM). Apoptosis, inflammation, and oxidative stress were analyzed via western blotting, real-time PCR, light microscopy, and immunofluorescence. Results. In the ADR+GM group, urine albumin creatinine ratio decreased significantly compared with that in the ADR group on day 15. Glomerulosclerosis index and tubulointerstitial injury index in mice with adriamycin-induced nephropathy decreased after gemigliptin treatment. ADR group showed higher levels of apoptosis, inflammation, and oxidative stress-related molecules compared with the control group. The upregulation of these molecules was significantly reduced by gemigliptin. In the ADR group, the staining intensities of WT-1 and nephrin reduced, but these changes were ameliorated in the ADR+GM group. Conclusion. We demonstrated that gemigliptin ameliorates nephropathy by suppressing apoptosis, inflammation, and oxidative stress in mice administered adriamycin. Our data demonstrate that gemigliptin has renoprotective effects on adriamycin-induced nephropathy. PMID:28326327

  11. Serum- and glucocorticoid-inducible kinase 1 in the regulation of renal and extrarenal potassium transport.

    PubMed

    Lang, Florian; Vallon, Volker

    2012-02-01

    Serum- and glucocorticoid inducible-kinase 1 (SGK1) is an early gene transcriptionally upregulated by cell stress such as cell shrinkage and hypoxia and several hormones including gluco- and mineralocorticoids. It is activated by insulin and growth factors. SGK1 is a powerful regulator of a wide variety of channels and transporters. The present review describes the role of SGK1 in the regulation of potassium (K(+)) channels, K(+) transporters and K(+) homeostasis. SGK1-regulated K(+) channels include renal outer medullary K+ channel, Kv1.3, Kv1.5, KCNE1/KCNQ1, KCNQ4 and, via regulation of calcium (Ca(2+)) entry, Ca(2+)-sensitive K(+) channels. SGK1-sensitive transporters include sodium-potassium-chloride cotransporter 2 and sodium/potassium-adenosine triphosphatase. SGK1-dependent regulation of K(+) channels and K(+) transport contributes to the stimulation of renal K(+) excretion following high K(+) intake, to insulin-induced cellular K(+) uptake and hypokalemia, to inhibition of insulin release by glucocorticoids, to stimulation of mast cell degranulation and gastric acid secretion, and to cardiac repolarization. Thus, SGK1 has a profound effect on K(+) homeostasis and on a multitude of K(+)-sensitive cellular functions.

  12. Characterization of Batracylin-induced Renal and Bladder Toxicity in Rats.

    PubMed

    Davis, Myrtle; Bunin, Deborah I; Samuelsson, Steven J; Altera, Kenneth P; Kinders, Robert J; Lawrence, Scott M; Ji, Jiuping; Ames, Matthew M; Buhrow, Sarah A; Walden, Chad; Reid, Joel M; Rausch, Linda L; Parman, Toufan

    2015-06-01

    Batracylin (NSC-320846) is a dual inhibitor of DNA topoisomerases I and II. Batracylin advanced as an anticancer agent to Phase I clinical trials where dose limiting hemorrhagic cystitis (bladder inflammation and bleeding) was observed. To further investigate batracylin's mechanism of toxicity, studies were conducted in Fischer 344 rats. Once daily oral administration of 16 or 32 mg/kg batracylin to rats for 4 days caused overt toxicity. Abnormal clinical observations and adverse effects on clinical pathology, urinalysis, and histology indicated acute renal damage and urothelial damage and bone marrow dysfunction. Scanning electron microscopy revealed sloughing of the superficial and intermediate urothelial layers. DNA damage was evident in kidney and bone marrow as indicated by histone γ-H2AX immunofluorescence. After a single oral administration of 16 or 32 mg/kg, the majority of batracylin was converted to N-acetylbatracylin (NAB) with a half-life of 4 hr to 11 hr. Mesna (Mesnex™), a drug known to reduce the incidence of hemorrhagic cystitis induced by ifosfamide or cyclophosphamide, was administered to rats prior to batracylin, but did not alleviate batracylin-induced bladder and renal toxicity. These findings suggest that batracylin results in DNA damage-based mechanisms of toxicity and not an acrolein-based mechanism of toxicity as occurs after ifosfamide or cyclophosphamide administration. © 2014 by The Author(s).

  13. Gold nanoparticles ameliorate acetaminophen induced hepato-renal injury in rats.

    PubMed

    Reshi, Mohd Salim; Shrivastava, Sadhana; Jaswal, Amita; Sinha, Neelu; Uthra, Chhavi; Shukla, Sangeeta

    2017-04-04

    Valuable effects of gold particles have been reported and used in complementary medicine for decades. The aim of this study was to evaluate the therapeutic efficacy of gold nanoparticles (AuNPs) against acetaminophen (APAP) induced toxicity. Albino rats were administered APAP at a dose of 2g/kg p.o. once only. After 24h of APAP intoxication, animals were treated with three different doses of AuNPs (50μg/kg, 100μg/kg, 150μg/kg) orally or silymarin at a dose of 50mg/kg p.o., once only. Animals of all the groups were sacrificed after 24h of last treatment. APAP administered group showed a significant rise in the AST, ALT, SALP, LDH, cholesterol, bilirubin, albumin, urea and creatinine in serum which indicated the hepato-renal damage. A significantly enhanced LPO and a depleted level of GSH were observed in APAP intoxicated rats. Declined activities of SOD and Catalase, after acetaminophen exposure indicated oxidative stress in liver and kidney. The activities of ATPase and glucose-6-Phosphatase were significantly inhibited after APAP administration. AuNPs treatment reversed all variables significantly towards normal level and was found nontoxic. Thus it is concluded that gold nanoparticles played a beneficial role in reducing acetaminophen induced toxicity and can be used in the development of drug against hepatic as well as renal diseases, after further preclinical and clinical studies. Copyright © 2017 Elsevier GmbH. All rights reserved.

  14. Cisplatin-induced acute renal failure is ameliorated by erdosteine in a dose-dependent manner.

    PubMed

    Ozyurt, Hüseyin; Yildirim, Zeki; Kotuk, Mahir; Yilmaz, H Ramazan; Yağmurca, Murat; Iraz, Mustafa; Söğüt, Sad; Gergerlioglu, Serdar

    2004-01-01

    The aim of this study was to investigate the optimum dosage of erdosteine to ameliorate cisplatin-induced nephrotoxicity. Three different doses of erdosteine at 25, 50 and 75 mg kg(-1) were studied in rats. Intraperitoneal administration of 7 mg kg(-1) cisplatin led to acute renal failure, as indicated by kidney histology and increases in plasma creatinine and blood urea nitrogen (BUN) levels. At 5 days after cisplatin injection the BUN level was increased significantly from 15.1 +/- 4.3 to 126.7 +/- 152.6 mg dl(-1) and plasma creatinine levels increased from 0.37 +/- 0.005 to 1.68 +/- 1.9 mg dl(-1). When the rats were administered 50 and 75 mg kg(-1) erdosteine 24 h before cisplatin injection that was continued until sacrifice (total of 6 days), the BUN and creatinine levels remained similar to control levels and the grade of histology was similar. Erdosteine at doses of 50 and 75 mg kg(-1) ameliorates cisplatin-induced renal failure. The optimum dose of erdosteine may be 50 mg kg(-1) in this study.

  15. Sulfasalazine-induced renal and hepatic injury in rats and the protective role of taurine

    PubMed Central

    Heidari, Reza; Rasti, Maryam; Shirazi Yeganeh, Babak; Niknahad, Hossein; Saeedi, Arastoo; Najibi, Asma

    2016-01-01

    Introduction: Sulfasalazine is a drug commonly administrated against inflammatory-based disorders. On the other hand, kidney and liver injury are serious adverse events accompanied by sulfasalazine administration. No specific therapeutic option is available against this complication. The current investigation was designed to evaluate the potential protective effects of taurine against sulfasalazine-induced kidney and liver injury in rats. Methods: Male Sprague-Dawley rats were administered with sulfasalazine (600 mg/kg, oral) for 14 consecutive days. Animals received different doses of taurine (250, 500 and 1000 mg/ kg, i.p.) every day. Markers of organ injury were evaluated on day 15th, 24 h after the last dose of sulfasalazine. Results: Sulfasalazine caused renal and hepatic injury as judged by an increase in serum level of creatinine (Cr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP). The levels of reactive oxygen species (ROS) and lipid peroxidation were raised in kidney and liver of sulfasalazine-treated animals. Moreover, tissue glutathione reservoirs were depleted after sulfasalazine administration. Histopathological changes of kidney and liver also endorsed organ injury. Taurine administration (250, 500 and 1000 mg/kg/day, i.p) alleviated sulfasalazine-induced renal and hepatic damage. Conclusion: Taurine administration could serve as a potential protective agent with therapeutic capabilities against sulfasalazine adverse effects. PMID:27340618

  16. Cancer drug troglitazone stimulates the growth and response of renal cells to hypoxia inducible factors

    SciTech Connect

    Taub, Mary

    2016-03-11

    Troglitazone has been used to suppress the growth of a number of tumors through apoptosis and autophagy. However, previous in vitro studies have employed very high concentrations of troglitazone (≥10{sup −5} M) in order to elicit growth inhibitory effects. In this report, when employing lower concentrations of troglitazone in defined medium, troglitazone was observed to stimulate the growth of primary renal proximal tubule (RPT) cells. Rosiglitazone, like troglitazone, is a thiazolidinedione (TZD) that is known to activate Peroxisome Proliferator Activated Receptor Υ (PPARΥ). Notably, rosiglitazone also stimulates RPT cell growth, as does Υ-linolenic acids, another PPARΥ agonist. The PPARΥ antagonist GW9662 inhibited the growth stimulatory effect of troglitazone. In addition, troglitazone stimulated transcription by a PPAR Response Element/Luciferase construct. These results are consistent with the involvement of PPARΥ as a mediator of the growth stimulatory effect of troglitazone. In a number of tumor cells, the expression of hypoxia inducible factor (HIF) is increased, promoting the expression of HIF inducible genes, and vascularization. Troglitazone was observed to stimulate transcription by a HIF/luciferase construct. These observations indicate that troglitazone not only promotes growth, also the survival of RPT cells under conditions of hypoxia. - Highlights: • Troglitazone and rosiglitazone stimulate renal proximal tubule cell growth. • Troglitazone and linolenic acid stimulate growth via PPARϒ. • Linolenic acid stimulates growth in the presence of fatty acid free serum albumin. • Rosiglitazone stimulates transcription by a HRE luciferase construct.

  17. Renal disease in pregnancy.

    PubMed

    Thorsen, Martha S; Poole, Judith H

    2002-03-01

    Anatomic and physiologic adaptations within the renal system during pregnancy are significant. Alterations are seen in renal blood flow and glomerular filtration, resulting in changes in normal renal laboratory values. When these normal renal adaptations are coupled with pregnancy-induced complications or preexisting renal dysfunction, the woman may demonstrate a reduction of renal function leading to an increased risk of perinatal morbidity and mortality. This article will review normal pregnancy adaptations of the renal system and discuss common pregnancy-related renal complications.

  18. Changes in expression of renal Oat1, Oat3 and Mrp2 in cisplatin-induced acute renal failure after treatment of JBP485 in rats

    SciTech Connect

    Liu, Tao; Meng, Qiang; Wang, Changyuan; Liu, Qi; Guo, Xinjin; Sun, Huijun; Peng, Jinyong; and others

    2012-11-01

    The purpose of this study is to investigate whether the effect of cyclo-trans-4-L-hydroxyprolyl-L-serine (JBP485) on acute renal failure (ARF) induced by cisplatin is related to change in expression of renal Oat1, Oat3 and Mrp2 in rats. JBP485 reduced creatinine, blood urea nitrogen (BUN) and indoxyl sulfate (IS) in plasma and malondialdehyde (MDA) in kidney, and recovered the glomerular filtration rate (GFR) and the activity of superoxide dismutase (SOD) in cisplatin-treated rats. The plasma concentration of PAH (para-aminohippurate) determined by LC–MS/MS was increased markedly after intravenous administration of cisplatin, whereas cumulative urinary excretion of PAH and the uptake of PAH in kidney slices were significantly decreased. qRT-PCR and Western-blot showed a decrease in mRNA and protein of Oat1 and Oat3, an increase in mRNA and protein of Mrp2 in cisplatin-treated rats, and an increase in IS (a uremic toxin) after co-treatment with JBP485. It indicated that JBP485 promoted urinary excretion of toxins by upregulating renal Mrp2. This therefore gives in part the explanation about the mechanism by which JBP485 improves ARF induced by cisplatin in rats. -- Highlights: ► Cisplatin induces acute renal failure (ARF). ► The expression of Oat1, Oat3 and Mrp2 were changed during ARF. ► The regulated expression of Oat1, Oat3 and Mrp2 is an adaptive protected response. ► JBP485 could facilitate the adaptive protective action.

  19. Protective Immunity and Reduced Renal Colonization Induced by Vaccines Containing Recombinant Leptospira interrogans Outer Membrane Proteins and Flagellin Adjuvant

    PubMed Central

    Monaris, D.; Sbrogio-Almeida, M. E.; Dib, C. C.; Canhamero, T. A.; Souza, G. O.; Vasconcellos, S. A.; Ferreira, L. C. S.

    2015-01-01

    Leptospirosis is a global zoonotic disease caused by different Leptospira species, such as Leptospira interrogans, that colonize the renal tubules of wild and domestic animals. Thus far, attempts to develop effective leptospirosis vaccines, both for humans and animals, have failed to induce immune responses capable of conferring protection and simultaneously preventing renal colonization. In this study, we evaluated the protective immunity induced by subunit vaccines containing seven different recombinant Leptospira interrogans outer membrane proteins, including the carboxy-terminal portion of the immunoglobulinlike protein A (LigAC) and six novel antigens, combined with aluminum hydroxide (alum) or Salmonella flagellin (FliC) as adjuvants. Hamsters vaccinated with the different formulations elicited high antigen-specific antibody titers. Immunization with LigAC, either with alum or flagellin, conferred protective immunity but did not prevent renal colonization. Similarly, animals immunized with LigAC or LigAC coadministered with six leptospiral proteins with alum adjuvant conferred protection but did not reduce renal colonization. In contrast, immunizing animals with the pool of seven antigens in combination with flagellin conferred protection and significantly reduced renal colonization by the pathogen. The present study emphasizes the relevance of antigen composition and added adjuvant in the efficacy of antileptospirosis subunit vaccines and shows the complex relationship between immune responses and renal colonization by the pathogen. PMID:26108285

  20. Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction.

    PubMed

    Sato, Misako; Muragaki, Yasuteru; Saika, Shizuya; Roberts, Anita B; Ooshima, Akira

    2003-11-01

    Tubulointerstitial fibrosis is the final common result of a variety of progressive injuries leading to chronic renal failure. Transforming growth factor-beta (TGF-beta) is reportedly upregulated in response to injurious stimuli such as unilateral ureteral obstruction (UUO), causing renal fibrosis associated with epithelial-mesenchymal transition (EMT) of the renal tubules and synthesis of extracellular matrix. We now show that mice lacking Smad3 (Smad3ex8/ex8), a key signaling intermediate downstream of the TGF-beta receptors, are protected against tubulointerstitial fibrosis following UUO as evidenced by blocking of EMT and abrogation of monocyte influx and collagen accumulation. Culture of primary renal tubular epithelial cells from wild-type or Smad3-null mice confirms that the Smad3 pathway is essential for TGF-beta1-induced EMT and autoinduction of TGF-beta1. Moreover, mechanical stretch of the cultured epithelial cells, mimicking renal tubular distention due to accumulation of urine after UUO, induces EMT following Smad3-mediated upregulation of TGF-beta1. Exogenous bone marrow monocytes accelerate EMT of the cultured epithelial cells and renal tubules in the obstructed kidney after UUO dependent on Smad3 signaling. Together the data demonstrate that the Smad3 pathway is central to the pathogenesis of interstitial fibrosis and suggest that inhibitors of this pathway may have clinical application in the treatment of obstructive nephropathy.

  1. Protective Immunity and Reduced Renal Colonization Induced by Vaccines Containing Recombinant Leptospira interrogans Outer Membrane Proteins and Flagellin Adjuvant.

    PubMed

    Monaris, D; Sbrogio-Almeida, M E; Dib, C C; Canhamero, T A; Souza, G O; Vasconcellos, S A; Ferreira, L C S; Abreu, P A E

    2015-08-01

    Leptospirosis is a global zoonotic disease caused by different Leptospira species, such as Leptospira interrogans, that colonize the renal tubules of wild and domestic animals. Thus far, attempts to develop effective leptospirosis vaccines, both for humans and animals, have failed to induce immune responses capable of conferring protection and simultaneously preventing renal colonization. In this study, we evaluated the protective immunity induced by subunit vaccines containing seven different recombinant Leptospira interrogans outer membrane proteins, including the carboxy-terminal portion of the immunoglobulinlike protein A (LigA(C)) and six novel antigens, combined with aluminum hydroxide (alum) or Salmonella flagellin (FliC) as adjuvants. Hamsters vaccinated with the different formulations elicited high antigen-specific antibody titers. Immunization with LigA(C), either with alum or flagellin, conferred protective immunity but did not prevent renal colonization. Similarly, animals immunized with LigA(C) or LigA(C) coadministered with six leptospiral proteins with alum adjuvant conferred protection but did not reduce renal colonization. In contrast, immunizing animals with the pool of seven antigens in combination with flagellin conferred protection and significantly reduced renal colonization by the pathogen. The present study emphasizes the relevance of antigen composition and added adjuvant in the efficacy of antileptospirosis subunit vaccines and shows the complex relationship between immune responses and renal colonization by the pathogen.

  2. HMGB1/TLR4 signaling induces an inflammatory response following high-pressure renal pelvic perfusion in a porcine model.

    PubMed

    Shao, Yi; Sha, Minglei; Chen, Lei; Li, Deng; Lu, Jun; Xia, Shujie

    2016-11-01

    Percutaneous nephrolithotomy (PCNL) causes a rapid increase in renal pelvic pressure in the kidney, which induces an inflammatory response. High-mobility group box-1 (HMGB1) is known to trigger the recruitment of inflammatory cells and the release of proinflammatory cytokines following ischemia reperfusion injury in the kidney, but the contribution of HMGB1 to the inflammatory response following high-pressure renal pelvic perfusion has not been investigated. In this study, high-pressure renal pelvic perfusion was induced in anesthetized pigs to examine the effect of HMGB1 on the inflammatory response. HMGB1 levels in the kidney increased following high-pressure renal pelvic perfusion, together with elevated levels of inflammatory cytokines in the plasma and kidney and an accumulation of neutrophils and macrophages. Inhibition of HMGB1 alleviated this inflammatory response while perfusion with recombinant HMGB1 had an augmentative effect, confirming the involvement of HMGB1 in the inflammatory response to high-pressure renal pelvic perfusion. HMGB1 regulated the inflammatory response by activating Toll-like receptor 4 (TLR4) signaling. In conclusion, this study has demonstrated that HMGB1/TLR4 signaling contributes to the inflammatory response following high-pressure renal pelvic perfusion in a porcine model and has implications for the management of inflammation after PCNL. Copyright © 2016 the American Physiological Society.

  3. Oxygen-dependent expression of hypoxia-inducible factor-1alpha in renal medullary cells of rats.

    PubMed

    Zou, A P; Yang, Z Z; Li, P L; Cowley AW, J R

    2001-08-28

    Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that regulates the oxygen-dependent expression of a number of genes. This transcription factor may contribute to the abundant expression of many genes in renal medullary cells that function normally under hypoxic conditions. The present study was designed to determine the characteristics of HIF-1alpha cDNA cloned from the rat kidney and the expression profile of HIF-1alpha in different kidney regions and to explore the mechanism activating or regulating HIF-1alpha expression in renal medullary cells. A 3,718-bp HIF-1alpha cDNA from the rat kidney was first cloned and sequenced using RT-PCR and TA cloning technique. It was found that 823 amino acids deduced from this renal HIF-1alpha cDNA had 99%, 96%, and 90% identity with rat, mouse, or human HIF-1alpha deposited in GenBank, respectively. The 3'-untranslated region of HIF-1alpha mRNA from the rat kidney contained seven AUUUA instability elements, five of which were found to be conserved among rat, mouse, and human HIF-1alpha. Northern blot analyses demonstrated a corticomedullary gradient of HIF-1alpha mRNA expression in the kidney, with the greatest abundance in the renal inner medulla. Western blot analyses also detected a higher HIF-1alpha protein level in the nuclear extracts from the renal medulla than the renal cortex. A classic loop diuretic, furosemide (10 mg/kg ip), markedly increased renal medullary Po(2) levels from 22.5 to 52.2 mmHg, which was accompanied by a significant reduction of HIF-1alpha transcripts in renal medullary tissue. In in vitro experiments, low Po(2), but not elevated osmolarity, was found to significantly increase HIF-1alpha mRNA in renal medullary interstitial cells and inner medullary collecting duct cells. These results indicate that HIF-1alpha is more abundantly expressed in the renal medulla compared with the renal cortex. Increased abundance of HIF-1alpha mRNA in the renal medulla may represent an adaptive

  4. Role of CDK5/cyclin complexes in ischemia-induced death and survival of renal tubular cells.

    PubMed

    Guevara, Tatiana; Sancho, Mónica; Pérez-Payá, Enrique; Orzáez, Mar

    2014-01-01

    Ischemia reperfusion processes induce damage in renal tubules and compromise the viability of kidney transplants. Understanding the molecular events responsible for tubule damage and recovery would help to develop new strategies for organ preservation. CDK5 has been traditionally considered a neuronal kinase with dual roles in cell death and survival. Here, we demonstrate that CDK5 and their regulators p35/p25 and cyclin I are also expressed in renal tubular cells. We show that treatment with CDK inhibitors promotes the formation of pro-survival CDK5/cyclin I complexes and enhances cell survival upon an ischemia reperfusion pro-apoptotic insult. These findings support the benefit of treating with CDK inhibitors for renal preservation, assisting renal tubule protection.

  5. Role of SRC family kinase in extracellular renal cyclic guanosine 3',5'-monophosphate- and pressure-induced natriuresis.

    PubMed

    Nascimento, Nilberto R F; Kemp, Brandon A; Howell, Nancy L; Gildea, John J; Santos, Cláudia F; Harris, Thurl E; Carey, Robert M

    2011-07-01

    cGMP functions as an extracellular (paracrine) messenger acting at the renal proximal tubule and is an important modulator of pressure-natriuresis (P-N). The signaling pathway activated by cGMP in the tubule cell basolateral membrane remains unknown. We hypothesized that renal interstitial microinfusion of cGMP (50 nmol/kg per minute) or P-N would be accompanied by increased renal protein levels of phospho-Src (Tyr 416) and that the natriuresis would be decreased by Src inhibition. Renal interstitial cGMP-induced natriuresis was blocked by Src inhibitor PP2 (2.0±0.4 versus 0.5±0.01 μEq/g per minute; P<0.001). The inactive analog of PP2, PP3, had no effect on cGMP-induced natriuresis. SU6656, another Src inhibitor, also inhibited cGMP-induced natriuresis (2.0±0.4 versus 1.02±0.01 μEq/g per minute; P<0.001). Renal interstitial cGMP infusion increased phospho-Src protein levels 5.6-fold at 15 minutes and 6.8-fold at 30 minutes compared with vehicle infusion but returned toward basal levels after 60 minutes. PP2 also blunted P-N (3.1±0.1 versus 1.1±0.3 μEq/g per minute; P<0.01) despite a similar increase in blood pressure. PP3 had no effect on P-N. Phospho-Src protein levels increased during P-N in vehicle- (1.8-fold) and PP3-treated (2.1-fold) groups compared with the sham-operated group. PP2 blocked the pressure-induced increase in renal phospho-Src protein levels. PP2 had no effect on renal hemodynamics but decreased both fractional excretion of Na(+) and lithium. Both extracellular cGMP and increased renal perfusion pressure increased renal phospho-Src protein levels and induced natriuresis in an Src-dependent manner, demonstrating that Src is an important downstream signaling molecule for extracellular cGMP-induced natriuresis.

  6. Mesenchymal Stromal Cells Epithelial Transition Induced by Renal Tubular Cells-Derived Extracellular Vesicles.

    PubMed

    Chiabotto, Giulia; Bruno, Stefania; Collino, Federica; Camussi, Giovanni

    2016-01-01

    Mesenchymal-epithelial interactions play an important role in renal tubular morphogenesis and in maintaining the structure of the kidney. The aim of this study was to investigate whether extracellular vesicles (EVs) produced by human renal proximal tubular epithelial cells (RPTECs) may induce mesenchymal-epithelial transition of bone marrow-derived mesenchymal stromal cells (MSCs). To test this hypothesis, we characterized the phenotype and the RNA content of EVs and we evaluated the in vitro uptake and activity of EVs on MSCs. MicroRNA (miRNA) analysis suggested the possible implication of the miR-200 family carried by EVs in the epithelial commitment of MSCs. Bone marrow-derived MSCs were incubated with EVs, or RPTEC-derived total conditioned medium, or conditioned medium depleted of EVs. As a positive control, MSCs were co-cultured in a transwell system with RPTECs. Epithelial commitment of MSCs was assessed by real time PCR and by immunofluorescence analysis of cellular expression of specific mesenchymal and epithelial markers. After one week of incubation with EVs and total conditioned medium, we observed mesenchymal-epithelial transition in MSCs. Stimulation with conditioned medium depleted of EVs did not induce any change in mesenchymal and epithelial gene expression. Since EVs were found to contain the miR-200 family, we transfected MSCs using synthetic miR-200 mimics. After one week of transfection, mesenchymal-epithelial transition was induced in MSCs. In conclusion, miR-200 carrying EVs released from RPTECs induce the epithelial commitment of MSCs that may contribute to their regenerative potential. Based on experiments of MSC transfection with miR-200 mimics, we suggested that the miR-200 family may be involved in mesenchymal-epithelial transition of MSCs.

  7. Mesenchymal Stromal Cells Epithelial Transition Induced by Renal Tubular Cells-Derived Extracellular Vesicles

    PubMed Central

    Chiabotto, Giulia; Bruno, Stefania; Collino, Federica

    2016-01-01

    Mesenchymal-epithelial interactions play an important role in renal tubular morphogenesis and in maintaining the structure of the kidney. The aim of this study was to investigate whether extracellular vesicles (EVs) produced by human renal proximal tubular epithelial cells (RPTECs) may induce mesenchymal-epithelial transition of bone marrow-derived mesenchymal stromal cells (MSCs). To test this hypothesis, we characterized the phenotype and the RNA content of EVs and we evaluated the in vitro uptake and activity of EVs on MSCs. MicroRNA (miRNA) analysis suggested the possible implication of the miR-200 family carried by EVs in the epithelial commitment of MSCs. Bone marrow-derived MSCs were incubated with EVs, or RPTEC-derived total conditioned medium, or conditioned medium depleted of EVs. As a positive control, MSCs were co-cultured in a transwell system with RPTECs. Epithelial commitment of MSCs was assessed by real time PCR and by immunofluorescence analysis of cellular expression of specific mesenchymal and epithelial markers. After one week of incubation with EVs and total conditioned medium, we observed mesenchymal-epithelial transition in MSCs. Stimulation with conditioned medium depleted of EVs did not induce any change in mesenchymal and epithelial gene expression. Since EVs were found to contain the miR-200 family, we transfected MSCs using synthetic miR-200 mimics. After one week of transfection, mesenchymal-epithelial transition was induced in MSCs. In conclusion, miR-200 carrying EVs released from RPTECs induce the epithelial commitment of MSCs that may contribute to their regenerative potential. Based on experiments of MSC transfection with miR-200 mimics, we suggested that the miR-200 family may be involved in mesenchymal-epithelial transition of MSCs. PMID:27409796

  8. Ras modulation of superoxide activates ERK-dependent fibronectin expression in diabetes-induced renal injuries.

    PubMed

    Lin, C-L; Wang, F-S; Kuo, Y-R; Huang, Y-T; Huang, H-C; Sun, Y-C; Kuo, Y-H

    2006-05-01

    Although previous studies have demonstrated that diabetic nephropathy is attributable to early extracellular matrix accumulation in glomerular mesangial cells, the molecular mechanism by which high glucose induces matrix protein deposition remains not fully elucidated. Rat mesangial cells pretreated with or without inhibitors were cultured in high-glucose or advanced glycation end product (AGE) conditions. Streptozotocin-induced diabetic rats were given superoxide dismutase (SOD)-conjugated propylene glycol to scavenge superoxide. Transforming growth factor (TGF)-beta1, fibronectin expression, Ras, ERK, p38, and c-Jun activation of glomerular mesangial cells or urinary albumin secretion were assessed. Superoxide, not nitric oxide or hydrogen peroxide, mediated high glucose- and AGE-induced TGF-beta1 and fibronectin expression. Pretreatment with diphenyliodonium, not allopurinol or rotenone, reduced high-glucose and AGE augmentation of superoxide synthesis and fibronection expression. High glucose and AGEs rapidly enhanced Ras activation and progressively increased cytosolic ERK and nuclear c-Jun activation. Inhibiting Ras by manumycin A reduced the stimulatory effects of high glucose and AGEs on superoxide and fibronectin expression. SOD or PD98059 pretreatment reduced high-glucose and AGE promotion of ERK and c-Jun activation. Exogenous SOD treatment in diabetic rats significantly attenuated diabetes induction of superoxide, urinary albumin excretion, 8-hydroxy-2'-deoxyguanosine, TGF-beta1, and fibronectin immunoreactivities in renal glomerular mesangial cells. Ras induction of superoxide activated ERK-dependent fibrosis-stimulatory factor and extracellular matrix gene transcription of mesangial cells. Reduction of oxidative stress by scavenging superoxide may provide an alternative strategy for controlling diabetes-induced early renal injury.

  9. The epoxyeicosatrienoic acid analog PVPA ameliorates cyclosporine-induced hypertension and renal injury in rats.

    PubMed

    Yeboah, Michael M; Hye Khan, Md Abdul; Chesnik, Marla A; Sharma, Amit; Paudyal, Mahesh P; Falck, John R; Imig, John D

    2016-09-01

    The introduction of calcineurin inhibitors (CNI) into clinical practice in the late 1970s transformed organ transplantation and led to significant improvement in acute rejection episodes. However, despite their significant clinical utility, the use of these agents is hampered by the development of hypertension and nephrotoxicity, which ultimately lead to end-stage kidney disease and overt cardiovascular outcomes. There are currently no effective agents to treat or prevent these complications. Importantly, CNI-free immunosuppressive regimens lack the overall efficacy of CNI-based treatments and put patients at risk of allograft rejection. Cytochrome P-450 epoxygenase metabolites of arachidonic acid, epoxyeicosatrienoic acids (EETs), have potent vasodilator and antihypertensive properties in addition to many cytoprotective effects, but their effects on CNI-induced nephrotoxicity have not been explored. Here, we show that PVPA, a novel, orally active analog of 14,15-EET, effectively prevents the development of hypertension and ameliorates kidney injury in cyclosporine-treated rats. PVPA treatment reduced proteinuria and renal dysfunction induced by cyclosporine. PVPA inhibited inflammatory cell infiltration into the kidney and decreased renal fibrosis. PVPA also reduced tubular epithelial cell apoptosis, attenuated the generation of reactive oxygen species, and modulated the unfolded protein response that is associated with endoplasmic reticulum stress. Consistent with the in vivo data, PVPA attenuated cyclosporine-induced apoptosis of NRK-52E cells in vitro. These data indicate that the cytochrome P-450/EET system offers a novel therapeutic strategy to treat or prevent CNI-induced nephrotoxicity. Copyright © 2016 the American Physiological Society.

  10. Inactivation of the von Hippel-Lindau tumour suppressor gene induces Neuromedin U expression in renal cancer cells.

    PubMed

    Harten, Sarah K; Esteban, Miguel A; Shukla, Deepa; Ashcroft, Margaret; Maxwell, Patrick H

    2011-07-26

    209 000 new cases of renal carcinoma are diagnosed each year worldwide and new therapeutic targets are urgently required. The great majority of clear cell renal cancer involves inactivation of VHL, which acts as a gatekeeper tumour suppressor gene in renal epithelial cells. However how VHL exerts its tumour suppressor function remains unclear. A gene expression microarray comparing RCC10 renal cancer cells expressing either VHL or an empty vector was used to identify novel VHL regulated genes. NMU (Neuromedin U) is a neuropeptide that has been implicated in energy homeostasis and tumour progression. Here we show for the first time that VHL loss-of-function results in dramatic upregulation of NMU expression in renal cancer cells. The effect of VHL inactivation was found to be mediated via activation of Hypoxia Inducible Factor (HIF). Exposure of VHL expressing RCC cells to either hypoxia or dimethyloxalylglycine resulted in HIF activation and increased NMU expression. Conversely, suppression of HIF in VHL defective RCC cells via siRNA of HIF-α subunits or expression of Type 2C mutant VHLs reduced NMU expression levels. We also show that renal cancer cells express a functional NMU receptor (NMUR1), and that NMU stimulates migration of renal cancer cells. These findings suggest that NMU may act in an autocrine fashion, promoting progression of kidney cancer. Hypoxia and HIF expression are frequently observed in many non-renal cancers and are associated with a poor prognosis. Our study raises the possibility that HIF may also drive NMU expression in non-renal tumours.

  11. The effect of oculo-acupuncture on recovery from ethylene glycol-induced acute renal injury in dogs.

    PubMed

    Liu, Jianzhu; Song, Kun-Ho; You, Myung-Jo; Son, Dong-Soo; Cho, Sung-Whan; Kim, Duck-Hwan

    2007-01-01

    The potential recovery effect by oculo-acupuncture (OA) on ethylene glycol-induced acute renal injury in dogs was investigated. Acute renal damage was induced by ingestion of ethylene glycol in six mongrel dogs. The dogs were assigned to control (three dogs) and experimental (three dogs) groups. The control group did not receive any treatment, while the experimental group was treated with oculo-acupuncture at kidney/urinary bladder region plus zhong jiao region of the eyes after the induction of renal damage. Serum blood urea nitrogen (BUN), creatinine, sodium (Na), chloride (Cl), and potassium (K) were measured in both control and experimental groups. The blood RBC and Hb were also examined. The serum BUN and creatinine activities in the experimental group were lower than those in the control group, the serum Na and Cl had the irregular change in both groups, and the blood Hb in the control and experimental group showed decreasing tendency. Significant differences were observed on the 3rd and 7th day in BUN, 7th day in creatinine, 2nd day in Na and Cl, and 7th day in Hb when compared to the control group. Whereas, serum K concentration and RBC in the experimental group did not change significantly. The recovery findings of the renal injury were also observed in the experimental group histopathologically. In conclusion, OA therapy (kidney/urinary bladder region plus zhong jiao region) was effective for recovery of the renal injury induced by ethylene glycol in dogs.

  12. Hypoxia-Inducible Factor-1α Causes Renal Cyst Expansion through Calcium-Activated Chloride Secretion

    PubMed Central

    Schley, Gunnar; Faria, Diana; Kroening, Sven; Willam, Carsten; Schreiber, Rainer; Klanke, Bernd; Burzlaff, Nicolai; Jantsch, Jonathan; Kunzelmann, Karl; Eckardt, Kai-Uwe

    2014-01-01

    Polycystic kidney diseases are characterized by numerous bilateral renal cysts that continuously enlarge and, through compression of intact nephrons, lead to a decline in kidney function over time. We previously showed that cyst enlargement is accompanied by regional hypoxia, which results in the stabilization of hypoxia-inducible transcription factor-1α (HIF-1α) in the cyst epithelium. Here we demonstrate a correlation between cyst size and the expression of the HIF-1α–target gene, glucose transporter 1, and report that HIF-1α promotes renal cyst growth in two in vitro cyst models—principal-like MDCK cells (plMDCKs) within a collagen matrix and cultured embryonic mouse kidneys stimulated with forskolin. In both models, augmenting HIF-1α levels with the prolyl hydroxylase inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate enhanced cyst growth. In addition, inhibition of HIF-1α degradation through tubule-specific knockdown of the von Hippel-Lindau tumor suppressor increased cyst size in the embryonic kidney cyst model. In contrast, inhibition of HIF-1α by chetomin and knockdown of HIF-1α both decreased cyst growth in these models. Consistent with previous reports, plMDCK cyst enlargement was driven largely by transepithelial chloride secretion, which consists, in part, of a calcium-activated chloride conductance. plMDCKs deficient for HIF-1α almost completely lacked calcium-activated chloride secretion. We conclude that regional hypoxia in renal cysts contributes to cyst growth, primarily due to HIF-1α–dependent calcium-activated chloride secretion. These findings identify the HIF system as a novel target for inhibition of cyst growth. PMID:24203996

  13. Beneficial effects of previous exercise training on renal changes in streptozotocin-induced diabetic female rats

    PubMed Central

    Amaral, Liliany S de Brito; Silva, Fernanda A; Correia, Vicente B; Andrade, Clara EF; Dutra, Bárbara A; Oliveira, Márcio V; de Magalhães, Amélia CM; Volpini, Rildo A; Seguro, Antonio C; Coimbra, Terezila M

    2016-01-01

    This study evaluated the effects of aerobic exercise performed both previously and after the induction of diabetes mellitus on changes of renal function and structure in streptozotocin-induced diabetic rats. Female wistar rats were divided into five groups: sedentary control (C + Se); trained control (C + Ex); sedentary diabetic (D + Se); trained diabetic (D + Ex) and previously trained diabetic (D + PEx). The previous exercise consisted of treadmill running for four weeks before the induction of diabetes mellitus. After induction of diabetes mellitus with streptozotocin, the D + PEx, D + Ex and C + Ex groups were submitted to eight weeks of aerobic exercise. At the end of the training protocol, we evaluate the serum glucose, insulin and 17β-estradiol levels, renal function and structure, proteinuria, and fibronectin, collagen IV and transforming growth factor beta 1 (TGF-β1) renal expressions. Induction of diabetes mellitus reduced the insulin and did not alter 17β-estradiol levels, and exercise did not affect any of these parameters. Previous exercise training attenuated the loss of body weight, the blood glucose, the increase of glomerular filtration rate and prevented the proteinuria in the D + PEx group compared to D + Se group. Previous exercise also reduced glomerular hypertrophy, tubular and glomerular injury, as well as the expressions of fibronectin and collagen IV. These expressions were associated with reduced expression of TGF-β1. In conclusion, our study shows that regular aerobic exercise especially performed previously to induction of diabetes mellitus improved metabolic control and has renoprotective action on the diabetic kidney. PMID:26490345

  14. Renal effects of fresh water-induced hypo-osmolality in a marine adapted seal

    NASA Technical Reports Server (NTRS)

    Ortiz, R. M.; Wade, C. E.; Costa, D. P.; Ortiz, C. L.

    2002-01-01

    With few exceptions, marine mammals are not exposed to fresh water; however quantifying the endocrine and renal responses of a marine-adapted mammal to the infusion of fresh water could provide insight on the evolutionary adaptation of kidney function and on the renal capabilities of these mammals. Therefore, renal function and hormonal changes associated with fresh water-induced diuresis were examined in four, fasting northern elephant seal ( Mirounga angustirostris) (NES) pups. A series of plasma samples and 24-h urine voids were collected prior to (control) and after the infusion of water. Water infusion resulted in an osmotic diuresis associated with an increase in glomerular filtration rate (GFR), but not an increase in free water clearance. The increase in excreted urea accounted for 96% of the increase in osmotic excretion. Following infusion of fresh water, plasma osmolality and renin activity decreased, while plasma aldosterone increased. Although primary regulators of aldosterone release (Na(+), K(+) and angiotensin II) were not significantly altered in the appropriate directions to individually stimulate aldosterone secretion, increased aldosterone may have resulted from multiple, non-significant changes acting in concert. Aldosterone release may also be hypersensitive to slight reductions in plasma Na(+), which may be an adaptive mechanism in a species not known to drink seawater. Excreted aldosterone and urea were correlated suggesting aldosterone may regulate urea excretion during hypo-osmotic conditions in NES pups. Urea excretion appears to be a significant mechanism by which NES pups sustain electrolyte resorption during conditions that can negatively affect ionic homeostasis such as prolonged fasting.

  15. Remanent cell traction force in renal vascular smooth muscle cells induced by integrin-mediated mechanotransduction.

    PubMed

    Balasubramanian, Lavanya; Lo, Chun-Min; Sham, James S K; Yip, Kay-Pong

    2013-02-15

    It was previously demonstrated in isolated renal vascular smooth muscle cells (VSMCs) that integrin-mediated mechanotransduction triggers intracellular Ca(2+) mobilization, which is the hallmark of myogenic response in VSMCs. To test directly whether integrin-mediated mechanotransduction results in the myogenic response-like behavior in renal VSMCs, cell traction force microscopy was used to monitor cell traction force when the cells were pulled with fibronectin-coated or low density lipoprotein (LDL)-coated paramagnetic beads. LDL-coated beads were used as a control for nonintegrin-mediated mechanotransduction. Pulling with LDL-coated beads increased the cell traction force by 61 ± 12% (9 cells), which returned to the prepull level after the pulling process was terminated. Pulling with noncoated beads had a minimal increase in the cell traction force (12 ± 9%, 8 cells). Pulling with fibronectin-coated beads increased the cell traction force by 56 ± 20% (7 cells). However, the cell traction force was still elevated by 23 ± 14% after the pulling process was terminated. This behavior is analogous to the changes of vascular resistance in pressure-induced myogenic response, in which vascular resistance remains elevated after myogenic constriction. Fibronectin is a native ligand for α(5)β(1)-integrins in VSMCs. Similar remanent cell traction force was found when cells were pulled with beads coated with β(1)-integrin antibody (Ha2/5). Activation of β(1)-integrin with soluble antibody also triggered variations of cell traction force and Ca(2+) mobilization, which were abolished by the Src inhibitor. In conclusion, mechanical force transduced by α(5)β(1)-integrins triggered a myogenic response-like behavior in isolated renal VSMCs.

  16. Remanent cell traction force in renal vascular smooth muscle cells induced by integrin-mediated mechanotransduction

    PubMed Central

    Balasubramanian, Lavanya; Lo, Chun-Min; Sham, James S. K.

    2013-01-01

    It was previously demonstrated in isolated renal vascular smooth muscle cells (VSMCs) that integrin-mediated mechanotransduction triggers intracellular Ca2+ mobilization, which is the hallmark of myogenic response in VSMCs. To test directly whether integrin-mediated mechanotransduction results in the myogenic response-like behavior in renal VSMCs, cell traction force microscopy was used to monitor cell traction force when the cells were pulled with fibronectin-coated or low density lipoprotein (LDL)-coated paramagnetic beads. LDL-coated beads were used as a control for nonintegrin-mediated mechanotransduction. Pulling with LDL-coated beads increased the cell traction force by 61 ± 12% (9 cells), which returned to the prepull level after the pulling process was terminated. Pulling with noncoated beads had a minimal increase in the cell traction force (12 ± 9%, 8 cells). Pulling with fibronectin-coated beads increased the cell traction force by 56 ± 20% (7 cells). However, the cell traction force was still elevated by 23 ± 14% after the pulling process was terminated. This behavior is analogous to the changes of vascular resistance in pressure-induced myogenic response, in which vascular resistance remains elevated after myogenic constriction. Fibronectin is a native ligand for α5β1-integrins in VSMCs. Similar remanent cell traction force was found when cells were pulled with beads coated with β1-integrin antibody (Ha2/5). Activation of β1-integrin with soluble antibody also triggered variations of cell traction force and Ca2+ mobilization, which were abolished by the Src inhibitor. In conclusion, mechanical force transduced by α5β1-integrins triggered a myogenic response-like behavior in isolated renal VSMCs. PMID:23325413

  17. Lycium barbarum polysaccharides ameliorates renal injury and inflammatory reaction in alloxan-induced diabetic nephropathy rabbits.

    PubMed

    Zhao, Qihan; Li, Jingjing; Yan, Jun; Liu, Shuai; Guo, Yulin; Chen, Dajie; Luo, Qiong

    2016-07-15

    This study was aimed to investigate the effect of Lycium barbarum polysaccharides (LBP) on renal function and inflammatory reaction in rabbits with diabetic nephropathy. Diabetes was induced by injecting alloxan (ALX). Japanese male white rabbits were randomly assigned into 5 groups: normal control group, diabetic nephropathy (DN) model group, LBP prevention group, positive control group and LBP treatment group. LBP (10mg/kg) was given to the LBP prevention group after diabetes mellitus (DM) model succeeded for 12weeks and to the LBP treatment group after DN model succeeded for 4weeks. Telmisartan (3.7mg/kg) was given to the positive group after DN model succeeded for 4weeks, and the same volume of balanced saline was given to the normal group and DN group for 12weeks. Urea nitrogen (BUN), creatinine (SCr), and C-reaction protein (CRP) in serum were detected at the end of the 12th week. The expression of MCP-1 mRNA and ICAM-1 mRNA extracted from cortex were detected by RT-PCR. Western blot analysis was carried out to examine NF-κB p65 protein expression. LBP improves the renal function and alleviates the inflammatory reaction in the kidneys of diabetic rabbits. In addition, the prevention effect of LBP is better than the treatment effect of LBP. LBP has obvious protective effect on the diabetic nephropathy rabbits' renal function and postpones the appearance and development of DN. The mechanisms may be related to the reduction the expression of MCP-1mRNA and ICAM-1mRNA by restraining the expression of NF-κB and AngII. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. The effect of aqueous leaf extract of Telfairia occidentalis (Cucurbitaceae) on gentamycin-induced renal damage.

    PubMed

    Maduka, Stephen O; Ugwu, Chidiebere E; Onwudinjo, Oluchi J

    2017-01-01

    Despite the acclaimed beneficial effects of Telfaria occidentalis (TO), it is yet to be established that its aqueous extract is safe in the condition of renal impairment. Thus, the study investigated the effects of TO aqueous leaves extract on gentamycin-induced renal damage. The animals were distributed into five groups. Group A (control) was placed on standard rat feed. Groups B and C received 500 mg/kg and 80 mg/kg of TO and gentamicin for 21 days, respectively. Group D received 500 mg/kg of TO 14 days before 7 days administration of 80 mg/kg of gentamycin. Group E received 80 mg/kg of gentamicin for 14 days before 7 days administration of 500 mg/kg TO. Group F received 500 mg/kg of TO and 80mg/kg of gentamycin concurrently for 21 days. Biochemical and histological examinations were analysed by standard methods. The administration of TO for 7 days after 14 days of gentamycin injection and its concomitant administration with gentamicin for 21 days caused significant reduction (p<0.05) on the relative kidney weight, creatinine and uric acid levels compared to groups C and D. There was a significant decrease (p<0.05) in the mean serum potassium level in group C compared to groups A, B, D, and F. The histological reports showed that the combination of the extract and gentamycin (group F) seems to ameliorate the deleterious effect observed when gentamycin was administered alone. The administration of the extract together with and after the administration of gentamycin reverses renal damage caused by gentamycin.

  19. Renal arteriography

    MedlinePlus

    Renal angiogram; Angiography - kidney; Renal angiography; Renal artery stenosis - arteriography ... an artery by a blood clot Renal artery stenosis Renal cell cancer Angiomyolipomas (noncancerous tumors of the ...

  20. Galangin inhibits cell invasion by suppressing the epithelial-mesenchymal transition and inducing apoptosis in renal cell carcinoma.

    PubMed

    Cao, Jingyi; Wang, Hainan; Chen, Feifei; Fang, Jianzheng; Xu, Aiming; Xi, Wei; Zhang, Shengli; Wu, Gang; Wang, Zengjun

    2016-05-01

    Galangin, a flavonoid extracted from the root of the Alpinia officinarum Hence, has been shown to have anticancer properties against several types of cancer cells. However, the influence of galangin on human renal cancer cells remains to be elucidated. In the present study, proliferation of 786‑0 and Caki‑1 cells was suppressed following exposure to various doses of galangin. Cell invasion and wound healing assays were used to observe the effect of galangin on invasion and migration. The results demonstrated that Galangin inhibited cell invasion by suppressing the epithelial mesenchymal transition (EMT), with an increase in the expression of E‑cadherin and decreased expression levels of N‑cadherin and vimentin. The apoptosis induced by galangin was analyzed by flow cytometry. The results revealed that galangin induced apoptosis in a dose‑dependent manner. The accumulation of reactive oxygen species (ROS) is an important contributing factor for the apoptosis of various types of cancer cell. The dichlorofluorescein-diacetate method was used to determine the level of ROS. Galangin induced the accumulation of intracellular ROS and malondialdehyde, and decreased the activities of total antioxidant and superoxide dismutase in renal cell carcinoma cells. Galangin exerted an antiproliferative effect and inhibited renal cell carcinoma invasion by suppressing the EMT. This treatment also induced apoptosis, accompanied by the production of ROS. Therefore, the present data suggested that galangin may have beneficial effects by preventing renal cell carcinoma growth, inhibiting cell invasion via the EMT and inducing cell apoptosis.

  1. Galangin inhibits cell invasion by suppressing the epithelial-mesenchymal transition and inducing apoptosis in renal cell carcinoma

    PubMed Central

    CAO, JINGYI; WANG, HAINAN; CHEN, FEIFEI; FANG, JIANZHENG; XU, AIMING; XI, WEI; ZHANG, SHENGLI; WU, GANG; WANG, ZENGJUN

    2016-01-01

    Galangin, a flavonoid extracted from the root of the Alpinia officinarum Hence, has been shown to have anticancer properties against several types of cancer cells. However, the influence of galangin on human renal cancer cells remains to be elucidated. In the present study, proliferation of 786-0 and Caki-1 cells was suppressed following exposure to various doses of galangin. Cell invasion and wound healing assays were used to observe the effect of galangin on invasion and migration. The results demonstrated that Galangin inhibited cell invasion by suppressing the epithelial mesenchymal transition (EMT), with an increase in the expression of E-cadherin and decreased expression levels of N-cadherin and vimentin. The apoptosis induced by galangin was analyzed by flow cytometry. The results revealed that galangin induced apoptosis in a dose-dependent manner. The accumulation of reactive oxygen species (ROS) is an important contributing factor for the apoptosis of various types of cancer cell. The dichlorofluorescein-diacetate method was used to determine the level of ROS. Galangin induced the accumulation of intracellular ROS and malondialdehyde, and decreased the activities of total antioxidant and superoxide dismutase in renal cell carcinoma cells. Galangin exerted an antiproliferative effect and inhibited renal cell carcinoma invasion by suppressing the EMT. This treatment also induced apoptosis, accompanied by the production of ROS. Therefore, the present data suggested that galangin may have beneficial effects by preventing renal cell carcinoma growth, inhibiting cell invasion via the EMT and inducing cell apoptosis. PMID:27035542

  2. Calcium, zinc and vitamin E ameliorate cadmium-induced renal oxidative damage in albino Wistar rats.

    PubMed

    Adi, Pradeepkiran Jangampalli; Burra, Siva Prasad; Vataparti, Amardev Rajesh; Matcha, Bhaskar

    2016-01-01

    This study was aimed to examine the protective effects of supplementation with calcium + zinc (Ca + Zn) or vitamin E (Vit-E) on Cd-induced renal oxidative damage. Young albino Wistar rats (180 ± 10 g) (n = 6) control rats, Cd, Cd + Ca + Zn, and Cd + Vit-E experimental groups and the experimental period was 30 days. Rats were exposed to Cd (20 mg/kg body weight) alone treated as Cd treated group and the absence or presence of Ca + Zn (2 mg/kg each) or Vit-E (20 mg/kg body weight) supplementation treated as two separate groups. The activities of the stress marker enzymes superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and lipid peroxidase (LPx) were determined in renal mitochondrial fractions of experimental rats. We observed quantitative changes in SOD isoenzymatic patterns by non-denaturing PAGE analysis, and quantified band densities. These results showed that Cd exposure leads to decreases in SOD, CAT, GR, and GPx activities and a concomitant increase in LPx and GST activities. Ca + Zn and Vit-E administration with Cd significantly reversed Cd-induced perturbations in oxidative stress marker enzymes. However, Vit-E showed more inhibitory activity against Cd than did Ca + Zn, and it protected against Cd-induced nephrotoxicity.

  3. Decay-Accelerating Factor 1 Deficiency Exacerbates Leptospiral-Induced Murine Chronic Nephritis and Renal Fibrosis

    PubMed Central

    Ferrer, María F.; Scharrig, Emilia; Alberdi, Lucrecia; Cedola, Maia; Pretre, Gabriela; Drut, Ricardo; Song, Wen-Chao; Gomez, Ricardo M.

    2014-01-01

    Leptospirosis is a global zoonosis caused by pathogenic Leptospira, which can colonize the proximal renal tubules and persist for long periods in the kidneys of infected hosts. Here, we characterized the infection of C57BL/6J wild-type and Daf1−/− mice, which have an enhanced host response, with a virulent Leptospira interrogans strain at 14 days post-infection, its persistence in the kidney, and its link to kidney fibrosis at 90 days post-infection. We found that Leptospira interrogans can induce acute moderate nephritis in wild-type mice and is able to persist in some animals, inducing fibrosis in the absence of mortality. In contrast, Daf1−/− mice showed acute mortality, with a higher bacterial burden. At the chronic stage, Daf1−/− mice showed greater inflammation and fibrosis than at 14 days post-infection and higher levels at all times than the wild-type counterpart. Compared with uninfected mice, infected wild-type mice showed higher levels of IL-4, IL-10 and IL-13, with similar levels of α-smooth muscle actin, galectin-3, TGF-β1, IL-17, IFN-γ, and lower IL-12 levels at 90 days post-infection. In contrast, fibrosis in Daf1−/− mice was accompanied by high expression of α-smooth muscle actin, galectin-3, IL-10, IL-13, and IFN-γ, similar levels of TGF-β1, IL-12, and IL-17 and lower IL-4 levels. This study demonstrates the link between Leptospira-induced murine chronic nephritis with renal fibrosis and shows a protective role of Daf1. PMID:25032961

  4. Barnidipine ameliorates the vascular and renal injury in L-NAME-induced hypertensive rats.

    PubMed

    Alp Yildirim, F Ilkay; Eker Kizilay, Deniz; Ergin, Bülent; Balci Ekmekçi, Özlem; Topal, Gökçe; Kucur, Mine; Demirci Tansel, Cihan; Uydeş Doğan, B Sönmez

    2015-10-05

    The present study was aimed to investigate the influence of Barnidipine treatment on early stage hypertension by determining the function and morphology of the mesenteric and renal arteries as well as the kidney in N(ω)-Nitro-L-Arginine Methyl Ester (L-NAME)-induced hypertensive rats. Barnidipine (3 mg/kg/day p.o) was applied to rats after 2 weeks of L-NAME (60 mg/kg/day) administration, and continued for the next 3 weeks concomitantly with L-NAME. The systolic blood pressure (SBP) of rats was determined to decrease significantly in Barnidipine treated hypertensive group when compared to that of rats received L-NAME alone. Myograph studies demonstrated that the contractile reactivity to noradrenaline were significantly reduced in both of the resistance arteries while endothelium-dependent relaxations to acethylcholine were significantly diminished particularly in the mesenteric arteries of L-NAME-induced hypertensive rats. The impaired contractile and endothelial responses were completely restored by concomitant treatment of Barnidipine with L-NAME. Histopathological examinations verified structural alterations in the arteries as well as the kidney. Moreover, a decrease in endothelial nitric oxide synthase (eNOS) expression was presented both in the arteries and kidney of hypertensive rats which were increased following Barnidipine treatment. Elevated plasma levels of malondialdehyde (MDA) and myeloperoxidase (MPO) were also reduced in Barnidipine treated hypertensive rats. In conclusion, besides to its efficacy in reducing the elevated SBP, amelioration of vascular function, modulation of arterial and renal eNOS expressions as well as reduction of the plasma levels of oxidative and inflammatory biomarkers are possible supportive mechanisms mediating the favorable implications of Barnidipine in L-NAME-induced hypertension model.

  5. The peroxisome proliferator-activated receptor-γ agonist pioglitazone protects against cisplatin-induced renal damage in mice.

    PubMed

    Jesse, Cristiano R; Bortolatto, Cristiani F; Wilhelm, Ethel A; Roman, Silvane Souza; Prigol, Marina; Nogueira, Cristina W

    2014-01-01

    Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against non-diabetic kidney disease in experimental models. Here, we investigated the effect of PPAR-γ agonist pioglitazone against acute renal injury on a cisplatin model in mice. Nephrotoxicity was induced by a single intraperitoneal (i.p.) injection of cisplatin (10 mg kg(-1)). Pioglitazone was administered for six consecutive days in doses of 15 or 30 mg kg(-1)  day(-1), per os (p.o.), starting 3 days before cisplatin injection. Cisplatin treatment to mice induced a marked renal failure, characterized by a significant increase in serum urea and creatinine levels and alterations in renal tissue architecture. Cisplatin exposure induced oxidative stress as indicated by decreased levels of non-enzymatic antioxidant defenses [glutathione (GSH) and ascorbic acid levels] and components of the enzymatic antioxidant defenses [superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (GPx), glutathione reductase (GR) and and glutathione S-transferase(GST) activities)] in renal tissue. Administration of pioglitazone markedly protected against the increase in urea and creatinine levels and histological alterations in kidney induced by cisplatin treatment. Pioglitazone administration ameliorated GSH and ascorbic acid levels decreased by cisplatin exposure in mice. Pioglitazone protected against the inhibition of CAT, SOD, GPx, GR and GST activities induced by cisplatin in the kidneys of mice. These results indicated that pioglitazone has a protective effect against cisplatin-induced renal damage in mice. The protection is mediated by preventing the decline of antioxidant status. The results have implications in use of PPAR-γ agonists in human application for protecting against drugs-induced nephrotoxicity. Copyright © 2012 John Wiley & Sons, Ltd.

  6. Early Detection of Drug-Induced Renal Hemodynamic Dysfunction Using Sonographic Technology in Rats

    PubMed Central

    Fisch, Sudeshna; Liao, Ronglih; Hsiao, Li-Li; Lu, Tzongshi

    2016-01-01

    The kidney normally functions to maintain hemodynamic homeostasis and is a major site of damage caused by drug toxicity. Drug-induced nephrotoxicity is estimated to contribute to 19- 25% of all clinical cases of acute kidney injury (AKI) in critically ill patients. AKI detection has historically relied on metrics such as serum creatinine (sCr) or blood urea nitrogen (BUN) which are demonstrably inadequate in full assessment of nephrotoxicity in the early phase of renal dysfunction. Currently, there is no robust diagnostic method to accurately detect hemodynamic alteration in the early phase of AKI while such alterations might actually precede the rise in serum biomarker levels. Such early detection can help clinicians make an accurate diagnosis and help in in decision making for therapeutic strategy. Rats were treated with Cisplatin to induce AKI. Nephrotoxicity was assessed for six days using high-frequency sonography, sCr measurement and upon histopathology of kidney. Hemodynamic evaluation using 2D and Color-Doppler images were used to serially study nephrotoxicity in rats, using the sonography. Our data showed successful drug-induced kidney injury in adult rats by histological examination. Color-Doppler based sonographic assessment of AKI indicated that resistive-index (RI) and pulsatile-index (PI) were increased in the treatment group; and peak-systolic velocity (mm/s), end-diastolic velocity (mm/s) and velocity-time integral (VTI, mm) were decreased in renal arteries in the same group. Importantly, these hemodynamic changes evaluated by sonography preceded the rise of sCr levels. Sonography-based indices such as RI or PI can thus be useful predictive markers of declining renal function in rodents. From our sonography-based observations in the kidneys of rats that underwent AKI, we showed that these noninvasive hemodynamic measurements may consider as an accurate, sensitive and robust method in detecting early stage kidney dysfunction. This study also

  7. Numb Protects Human Renal Tubular Epithelial Cells From Bovine Serum Albumin-Induced Apoptosis Through Antagonizing CHOP/PERK Pathway.

    PubMed

    Ding, Xuebing; Ma, Mingming; Teng, Junfang; Shao, Fengmin; Wu, Erxi; Wang, Xuejing

    2016-01-01

    In recent studies, we found that Numb is involved in oxidative stress-induced apoptosis of renal proximal tubular cells; however, its function on ER stress-induced apoptosis in proteinuric kidney disease remains unknown. The objective of the present study is to explore the role of Numb in urinary albumin-induced apoptosis of human renal tubular epithelial cells (HKCs). In this study, we demonstrate that incubation of HKCs with bovine serum albumin (BSA) resulted in caspase three-dependent cell death. Numb expression was down-regulated by BSA in a time- and dose-dependent manner. Knockdown of Numb by siRNA sensitized HKCs to BSA-induced apoptosis, whereas overexpression of Numb protected HKCs from BSA-induced apoptosis. Moreover, BSA activated CHOP/PERK signaling pathway in a time- and dose-dependent manner as indicated by increased expression of CHOP, PERK, and P-PERK. Furthermore, knockdown of CHOP or PERK significantly attenuated the promoting effect of Numb on BSA-induced apoptosis, while overexpression of CHOP impaired the protective effect of Numb on BSA-induced apoptosis. Taken together, our findings demonstrate that Numb plays a protective role on BSA-induced apoptosis through inhibiting CHOP/PERK signaling pathway in human renal tubular epithelial cells. Therefore, the results from this study provides evidence that Numb is a new target of ER-associated apoptotic signaling networks and Numb may serve as a promising therapeutic target for proteinuric diseases.

  8. Antioxidant and Nephroprotective Activities of Aconitum heterophyllum Root in Glycerol Induced Acute Renal Failure in Rats

    PubMed Central

    Eerike, Madhavi; Raghuraman, Lakshmipathy Prabhu; Rajamanickam, Maignana Kumar

    2016-01-01

    Aim The present study was to evaluate the antioxidant and nephroprotective activities of ethanolic extract of Aconitum heterophyllum root (EEAHR) in glycerol induced acute renal failure (ARF) in Wistar albino rats. Materials and Methods In vitro antioxidant activity of EEAHR was assessed using the 2, 2-diphenyl-picrylhydrazyl (DPPH assay), nitric oxide radical scavenging (NO assay), hydrogen peroxide (H2O2 assay) and ferric reducing antioxidant power (FRAP) scavenging activity assays. In vivo study, rats were divided into four groups of six each for assessing the nephroprotective activity. Group-1 received normal saline, group-2 received 50% glycerol (10 ml/kg) alone, group-3 received glycerol and 250 mg/kg of EEAHR and group-4 received glycerol and 500 mg/kg of EEAHR. The renal injury and recovery was measured by serum creatinine, blood urea nitrogen (BUN), total proteins, albumin, urine output and histopathological changes. Results In vitro antioxidant activity of root extract was found to be equal to Vitamin C and in an in vivo study root extract treated animals showed significant attenuation of biochemical parameters and histopathological changes of the kidney compared to glycerol treated group and it was found to be more significant with the extract at 500 mg/kg than 250mg/kg. Conclusion The present study revealed that Aconitum heterophyllum root has shown antioxidant and nephroprotective activities. PMID:27134892

  9. Ameliorative effect of green tea against contrast-induced renal tubular cell injury.

    PubMed

    Nasri, Hamid; Hajian, Shabnam; Ahmadi, Ali; Baradaran, Azar; Kohi, Golnoosh; Nasri, Parto; Rafieian-Kopaei, Mahmoud

    2015-11-01

    Reactive oxygen species are a mediator of kidney damage by contrast media, and green tea is a potent-free radical scavenger. This study was designed to examine whether green tea could protect against the nephrotoxicity induced by contrast media. Forty rats were randomly divided into 4 groups. Group 1 was control; group 2 received contrast medium (intravenous iodixanol, 10 mL/kg, as a single dose); group 3 received contrast medium and then green tea extract for 3 days (10 mg/kg/d, intraperitoneal); and group 4 first received green tea and then contrast medium. Histological changes (degeneration, vacuolization of tubular renal cells, dilatation of tubular lumen, and presence of debris in the lumens) were assessed and recorded as scores from zero to 4. The sum of scores were used as the overal renal injury level. Groups 3 and 4 with green tea treatment had significantly higher overall scores than the control group, but significantly lower scores than group 2 with contrast medium only. A similar trend was seen for dilatation and degeneration levels. Vacuolization level was not significantly lower in the green tea groups as compared to the contrast medium group. Debris level was not significantly lower in group 3 than group 2. The differences were not significant between groups 3 and 4.   Conclusions. We observed beneficial effect of green tea against nephrotoxicity of contrast media. Green tea extract may offer an inexpensive and nontoxic intervention strategy in patients with a risk for nephrotoxicity with contrast media.

  10. Citrus Bioflavonoids Ameliorate Hyperoxaluria Induced Renal Injury and Calcium Oxalate Crystal Deposition in Wistar Rats

    PubMed Central

    Badrinathan, Sridharan; Shiju, Micheal Thomas; Arya, Ramachandran; Rajesh, Ganesh Nachiappa; Viswanathan, Pragasam

    2015-01-01

    Purpose: Citrus is considered as a medically important plant from ancient times and the bioflavonoids of different variety of citrus fruits were well explored for their biological activities. The study aim was to explore the effect of citrus bioflavonoids (CB) to prevent and cure hyperoxaluria induced urolithiasis. Methods: Twenty four Wistar rats were segregated into 4 Groups. Group 1: Control; Group 2: Urolithic (EG-0.75%); Group 3: Preventive study (EG+CB, day 1-50); Group 4: Curative study (EG+CB, day 30-50). Animals received CB orally (20mg/kg body weight) after performing a toxicity study. Results: Urinary risk factors and serum renal function parameters were significantly reduced by CB administration in both preventive and curative study (p<0.001). Hematoxylin & Eosin and von Kossa staining demonstrated that renal protection was offered by CB against EG insult. Immunohistochemical analyses revealed over expression and abnormal localization of THP and NF-κB in urolithic rats, while it was effectively regulated by CB supplementation. Conclusion: CB prevented and significantly controlled lithogenic factors and CaOx deposition in rats. We propose CB as a potential therapy in management of urolithiasis. PMID:26504765

  11. Enhanced renal clearance of vancomycin in rats with carcinogen-induced osteosarcoma.

    PubMed

    Shimada, Izumi; Iwata, Chieko; Taga, Shino; Teramachi, Hitomi; Nomura, Masaaki; Miyamoto, Ken-Ichi; Tsuciya, Hiroyuki; Wada, Takashi; Kimura, Kazuko; Matsushita, Ryo

    2012-03-01

    Recently, it has been reported that total clearance (CLtot) of vancomycin is significantly higher in patients with malignancies compared to those without malignancies. In the present study, to clarify the mechanism of this enhancement in malignancy, we adopted rat animal models, using chemical carcinogen-induced osteosarcoma, selected lung metastatic lesions (C-SLM), transplanted into thigh muscles. The CLtot and renal clearance (CLr) of vancomycin in the tumor-bearing rats were increased compared to the ones of the control rats without tumor. However, there was no difference in the glomerular filtration rate. The plasma concentrations of interleukin (IL)-1β and IL-6, were elevated in the tumor-bearing rats. When renal proximal tubular epithelial cells (RPTEC) were exposed to IL-1β, IL-6, and tumor necrosis factor (TNF)-α simultaneously, the excretory ratio increased significantly. These findings suggest that tubular excretion or re-absorption by cytokines might be associated with changes in the vancomycin CLtot enhancement in the tumor-bearing rats.

  12. Isoproterenol inhibits fibroblast growth factor-2-induced growth of renal epithelial cells.

    PubMed

    Izevbigie, E B; Gutkind, J S; Ray, P E

    2000-08-01

    The signal transduction pathways modulating bFGF effects in renal tubular epithelial cells (RTEc) are not completely understood. Since the cAMP and the mitogen-activated protein kinase (MAPK) pathways can modulate the growth of RTEc, we studied whether two cAMP elevating agents, isoproterenol and 8-bromo-cAMP, would modulate basic fibroblast growth factor (bFGF) induction of MAPK activity (ERK-2) and cell proliferation in human renal proximal tubular epithelial cells (RPTEc) and Madin-Darby canine kidney cells (MDCK clone EI1). Isoproterenol, but not bFGF, stimulated cAMP production in RPTEc and MDCKEI1 cells. bFGF, isoproterenol, and 8-bromo-cAMP alone increased ERK-2 activity in both cell types. However, isoproterenol and 8-bromo-cAMP partially inhibited the bFGF induction of ERK-2 activity, but only isoproterenol inhibited the proliferation of both cell types. PD098059 (25 microM), an inhibitor of MAPK kinase (MEK 1/2), blocked the bFGF mitogenic effects, but did not affect the 8-bromo-cAMP-induced mitogenic effects in MDCKEI1 cells. These findings suggest that activation of ERK-2 is required but not sufficient for mitogenesis in RTEc. We conclude that isoproterenol inhibits the growth-promoting effects of bFGF in RTEc via MEK-dependent and -independent pathways.

  13. Molecular mechanisms for uremic toxin-induced oxidative tissue damage via a cardiovascular-renal connection.

    PubMed

    Watanabe, Hiroshi

    2013-01-01

    Chronic kidney disease (CKD), marked by a progressive loss in renal function, is a leading cause of hemodialysis initiation and cardiovascular disease (CVD). There are currently 13.3 million patients with CKD and 300 thousand patients are currently undergoing hemodialysis in Japan. Therefore, preventing the initiation of dialysis and reducing the risk of cardiovascular death are high-priority issues from the viewpoint of public health and economic implications. Understanding the molecular mechanism responsible for the progression of CKD and cardiovascular damage regarding crosstalk between the kidney and cardiovascular system is an important issue in controlling the pathogenesis of CKD-CVD. However, the mechanisms involved in CKD-CVD are not well understood. This hinders the development of new treatment strategies. We have been investigating the role of protein bound uremic toxins, that are difficult to remove by hemodialysis, on the onset and progression of CKD and CVD. The relationship between their redox properties and the pathogenesis of CKD-CVD was examined. In this review, we focus on two sulfate conjugated uremic toxins, namely, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), and summarize recent studies that provide new insights on the molecular mechanisms responsible for uremic toxin-induced oxidative tissue damage via a cardiovascular-renal connection.

  14. Thiazolidinediones and Edema: Recent Advances in the Pathogenesis of Thiazolidinediones-Induced Renal Sodium Retention.

    PubMed

    Horita, Shoko; Nakamura, Motonobu; Satoh, Nobuhiko; Suzuki, Masashi; Seki, George

    2015-01-01

    Thiazolidinediones (TZDs) are one of the major classes of antidiabetic drugs that are used widely. TZDs improve insulin resistance by activating peroxisome proliferator-activated receptor gamma (PPARγ) and ameliorate diabetic and other nephropathies, at least, in experimental animals. However, TZDs have side effects, such as edema, congestive heart failure, and bone fracture, and may increase bladder cancer risk. Edema and heart failure, which both probably originate from renal sodium retention, are of great importance because these side effects make it difficult to continue the use of TZDs. However, the pathogenesis of edema remains a matter of controversy. Initially, upregulation of the epithelial sodium channel (ENaC) in the collecting ducts by TZDs was thought to be the primary cause of edema. However, the results of other studies do not support this view. Recent data suggest the involvement of transporters in the proximal tubule, such as sodium-bicarbonate cotransporter and sodium-proton exchanger. Other studies have suggested that sodium-potassium-chloride cotransporter 2 in the thick ascending limb of Henle and aquaporins are also possible targets for TZDs. This paper will discuss the recent advances in the pathogenesis of TZD-induced sodium reabsorption in the renal tubules and edema.

  15. Gut microbial metabolite TMAO contributes to renal dysfunction in a mouse model of diet-induced obesity.

    PubMed

    Sun, Guangping; Yin, Zhongmin; Liu, Naiquan; Bian, Xiaohui; Yu, Rui; Su, Xiaoxiao; Zhang, Beiru; Wang, Yanqiu

    2017-11-18

    Emerging evidence shows that obesity induces renal injury and is an independent risk factor for the development of chronic kidney disease (CKD), even without diabetes or hyperglycemia. Although multiple metabolic factors have been suggested to account for obesity-associated renal injury, the precious underlying mechanisms are not completely understood. Recent study shows that increased trimethylamine N-Oxide (TMAO), a gut microbiota-generated metabolite, directly contributes to renal interstitial fibrosis and dysfunction. Circulating TMAO is elevated in high-fat diets (HFD)-induced obese animals. Here we tested the hypothesis that elevated TMAO might play a contributory role in the development of renal dysfunction in a mouse model of HFD-induced obesity that mimics human obesity syndrome. Male C57BL/6 mice received either a low-fat diet (LFD) or a HFD, without or with 3,3-Dimethyl-1-butanol (DMB, a trimethylamine formation inhibitor) for 16 weeks. Compared with mice fed a LFD, mice fed a HFD developed obesity and metabolic disorders, and exhibited significantly elevated plasma TMAO levels at the end of the experiment. Molecular and morphological studies revealed that renal interstitial fibrosis, phosphorylation of SMAD3 (a key regulator of renal fibrosis), expression of kidney injury molecule-1 and plasma cystatin C were significantly increased in mice fed a HFD, compared with mice fed a LFD. Additionally, expression of NADPH oxidase-4 and pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1 β was also augmented in mice fed a HFD as compared to mice fed a LFD. These molecular and morphological alterations observed in mice fed a HFD were prevented by concomitant treatment with DMB, which reduced plasma TMAO levels. Furthermore, elevated circulating TMAO levels were positively correlated with increased renal interstitial fibrosis and expression of kidney injury molecule-1. Notable, there was no difference in blood pressure among groups, and DMB

  16. Hypoxia-inducible factor-1α activation improves renal oxygenation and mitochondrial function in early chronic kidney disease.

    PubMed

    Thomas, Joanna L; Pham, Hai; Li, Ying; Hall, Elanore; Perkins, Guy A; Ali, Sameh S; Patel, Hemal H; Singh, Prabhleen

    2017-08-01

    The pathophysiology of chronic kidney disease (CKD) is driven by alterations in surviving nephrons to sustain renal function with ongoing nephron loss. Oxygen supply-demand mismatch, due to hemodynamic adaptations, with resultant hypoxia, plays an important role in the pathophysiology in early CKD. We sought to investigate the underlying mechanisms of this mismatch. We utilized the subtotal nephrectomy (STN) model of CKD to investigate the alterations in renal oxygenation linked to sodium (Na) transport and mitochondrial function in the surviving nephrons. Oxygen delivery was significantly reduced in STN kidneys because of lower renal blood flow. Fractional oxygen extraction was significantly higher in STN. Tubular Na reabsorption was significantly lower per mole of oxygen consumed in STN. We hypothesized that decreased mitochondrial bioenergetic capacity may account for this and uncovered significant mitochondrial dysfunction in the early STN kidney: higher oxidative metabolism without an attendant increase in ATP levels, elevated superoxide levels, and alterations in mitochondrial morphology. We further investigated the effect of activation of hypoxia-inducible factor-1α (HIF-1α), a master regulator of cellular hypoxia response. We observed significant improvement in renal blood flow, glomerular filtration rate, and tubular Na reabsorption per mole of oxygen consumed with HIF-1α activation. Importantly, HIF-1α activation significantly lowered mitochondrial oxygen consumption and superoxide production and increased mitochondrial volume density. In conclusion, we report significant impairment of renal oxygenation and mitochondrial function at the early stages of CKD and demonstrate the beneficial role of HIF-1α activation on renal function and metabolism.

  17. Uric Acid Induces Renal Inflammation via Activating Tubular NF-κB Signaling Pathway

    PubMed Central

    Zhou, Yang; Fang, Li; Jiang, Lei; Wen, Ping; Cao, Hongdi; He, Weichun; Dai, Chunsun; Yang, Junwei

    2012-01-01

    Inflammation is a pathologic feature of hyperuricemia in clinical settings. However, the underlying mechanism remains unknown. Here, infiltration of T cells and macrophages were significantly increased in hyperuricemia mice kidneys. This infiltration of inflammatory cells was accompanied by an up-regulation of TNF-α, MCP-1 and RANTES expression. Further, infiltration was largely located in tubular interstitial spaces, suggesting a role for tubular cells in hyperuricemia-induced inflammation. In cultured tubular epithelial cells (NRK-52E), uric acid, probably transported via urate transporter, induced TNF-α, MCP-1 and RANTES mRNA as well as RANTES protein expression. Culture media of NRK-52E cells incubated with uric acid showed a chemo-attractive ability to recruit macrophage. Moreover uric acid activated NF-κB signaling. The uric acid-induced up-regulation of RANTES was blocked by SN 50, a specific NF-κB inhibitor. Activation of NF-κB signaling was also observed in tubule of hyperuricemia mice. These results suggest that uric acid induces renal inflammation via activation of NF-κB signaling. PMID:22761883

  18. Rapamycin inhibition of mTORC1 reverses lithium-induced proliferation of renal collecting duct cells

    PubMed Central

    Gao, Yang; Romero-Aleshire, Melissa J.; Cai, Qi; Price, Theodore J.

    2013-01-01

    Nephrogenic diabetes insipidus (NDI) is the most common renal side effect in patients undergoing lithium therapy for bipolar affective disorders. Approximately 2 million US patients take lithium of whom ∼50% will have altered renal function and develop NDI (2, 37). Lithium-induced NDI is a defect in the urinary concentrating mechanism. Lithium therapy also leads to proliferation and abundant renal cysts (microcysts), commonly in the collecting ducts of the cortico-medullary region. The mTOR pathway integrates nutrient and mitogen signals to control cell proliferation and cell growth (size) via the mTOR Complex 1 (mTORC1). To address our hypothesis that mTOR activation may be responsible for lithium-induced proliferation of collecting ducts, we fed mice lithium chronically and assessed mTORC1 signaling in the renal medulla. We demonstrate that mTOR signaling is activated in the renal collecting ducts of lithium-treated mice; lithium increased the phosphorylation of rS6 (Ser240/Ser244), p-TSC2 (Thr1462), and p-mTOR (Ser2448). Consistent with our hypothesis, treatment with rapamycin, an allosteric inhibitor of mTOR, reversed lithium-induced proliferation of medullary collecting duct cells and reduced levels of p-rS6 and p-mTOR. Medullary levels of p-GSK3β were increased in the renal medullas of lithium-treated mice and remained elevated following rapamycin treatment. However, mTOR inhibition did not improve lithium-induced NDI and did not restore the expression of collecting duct proteins aquaporin-2 or UT-A1. PMID:23884148

  19. Rapamycin inhibition of mTORC1 reverses lithium-induced proliferation of renal collecting duct cells.

    PubMed

    Gao, Yang; Romero-Aleshire, Melissa J; Cai, Qi; Price, Theodore J; Brooks, Heddwen L

    2013-10-15

    Nephrogenic diabetes insipidus (NDI) is the most common renal side effect in patients undergoing lithium therapy for bipolar affective disorders. Approximately 2 million US patients take lithium of whom ∼50% will have altered renal function and develop NDI (2, 37). Lithium-induced NDI is a defect in the urinary concentrating mechanism. Lithium therapy also leads to proliferation and abundant renal cysts (microcysts), commonly in the collecting ducts of the cortico-medullary region. The mTOR pathway integrates nutrient and mitogen signals to control cell proliferation and cell growth (size) via the mTOR Complex 1 (mTORC1). To address our hypothesis that mTOR activation may be responsible for lithium-induced proliferation of collecting ducts, we fed mice lithium chronically and assessed mTORC1 signaling in the renal medulla. We demonstrate that mTOR signaling is activated in the renal collecting ducts of lithium-treated mice; lithium increased the phosphorylation of rS6 (Ser240/Ser244), p-TSC2 (Thr1462), and p-mTOR (Ser2448). Consistent with our hypothesis, treatment with rapamycin, an allosteric inhibitor of mTOR, reversed lithium-induced proliferation of medullary collecting duct cells and reduced levels of p-rS6 and p-mTOR. Medullary levels of p-GSK3β were increased in the renal medullas of lithium-treated mice and remained elevated following rapamycin treatment. However, mTOR inhibition did not improve lithium-induced NDI and did not restore the expression of collecting duct proteins aquaporin-2 or UT-A1.

  20. Febuxostat exerts dose-dependent renoprotection in rats with cisplatin-induced acute renal injury.

    PubMed

    Fahmi, Alaa N A; Shehatou, George S G; Shebl, Abdelhadi M; Salem, Hatem A

    2016-08-01

    The aim of the present study was to investigate possible renoprotective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against cisplatin (CIS)-induced acute kidney injury in rats. Male Sprague Dawley rats were randomly assigned into four groups of six rats each, as follows: normal control; CIS, received a single intraperitoneal injection of CIS (7.5 mg/kg); [febuxostat 10 + CIS] and [febuxostat 15 + CIS], received febuxostat (10 and 15 mg/kg/day, respectively, orally) for 14 days, starting 7 days before CIS injection. At the end of experiment, 24-h urine output was collected and serum was separated for biochemical assessments. Kidney tissue homogenate was prepared for determination of oxidative stress-related parameters, nitric oxide (NO), and tumor necrosis factor-α (TNF-α). Moreover, histological alterations of kidney tissues were evaluated. Serum creatinine, blood urea, and urinary total protein were significantly elevated, while serum albumin and creatinine clearance were significantly reduced, in CIS-intoxicated rats, indicating depressed renal function. CIS administration also elicited renal oxidative stress, evidenced by increased malondialdehyde content and depleted levels of reduced glutathione and superoxide dismutase activity. Moreover, enhancement of renal levels of the pro-inflammatory TNF-α indicated renal inflammation. CIS-administered rats also showed increased serum lactate dehydrogenase activity and reduced renal NO bioavailability. Febuxostat dose-dependently improved or restored these changes to near-normal (e.g., mean ± SD of serum creatinine levels in control, CIS, [febuxostat 10 + CIS] and [febuxostat 15 + CIS] groups were 0.78 ± 0.19, 3.28 ± 2.0 (P < 0.01 versus control group), 1.03 ± 0.36 (P < 0.01 versus CIS group), and 0.93 ± 0.21 (P < 0.01 versus CIS group) mg/dl, respectively, and blood urea levels for the different groups were 36.80 ± 4.36, 236.10 ± 89.19 (P < 0

  1. Beneficial effects of diminished production of hydrogen sulfide or carbon monoxide on hypertension and renal injury induced by NO withdrawal

    PubMed Central

    Wesseling, Sebastiaan; Fledderus, Joost O; Verhaar, Marianne C; Joles, Jaap A

    2015-01-01

    Background and Purpose Whether NO, carbon monoxide (CO) and hydrogen sulfide (H2S) compensate for each other when one or more is depleted is unclear. Inhibiting NOS causes hypertension and kidney injury. Both global depletion of H2S by cystathionine γ-lyase (CSE) gene deletion and low levels of exogenous H2S cause hypertension. Inhibiting CO-producing enzyme haeme oxygenase-1 (HO-1) makes rodents hypersensitive to hypertensive stimuli. We hypothesized that combined inhibition of NOS and HO-1 exacerbates hypertension and renal injury, but how combined inhibition of NOS and CSE affect hypertension and renal injury was unclear. Experimental Approach Rats were treated with inhibitors of NOS (L-nitroarginine; LNNA), CSE (DL-propargylglycine; PAG), or HO-1 (tin protoporphyrin; SnPP) singly for 1 or 4 weeks or in combinations for 4 weeks. Key Results LNNA always reduced NO, decreased H2S and increased CO after 4 weeks. PAG abolished H2S, always enhanced CO and reduced NO, but not when used in combination with other inhibitors. SnPP always increased NO, enhanced H2S and inhibited CO after 1 week. Rats treated with LNNA, but not PAG and SnPP, rapidly developed hypertension followed by renal dysfunction. LNNA-induced hypertension was ameliorated and renal dysfunction prevented by all additional treatments. Renal HO-1 expression was increased by LNNA in injured tubules and increased in all tubules by all other treatments. Conclusions and Implications The amelioration of LNNA-induced hypertension and renal injury by additional inhibition of H2S and/or CO-producing enzymes appeared to be associated with secondary increases in renal CO or NO production. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6 PMID:24597655

  2. Mechanism of chloroform-induced renal toxicity: Non-involvement of hepatic cytochrome P450-dependent metabolism

    SciTech Connect

    Fang Cheng; Behr, Melissa; Xie Fang; Lu Shijun; Doret, Meghan; Luo Hongxiu; Yang Weizhu; Aldous, Kenneth; Ding Xinxin; Gu Jun

    2008-02-15

    Chloroform causes hepatic and renal toxicity in a number of species. In vitro studies have indicated that chloroform can be metabolized by P450 enzymes in the kidney to nephrotoxic intermediate, although direct in vivo evidence for the role of renal P450 in the nephrotoxicity has not been reported. This study was to determine whether chloroform renal toxicity persists in a mouse model with a liver-specific deletion of the P450 reductase (Cpr) gene (liver-Cpr-null). Chloroform-induced renal toxicity and chloroform tissue levels were compared between the liver-Cpr-null and wild-type mice at 24 h following differing doses of chloroform. At a chloroform dose of 150 mg/kg, the levels of blood urea nitrogen (BUN) were five times higher in the exposed group than in the vehicle-treated one for the liver-Cpr-null mice, but they were only slightly higher in the exposed group than in the vehicle-treated group for the wild-type mice. Severe lesions were found in the kidney of the liver-Cpr-null mice, while only mild lesions were found in the wild-type mice. At a chloroform dose of 300 mg/kg, severe kidney lesions were observed in both strains, yet the BUN levels were still higher in the liver-Cpr-null than in the wild-type mice. Higher chloroform levels were found in the tissues of the liver-Cpr-null mice. These findings indicated that loss of hepatic P450-dependent chloroform metabolism does not protect against chloroform-induced renal toxicity, suggesting that renal P450 enzymes play an essential role in chloroform renal toxicity.

  3. CRM1 inhibitor S109 suppresses cell proliferation and induces cell cycle arrest in renal cancer cells.

    PubMed

    Liu, Xuejiao; Chong, Yulong; Liu, Huize; Han, Yan; Niu, Mingshan

    2016-03-01

    Abnormal localization of tumor suppressor proteins is a common feature of renal cancer. Nuclear export of these tumor suppressor proteins is mediated by chromosome region maintenance-1 (CRM1). Here, we investigated the antitumor eff ects of a novel reversible inhibitor of CRM1 on renal cancer cells. We found that S109 inhibits the CRM1-mediated nuclear export of RanBP1 and reduces protein levels of CRM1. Furthermore, the inhibitory eff ect of S109 on CRM1 is reversible. Our data demonstrated that S109 signifi cantly inhibits proliferation and colony formation of renal cancer cells. Cell cycle assay showed that S109 induced G1-phase arrest, followed by the reduction of Cyclin D1 and increased expression of p53 and p21. We also found that S109 induces nuclear accumulation of tumor suppressor proteins, Foxo1 and p27. Most importantly, mutation of CRM1 at Cys528 position abolished the eff ects of S109. Taken together, our results indicate that CRM1 is a therapeutic target in renal cancer and the novel reversible CRM1 inhibitor S109 can act as a promising candidate for renal cancer therapy.

  4. Renal vasculature reactivity to agonist of P2X7 receptor is increased in streptozotocin-induced diabetes.

    PubMed

    Kreft, Ewelina; Kowalski, Robert; Jankowski, Maciej; Szczepańska-Konkel, Mirosława

    2016-02-01

    Diabetic nephropathy is characterized by the dysfunction of renal microvasculature. The involvement of the P2X7 receptor, being a part of the purinergic system, is presumable in this process. The aim of our study was to investigate the P2X7 receptor-mediated renal microvasculature response and renal metabolism of extracellular adenine nucleotides in diabetic rats. Study was performed on streptozotocin-induced diabetic Wistar rats. The vascular response to BzATP, an agonist of the P2X7 receptor, was monitored based on the changes of cortical blood flow (CBF), glomerular filtration rate (GFR) and glomerular inulin space (GIS). The renal interstitial fluid (RIF) was probed by microdialysis technique and concentrations of ATP and adenosine were measured. Activity on NTDPase and 5'-nucleotidases was measured on renal membranes. Diabetic kidneys were characterized by decreased ATP RIF and increased adenosine RIF concentrations with accompanied enhancement of NTDPase and 5'-nucleotidase activities. BzATP induced a more pronounced increase of CBF and decrease of GFR and GIS in diabetes rats. These effects were abolished by A438079, an antagonist of the P2X7 receptor. It is possible that increased P2X7 receptor reactivity may be involved in the pathogenesis of diabetic nephropathy. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  5. Polyomavirus BK Induces Inflammation via Up-regulation of CXCL10 at Translation Levels in Renal Transplant Patients with Nephropathy.

    PubMed

    Kariminik, Ashraf; Dabiri, Shahriar; Yaghobi, Ramin

    2016-08-01

    Polyomavirus BK-associated nephropathy (BKAN) is an important mechanism for renal losing after kidney transplantation. It seems that Polyomavirus BK can induce nephropathy by direct cell lysis and stimulation of the immune system and induction of inflammation. CXCL10 is a pro-inflammatory cytokine which stimulates the migration and activation of immune cells to the infected sites. Therefore, the aim of the current study was to evaluate the messenger RNA (mRNA) and protein levels of CXCL10 in the Polyomavirus BK-infected and Polyomavirus BK-non-infected post renal transplanted nephropathic patients in comparison to healthy controls. In this cross-sectional study, Polyomavirus BK-infected post renal transplanted nephropathic patients, Polyomavirus BK-non-infected post renal transplanted nephropathic patients, and healthy controls were enrolled to evaluate mRNA and protein levels of CXCL10 by real-time PCR and ELISA techniques, respectively. mRNA levels of CXCL10 were not significantly different among participants, while serum levels of CXCL10 were significantly elevated in the Polyomavirus BK-infected patients when compared to non-infected patients as well as controls and in non-infected patients when compared to healthy controls. Due to the results, it seems that Polyomavirus BK may potentially induce renal losing through stimulation of inflammation via increasing translation of CXCL10, as a pro-inflammatory chemokine.

  6. Pre-procedural renal resistive index accurately predicts contrast-induced acute kidney injury in patients with preserved renal function submitted to coronary angiography.

    PubMed

    Wybraniec, Maciej T; Bożentowicz-Wikarek, Maria; Chudek, Jerzy; Mizia-Stec, Katarzyna

    2017-05-01

    The study aimed to evaluate the clinical utility of ultrasonographic intra-renal blood flow parameters, together with the wide range of different risk factors, for the prediction of contrast-induced acute kidney injury (CI-AKI) in patients with preserved renal function, referred for coronary angiography or percutaneous coronary interventions (CA/PCI). This prospective study covered 95 consecutive patients (69.5% men; median age 65 years) subject to elective or urgent CA/PCI. Data regarding 128 peri-procedural variables were collected. Ultrasonographic intra-renal blood flow parameters, including renal resistive index (RRI) and pulsatility index (RPI), were acquired directly before the procedure. CI-AKI was defined as ≥50% relative or ≥0.3 mg/dL absolute increase of serum creatinine 48 h after procedure. CI-AKI was confirmed in nine patients (9.5%). Patients with CI-AKI had higher SYNTAX score (p = 0.0002), higher rate of left main disease (p < 0.00001), peripheral artery disease (PAD; p = 0.02), coronary artery anomaly (p = 0.017), more frequently underwent surgical revascularization (p = 0.0003), 'had greater...' intima-(p = 0.004) and extra-medial thickness (p = 0.001), and received higher contrast media dose (p = 0.049), more often overused non-steroidal anti-inflammatory drugs (p = 0.001), and had substantially higher pre-procedural RRI (0.69 vs. 0.62; p = 0.005) and RPI values (1.54 vs. 1.36; p = 0.017). Logistic regression confirmed age, SYNTAX score, presence of PAD, diabetes mellitus, and pre-procedural RRI independently predicted CI-AKI onset (AUC = 0.95; p < 0.0001). Pre-procedural RRI > 0.69 had 78% sensitivity and 81% specificity in CI-AKI prediction. High pre-procedural RRI seems to be a useful novel risk factor for CI-AKI in patients with preserved renal function. Coronary, peripheral and renal vascular pathology contribute to the development of CI-AKI following CA/PCI.

  7. Mitigation of 5-Fluorouracil induced renal toxicity by chrysin via targeting oxidative stress and apoptosis in wistar rats.

    PubMed

    Rashid, Summya; Ali, Nemat; Nafees, Sana; Hasan, Syed Kazim; Sultana, Sarwat

    2014-04-01

    5-Fluorouracil (5-FU) is a potent antineoplastic agent commonly used for the treatment of various malignancies. It has diverse adverse effects such as cardiotoxicity, nephrotoxicity and hepatotoxicity which restrict its wide and extensive clinical usage. It causes marked organ toxicity coupled with increased oxidative stress and apoptosis. Chrysin (CH), a natural flavonoid found in many plant extracts, propolis, blue passion flower. It has antioxidative and anti-cancerous properties. The present study was designed to investigate the protective effects of CH against 5-FU induced renal toxicity in wistar rats using biochemical, histopathological and immunohistochemical approaches. Rats were subjected to prophylactic oral treatment of CH (50 and 100mg/kg b.wt.) for 21 days against renal toxicity induced by single intraperitoneal administration of 5-FU (150 mg/kg b.wt.). The possible mechanism of 5-FU induced renal toxicity is the induction of oxidative stress; activation of apoptotic pathway by upregulation of p53, bax, caspase-3 and down regulating Bcl-2. However prophylactic treatment of CH decreased serum toxicity markers, increased anti-oxidant armory as well as regulated apoptosis in kidney. Histopathological changes further confirmed the biochemical and immunohistochemical results. Therefore, results of the present finding suggest that CH may be a useful modulator in mitigating 5-FU induced renal toxicity.

  8. Dengue Fever-induced Thrombotic Microangiopathy: An Unusual Cause of Renal Failure.

    PubMed

    Bhargava, V; Gupta, P; Kauntia, R; Bajpai, G

    2017-01-01

    Dengue fever is a tropical infection, which is mosquito-borne disease, caused by dengue virus and spread by Aedes mosquitoes. The incidence of dengue fever has risen rapidly over the past few years. About half of dengue infections are asymptomatic, and a great majority present with fever and body ache. However, the occurrence of complications is well known, including acute kidney injury (AKI). AKI in dengue is usually attributable to a pre-renal cause. Thrombotic microangiopathy is an extremely rare complication of dengue fever, with only a few published case reports in medical literature. This case intends to highlight the importance of recognizing dengue fever-induced thrombotic microangiopathy by physicians and pathologists, enabling better diagnosis and management of this life-threatening condition.

  9. [Effect and mechanism of jianpi qinghua recipe on renal functions of adriamycin-induced nephropathic rats from the angle of inhibiting renal fibrosis].

    PubMed

    Ma, Xiao-hong; He, Li-qun

    2014-06-01

    To explore the effect of Jianpi Qinghua Recipe (JQR) on renal functions of adriamycin-induced focal segmental glomerular sclerosis (FSGS) rats from the angle of activating fibroblasts to myofibroblast (MyoF). Totally 56 rats were randomly divided into the normal control group (n=8), the sham-operation group (n =8), and the model group (n=40). The FSGS rat model was induced by nephrectomy of left kidney plus intravenous injection of adriamycin. Successfully modeled rats were further divided into 5 groups, i.e., the model group, the JQR group, the JPR (Jianpi Recipe) group, the QHR (Qinghua Recipe) group, and the NDQ (Niaoduqing) group, 8 in each group. Corresponding drugs were administered to rats in all groups, 2 mL each time, for 56 days. The effect of JQR on serum creatinine (SCr), urea nitrogen, 24-h urinary protein excretion, a-smooth muscle actin (alpha-SMA) mRNA, collagen type III (Col III) mRNA, fibronectin (FN) mRNA, and collagen type IV (Col IV) mRNA were observed. JQR could significantly lower SCr, urea nitrogen, and 24-h urinary protein excretion levels (P < 0.01), and significantly decrease mRNA levels of alpha-SMA, Col III, FN, and Col IV (P < 0.01). It was advantageous over the NDQ group. Compared with JPR, the relative expression levels of Col III mRNA and FN mRNA of JQR and QHR were significantly lower (P < 0.01). JQR could improve the renal function and renal fibrosis in the adriamycin-induced nephropathic model rats. Its efficacy was superior to that of NDQ. Its mechanisms might be linked with inhibiting activation of fibroblasts.

  10. MiR-138 induces renal carcinoma cell senescence by targeting EZH2 and is downregulated in human clear cell renal cell carcinoma.

    PubMed

    Liang, Jiaqian; Zhang, Yajing; Jiang, Guosong; Liu, Zhouqiang; Xiang, Wei; Chen, Xuanyu; Chen, Zhaohui; Zhao, Jun

    2013-01-01

    MiR-138 has been shown to be downregulated in various cancers, including head and neck squamous cell carcinoma (HNSCC) and clear cell renal carcinoma (ccRCC). In the present study, we aimed to reveal the mechanism of miR-138 induction of senescence in renal carcinoma cells and identify its specific target genes. We used qRT-PCR to analyze miR-138 expression levels in renal carcinoma cell lines and ccRCC samples. The activity of β-galactosidase was measured for functional analysis after miR-138 mimic transfection. To identify the targets of miR-138, we used three types of target prediction software to determine three candidate target genes. Furthermore, a 3'UTR luciferase assay was performed. Western blotting was used to detect the protein expression levels of candidate target genes. Additionally, knockdown of EZH2 by its siRNA was performed. The expression of miR-138 was downregulated in RCC cells lines and in tumor samples compared with their controls. Transfection of miR-138 mimic induced SN-12 cell senescence, decreased the protein expression of EZH2, and increased the protein expression of P16. Furthermore, miR-138 decreased the 3'UTR luciferase activity of EZH2. The knockdown of EZH2 by siRNA induced SN-12 cell senescence, decreased the protein expression level of EZH2, and increased the protein expression of P16. MiR-138 is a tumor-suppressor miRNA in ccRCC that induces SN-12 cell senescence by downregulating EZH2 expression and upregulating P16 expression.

  11. Nephroprotective effects of Isaria felina in rats with adenine-induced chronic renal failure.

    PubMed

    Yang, Xihua; Zhang, Shengwan; Ren, Liansheng; Zhang, Hong; Bai, Xihua

    2013-09-01

    Chronic renal failure (CRF) is a progressive, life-threatening condition with limited treatment options. Cordyceps sinensis is a fungus that has nephroprotective effects, and Isaria felina (IF) is a fungus isolated from C. sinensis fruiting bodies. We evaluated IF efficacy using an adenine-induced CRF animal model. Forty male Sprague-Dawley rats were divided into normal control (n = 8) and adenine groups (n = 32; 100 mg/kg for 30 days). The adenine group was subdivided into a model control group (n = 7), a positive control group (200 mg/kg Jinshuibao capsule (JSB; n = 8), and two IF groups (200 mg/kg, n = 8; 100 mg/kg, n = 8). After treatment for 30 days, animals were narcotized and abdominal aortic blood was analysed. Kidney functions were evaluated. Higher serum creatinine, blood urea nitrogen and uric acid levels, and lower creatinine clearance was observed in the model control group compared with JSB and IF groups (P < 0.05). Red blood cell count, haemoglobin and haematocrit levels in the 200 mg/kg IF group were higher than in the model control group (P < 0.05). Transforming growth factor-β1 mRNA expression in the model control group was higher than the normal control and 200 mg/kg IF groups (P < 0.05). Epidermal growth factor mRNA in the model control group was lower than in the normal control and both IF-treated groups (P < 0.05). Structural renal damage was observed in all adenine-treated rats, but was less severe in the JSB and IF groups. IF may reverse the damaged kidney functions-induced with adenine in rats. © 2013 Royal Pharmaceutical Society.

  12. Radiation induced esophageal adenocarcinoma in a woman previously treated for breast cancer and renal cell carcinoma

    PubMed Central

    2012-01-01

    Background Secondary radiation-induced cancers are rare but well-documented as long-term side effects of radiation in large populations of breast cancer survivors. Multiple neoplasms are rare. We report a case of esophageal adenocarcinoma in a patient treated previously for breast cancer and clear cell carcinoma of the kidney. Case presentation A 56 year-old non smoking woman, with no alcohol intake and no familial history of cancer; followed in the National Institute of Oncology of Rabat Morocco since 1999 for breast carcinoma, presented on consultation on January 2011 with dysphagia. Breast cancer was treated with modified radical mastectomy, 6 courses of chemotherapy based on CMF regimen and radiotherapy to breast, inner mammary chain and to pelvis as castration. Less than a year later, a renal right mass was discovered incidentally. Enlarged nephrectomy realized and showed renal cell carcinoma. A local and metastatic breast cancer recurrence occurred in 2007. Patient had 2 lines of chemotherapy and 2 lines of hormonotherapy with Letrozole and Tamoxifen assuring a stable disease. On January 2011, the patient presented dysphagia. Oesogastric endoscopy showed middle esophagus stenosing mass. Biopsy revealed adenocarcinoma. No evidence of metastasis was noticed on computed tomography and breast disease was controlled. Palliative brachytherapy to esophagus was delivered. Patient presented dysphagia due to progressive disease 4 months later. Jejunostomy was proposed but the patient refused any treatment. She died on July 2011. Conclusion We present here a multiple neoplasm in a patient with no known family history of cancers. Esophageal carcinoma is most likely induced by radiation. However the presence of a third malignancy suggests the presence of genetic disorders. PMID:22873795

  13. Chemopreventive role of Coriandrum sativum against gentamicin-induced renal histopathological damage in rats

    PubMed Central

    Lakhera, Abhijeet; Bansal, Divya; Dubey, Nazneen

    2015-01-01

    Drug induced nephrotoxicity is one of the most common causes of renal failure. Gentamicin belongs to aminoglycosides, which elicit nephrotoxic potential. Natural antioxidants from plants demonstrate a number of biotherapeutic activities. Coriander is an important medicinal plant known for its hepatoprotective, diuretic, carminative, digestive and antihelminthic potential. This study was designed to investigate whether the extract of Coriandrum sativum ameliorates the nephrotoxicity induced by gentamicin in rats. Dried coriander powder was coarsely grinded and subjected to defatting by petroleum ether and further with ethyl acetate. The extract was filtered and subjected to phytochemical and phytoanalytical studies. Acute toxicity in Wistar rats was determined by the OECD Guideline (423). Animals were divided into four groups. The first group served as positive control, while the second group was toxic control (gentamicin treated). The third and fourth group were treated with the extract (200 and 400 mg/kg gentamicin). After 8 days, the animals were sacrificed and biochemical and histopathological studies were carried out. Phytochemical screening of the extract demonstrated Coriandrum sativum to be rich in flavonoids, polyphenolics and alkaloids. Results of acute toxicity suggested the use of 200 mg/kg and 400 mg/kg for Coriandrum sativum in the study. Coriandrum sativum extract at the dose of 400 mg/kg significantly (p<0.01) decreased creatinine levels in the animals, along with a decrease in serum urea and blood urea nitrogen. Treatment with Coriandrum sativum extract ameliorated renal histological lesions. It is concluded that Coriandrum sativum is a potential source of nephroprotective phytochemical activity, with flavonoids and polyphenols as the major components. PMID:27486367

  14. Chemopreventive role of Coriandrum sativum against gentamicin-induced renal histopathological damage in rats.

    PubMed

    Lakhera, Abhijeet; Ganeshpurkar, Aditya; Bansal, Divya; Dubey, Nazneen

    2015-06-01

    Drug induced nephrotoxicity is one of the most common causes of renal failure. Gentamicin belongs to aminoglycosides, which elicit nephrotoxic potential. Natural antioxidants from plants demonstrate a number of biotherapeutic activities. Coriander is an important medicinal plant known for its hepatoprotective, diuretic, carminative, digestive and antihelminthic potential. This study was designed to investigate whether the extract of Coriandrum sativum ameliorates the nephrotoxicity induced by gentamicin in rats. Dried coriander powder was coarsely grinded and subjected to defatting by petroleum ether and further with ethyl acetate. The extract was filtered and subjected to phytochemical and phytoanalytical studies. Acute toxicity in Wistar rats was determined by the OECD Guideline (423). Animals were divided into four groups. The first group served as positive control, while the second group was toxic control (gentamicin treated). The third and fourth group were treated with the extract (200 and 400 mg/kg gentamicin). After 8 days, the animals were sacrificed and biochemical and histopathological studies were carried out. Phytochemical screening of the extract demonstrated Coriandrum sativum to be rich in flavonoids, polyphenolics and alkaloids. Results of acute toxicity suggested the use of 200 mg/kg and 400 mg/kg for Coriandrum sativum in the study. Coriandrum sativum extract at the dose of 400 mg/kg significantly (p<0.01) decreased creatinine levels in the animals, along with a decrease in serum urea and blood urea nitrogen. Treatment with Coriandrum sativum extract ameliorated renal histological lesions. It is concluded that Coriandrum sativum is a potential source of nephroprotective phytochemical activity, with flavonoids and polyphenols as the major components.

  15. Low sodium intake does not impair renal compensation of hypoxia-induced respiratory alkalosis.

    PubMed

    Höhne, Claudia; Boemke, Willehad; Schleyer, Nora; Francis, Roland C; Krebs, Martin O; Kaczmarczyk, Gabriele

    2002-05-01

    Acute hypoxia causes hyperventilation and respiratory alkalosis, often combined with increased diuresis and sodium, potassium, and bicarbonate excretion. With a low sodium intake, the excretion of the anion bicarbonate may be limited by the lower excretion rate of the cation sodium through activated sodium-retaining mechanisms. This study investigates whether the short-term renal compensation of hypoxia-induced respiratory alkalosis is impaired by a low sodium intake. Nine conscious, tracheotomized dogs were studied twice either on a low-sodium (LS = 0.5 mmol sodium x kg body wt-1 x day-1) or high-sodium (HS = 7.5 mmol sodium x kg body wt-1 x day-1) diet. The dogs breathed spontaneously via a ventilator circuit during the experiments: first hour, normoxia (inspiratory oxygen fraction = 0.21); second to fourth hour, hypoxia (inspiratory oxygen fraction = 0.1). During hypoxia (arterial PO2 34.4 +/- 2.1 Torr), plasma pH increased from 7.37 +/- 0.01 to 7.48 +/- 0.01 (P < 0.05) because of hyperventilation (arterial PCO2 25.6 +/- 2.4 Torr). Urinary pH and urinary bicarbonate excretion increased irrespective of the sodium intake. Sodium excretion increased more during HS than during LS, whereas the increase in potassium excretion was comparable in both groups. Thus the quick onset of bicarbonate excretion within the first hour of hypoxia-induced respiratory alkalosis was not impaired by a low sodium intake. The increased sodium excretion during hypoxia seems to be combined with a decrease in plasma aldosterone and angiotensin II in LS as well as in HS dogs. Other factors, e.g., increased mean arterial blood pressure, minute ventilation, and renal blood flow, may have contributed.

  16. Diabetes-Induced Decrease in Renal Oxygen Tension: Effects of an Altered Metabolism

    NASA Astrophysics Data System (ADS)

    Palm, Fredrik; Carlsson, Per-Ola; Fasching, Angelica; Hansell, Peter; Liss, Per

    During conditions with experimental diabetes mellitus, it is evident that several alterations in renal oxygen metabolism occur, including increased mitochondrial respiration and increased lactate accumulation in the renal tissue. Consequently, these alterations will contribute to decrease the interstitial pO2, preferentially in the renal medulla of animals with sustained long-term hyperglycemia.

  17. Renal effects of plant-derived oleanolic acid in streptozotocin-induced diabetic rats.

    PubMed

    Mapanga, R F; Tufts, M A; Shode, F O; Musabayane, C T

    2009-01-01

    Previous studies from our laboratories indicate that the anti-diabetic effects of Syzygium cordatum (Hochst.) [Myrtaceae] leaf extract in streptozotocin-induced diabetic rats may be attributed in part to mixtures of triterpenes, oleanolic acid (3ss-hydroxy-olea-12-en-28-oic acid, OA) and ursolic acid (3ss -hydroxyl-urs-12-en-28-oic acid, UA). For the bioactive compounds to have potential in diabetes management, they should alleviate or prevent complications of diabetes mellitus, kidney function, and cardiovascular disorders. This study was, therefore, designed to assess whether S. cordatum leaf derived OA influenced renal function evaluated by the ability to increase urinary Na(+) outputs parameters and creatinine clearance (Ccr) of streptozotocin (STZ)-induced diabetic rats. Extraction and fractionation of S. cordatum powdered leaf ethyl acetate-solubles (EAS) yielded mixtures of OA/UA and methyl maslinate/methyl corosolate. Recrystallization of OA/UA mixture using ethanol afforded OA, the structure of which was confirmed by NMR spectroscopy ((1)H & (13)C). Acute effects of OA on kidney function and mean arterial blood pressure (MAP) were investigated in anesthetized rats challenged with hypotonic saline after a 3.5-h equilibration for 4h of 1 h control, 1.5 h treatment, and 1.5 h recovery periods. OA was added to the infusate during the treatment period. Chronic effects of OA were studied in individually caged rats treated twice daily with OA (60 mg/kg, p.o.) for five weeks. By comparison with respective control animals administration, OA significantly increased Na(+) excretion rates of non-diabetic and STZ-induced diabetic rats without affecting urine flow, K(+) and Cl(-) rates. At the end of five weeks, OA treatment significantly (p < 0.05) increased Ccr in non-diabetic (2.88 +/- 0.14 vs. 3.71 +/- 0.30 ml/min) and STZ-diabetic rats (1.81 +/- 0.32 vs. 3.07 +/- 0.16 ml/min) with concomitant reduction of plasma creatinine concentration (n = 6 in all groups). OA

  18. Renal angiotensin II AT2 receptors promote natriuresis in streptozotocin-induced diabetic rats.

    PubMed

    Hakam, Amer C; Siddiqui, Athar H; Hussain, Tahir

    2006-02-01

    Angiotensin II AT2 receptors have been implicated to play a role in the regulation of renal/cardiovascular functions under pathological conditions. The present study is designed to investigate the function of the AT2 receptors on renal sodium excretion and AT(2) receptor expression in the cortical membranes of streptozotocin (STZ)-induced diabetic rats. The STZ treatment led to a significant weight loss, hyperglycemia, and decrease in plasma insulin levels compared with control rats. STZ-induced diabetic rats had significantly elevated basal urine flow, urinary sodium excretion rate (U(Na)V), urinary fractional sodium excretion, and urinary cGMP compared with control rats. Infusion of PD-123319, an AT2 receptor antagonist, caused a significant decrease in U(Na)V (mumol/min) in STZ-induced diabetic rats (1 +/- 0.09 vs. 0.45 +/- 0.1) but not in control rats (0.35 +/- 0.05 vs. 0.4 +/- 0.07). The decrease in U(Na)V was associated with a significant decrease in urinary cGMP levels (pmol/min) in STZ-induced diabetic rats (21 +/- 2 vs. 10 +/- 0.8) but not in control rats (11.75 +/- 3 vs. 12.6 +/- 2). The infusion of PD-123319 did not alter glomerular filtration rate (STZ: 0.3 +/- 0.02 vs. 0.25 +/- 0.03; control: 1.4 +/- 0.05 vs. 1.5 +/- 0.09 ml/min) or mean arterial pressure (STZ: 82 +/- 3 vs. 79 +/- 3.5; control: 90 +/- 4 vs. 89 +/- 4 mmHg), suggesting a tubular effect of the drug. Western blot analysis using an AT2 receptor antibody revealed a significantly enhanced expression of the AT2 receptor protein ( approximately 45 kDa) in brush-border ( approximately 50-fold) and basolateral membranes ( approximately 80-fold) of STZ-induced diabetic compared with control rats. In conclusion, our data suggest that the tubular AT2 receptors in diabetic rats are profoundly enhanced and possibly via a cGMP pathway promote sodium excretion in this model of diabetes.

  19. Renal antioxidant enzymes and glutathione redox status in leptin-induced hypertension.

    PubMed

    Bełtowski, Jerzy; Jamroz-Wiśniewska, Anna; Wójcicka, Grazyna; Lowicka, Ewelina; Wojtak, Andrzej

    2008-12-01

    Previously, we have demonstrated that leptin increases blood pressure (BP) in the rats through two oxidative stress-dependent mechanisms: stimulation of extracellular signal-regulated kinases (ERK) by H(2)O(2) and scavenging of nitric oxide (NO) by superoxide (O(2-.)). Herein, we examined if renal glutathione system and antioxidant enzymes determine the mechanism of prohypertensive effect of leptin. Leptin administered at 0.5 mg/kg/day for 4 or 8 days increased BP and renal Na(+),K(+)-ATPase activity and reduced fractional sodium excretion; these effects were prevented by NADPH oxidase inhibitor, apocynin. Superoxide scavenger, tempol, abolished the effect of leptin on BP and renal Na(+) pump in rats receiving leptin for 8 days, whereas ERK inhibitor, PD98059, was effective in animals treated with leptin for 4 days. Leptin administered for 4 days decreased glutathione (GSH) and increased glutathione disulfide (GSSG) in the kidney. In animals receiving leptin for 8 days GSH returned to normal level, which was accompanied by up-regulation of gamma-glutamylcysteine synthetase (gamma-GCS), a rate-limiting enzyme of the GSH biosynthetic pathway. In addition, superoxide dismutase (SOD) activity was decreased, whereas glutathione peroxidase (GPx) was increased in rats receiving leptin for 8 days. Cotreatment with gamma-GCS inhibitor, buthionine sulfoximine (BSO), accelerated, whereas GSH precursor, N-acetylcysteine (NAC), attenuated leptin-induced changes in gamma-GCS, SOD, and GPx. In addition, coadministration of BSO changed the mechanism of BP elevation from H(2)O(2)-ERK to (O(2-.))-NO dependent in animals receiving leptin for 4 days, whereas NAC had the opposite effect in rats treated with leptin for 8 days. These results suggest that initial change in GSH redox status induces decrease in SOD/GPx ratio, which results in greater amount of (O)2-.)) versus H(2)O(2) in later phase of leptin treatment, thus shifting the mechanism of BP elevation from H(2)O(2)-ERK to (O(2

  20. A high-fat diet increases oxidative renal injury and protein glycation in D-galactose-induced aging rats and its prevention by Korea red ginseng.

    PubMed

    Park, Sok; Kim, Chan-Sik; Min, Jinah; Lee, Soo Hwan; Jung, Yi-Sook

    2014-01-01

    Declining renal function is commonly observed with age. Obesity induced by a high-fat diet (HFD) may reduce renal function. Korean red ginseng (KRG) has been reported to ameliorate oxidative tissue injury and have an anti-aging effect. This study was designed to investigate whether HFD would accelerate the D-galactose-induced aging process in the rat kidney and to examine the preventive effect of KRG on HFD and D-galactose-induced aging-related renal injury. When rats with D-galactose-induced aging were fed an HFD for 9 wk, enhanced oxidative DNA damage, renal cell apoptosis, protein glycation, and extracellular high mobility group box 1 protein (HMGB1), a signal of tissue damage, were observed in renal glomerular cells and tubular epithelial cells. However, treatment of rats with HFD- plus D-galactose-induced aging with KRG restored all of these renal changes. Our data suggested that a long-term HFD may enhance D-galactose-induced oxidative renal injury in rats and that this age-related renal injury could be suppressed by KRG through the repression of oxidative injury.

  1. Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice.

    PubMed

    Li, Jinhua; Qu, Xinli; Bertram, John F

    2009-10-01

    Diabetic nephropathy is the leading cause of chronic renal failure. Myofibroblasts play a major role in the synthesis and secretion of extracellular matrix in diabetic renal fibrosis. Increasing evidence suggests that endothelial cells may undergo endothelial-myofibroblast transition under physiological and pathophysiological circumstances. Therefore, this study investigates whether endothelial-myofibroblast transition occurs and contributes to the development of diabetic renal interstitial fibrosis. Diabetes was induced by administration of streptozotocin to Tie2-Cre;LoxP-EGFP mice, an endothelial lineage-traceable mouse line generated by crossbreeding B6.Cg-Tg(Tek-cre)12F1v/J mice with B6.Cg-Tg(ACTB-Bgeo/GFP)21Lbe/J mice. The endothelial-myofibroblast transition was also studied in MMECs (a mouse pancreatic microvascular endothelial cell line) and primary cultures of CD31+/EYFP- (enhanced yellow fluorescent protein) endothelial cells isolated from adult normal alpha-smooth muscle actin promoter-driven-EYFP (alpha-SMA/EYFP) mouse kidneys. Confocal microscopy demonstrated that 10.4 +/- 4.2 and 23.5 +/- 7.4% of renal interstitial myofibroblasts (alpha-SMA+) in 1- and 6-month streptozotocin-induced diabetic kidneys were of endothelial origin (EGFP+/alpha-SMA+ cells), compared with just 0.2 +/- 0.1% of myofibroblasts in vehicle-treated Tie2-Cre;LoxP-EGFP mice (P < 0.01). Confocal microscopy and real-time PCR showed that transforming growth factor (TGF)-beta1 induced de novo expression of alpha-SMA and loss of expression of VE-cadherin and CD31 in MMECs and primary cultures of renal endothelial cells in a time- and dose-dependent fashion. These findings demonstrate that the endothelial-myofibroblast transition occurs and contributes to the early development and progression of diabetic renal interstitial fibrosis and suggest that the endothelial-myofibroblast transition may be a therapeutic target.

  2. Protocatechuic Aldehyde Attenuates Cisplatin-Induced Acute Kidney Injury by Suppressing Nox-Mediated Oxidative Stress and Renal Inflammation

    PubMed Central

    Gao, Li; Wu, Wei-Feng; Dong, Lei; Ren, Gui-Ling; Li, Hai-Di; Yang, Qin; Li, Xiao-Feng; Xu, Tao; Li, Zeng; Wu, Bao-Ming; Ma, Tao-Tao; Huang, Cheng; Huang, Yan; Zhang, Lei; Lv, Xiongwen; Li, Jun; Meng, Xiao-Ming

    2016-01-01

    Cisplatin is a classic chemotherapeutic agent widely used to treat different types of cancers including ovarian, head and neck, testicular and uterine cervical carcinomas. However, cisplatin induces acute kidney injury by directly triggering an excessive inflammatory response, oxidative stress, and programmed cell death of renal tubular epithelial cells, all of which lead to high mortality rates in patients. In this study, we examined the protective effect of protocatechuic aldehyde (PA) in vitro in cisplatin-treated tubular epithelial cells and in vivo in cisplatin nephropathy. PA is a monomer of Traditional Chinese Medicine isolated from the root of S. miltiorrhiza (Lamiaceae). Results show that PA prevented cisplatin-induced decline of renal function and histological damage, which was confirmed by attenuation of KIM1 in both mRNA and protein levels. Moreover, PA reduced renal inflammation by suppressing oxidative stress and programmed cell death in response to cisplatin, which was further evidenced by in vitro data. Of note, PA suppressed NAPDH oxidases, including Nox2 and Nox4, in a dosage-dependent manner. Moreover, silencing Nox4, but not Nox2, removed the inhibitory effect of PA on cisplatin-induced renal injury, indicating that Nox4 may play a pivotal role in mediating the protective effect of PA in cisplatin-induced acute kidney injury. Collectively, our data indicate that PA blocks cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation without compromising anti-tumor activity of cisplatin. These findings suggest that PA and its derivatives may serve as potential protective agents for cancer patients receiving cisplatin treatment. PMID:27999546

  3. Protocatechuic Aldehyde Attenuates Cisplatin-Induced Acute Kidney Injury by Suppressing Nox-Mediated Oxidative Stress and Renal Inflammation.

    PubMed

    Gao, Li; Wu, Wei-Feng; Dong, Lei; Ren, Gui-Ling; Li, Hai-Di; Yang, Qin; Li, Xiao-Feng; Xu, Tao; Li, Zeng; Wu, Bao-Ming; Ma, Tao-Tao; Huang, Cheng; Huang, Yan; Zhang, Lei; Lv, Xiongwen; Li, Jun; Meng, Xiao-Ming

    2016-01-01

    Cisplatin is a classic chemotherapeutic agent widely used to treat different types of cancers including ovarian, head and neck, testicular and uterine cervical carcinomas. However, cisplatin induces acute kidney injury by directly triggering an excessive inflammatory response, oxidative stress, and programmed cell death of renal tubular epithelial cells, all of which lead to high mortality rates in patients. In this study, we examined the protective effect of protocatechuic aldehyde (PA) in vitro in cisplatin-treated tubular epithelial cells and in vivo in cisplatin nephropathy. PA is a monomer of Traditional Chinese Medicine isolated from the root of S. miltiorrhiza (Lamiaceae). Results show that PA prevented cisplatin-induced decline of renal function and histological damage, which was confirmed by attenuation of KIM1 in both mRNA and protein levels. Moreover, PA reduced renal inflammation by suppressing oxidative stress and programmed cell death in response to cisplatin, which was further evidenced by in vitro data. Of note, PA suppressed NAPDH oxidases, including Nox2 and Nox4, in a dosage-dependent manner. Moreover, silencing Nox4, but not Nox2, removed the inhibitory effect of PA on cisplatin-induced renal injury, indicating that Nox4 may play a pivotal role in mediating the protective effect of PA in cisplatin-induced acute kidney injury. Collectively, our data indicate that PA blocks cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation without compromising anti-tumor activity of cisplatin. These findings suggest that PA and its derivatives may serve as potential protective agents for cancer patients receiving cisplatin treatment.

  4. Protective effects of molsidomine against doxorubicin-induced renal damage in rats.

    PubMed

    Oguz, Fatih; Beytur, Ali; Sarihan, Ediz; Oguz, Hilal K; Bentli, Recep; Samdanci, Emine; Kose, Evren; Polat, Alaaddin; Duran, Zeynep R; Parlakpinar, Hakan; Ekinci, Nihat

    2016-02-01

    The purpose of this study was to investigate the therapeutic and protective effects of molsidomine (MLS) against doxorubicin (DOX)-induced renal damage in rats. Forty rats were randomly divided into five groups (control, MLS, DOX, DOX+MLS and MLS+DOX groups). Thiobarbituric acid reactive substance (TBARS), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), nitric oxide (NO) and glutathione peroxidase (GPx) levels were determined from kidney tissues and blood urea nitrogen (BUN), creatinine (Cr) and albumin (Alb) levels also determined. DOX treatment caused a significant increase in TBARS levels and a significant decrease in the GSH and CAT levels compared with the control group. In comparison, MLS administration before DOX injection caused a significant decrease in TBARS levels and also increases in GSH and CAT levels, whereas treatment of MLS after DOX injection did not show any beneficial effect on these parameters. All groups showed a significant increase in NO levels compared to the control group. There were no significant differences among the all groups for BUN and Cr levels. Serum level of Alb decreased in the DOX-treated groups when compared with control and MLS groups. The histopathological findings were in accordance with the biochemical results. MLS treatment reversed the DOX-induced kidney damage in group 4. MLS treatment before DOX injection exerted a protective effect against DOX-induced kidney damage. MLS shows promise as a possible therapeutic intervention for the prevention of kidney injury associated with DOX treatment. Additional studies are warranted.

  5. Nephroprotective Effect of POLYCAN on Acute Renal Failure Induced by Cisplatin in Rats

    PubMed Central

    Ku, Sae-Kwang; Lee, Young-Joon; Lee, Sung-Dong; Cho, Hyung-Rae; Moon, Seung-Bae; Kim, Ki-Young; Kwon, Young-Sam; Kim, Joo Wan

    2012-01-01

    We performed to evaluate the effect of POLYCAN (β-glucan) on cisplatin-(CDDP-)induced acute renal failure (ARF) in rats. POLYCAN was administered orally once a day for 32 days. Each of 8 rats per group was selected based on the body weight (BW) after acclimatization and they were sacrificed at 5 days after CDDP injection. There was significant (P < 0.05) increase of BW after CDDP dosing in all POLYCAN groups than vehicle control and significant (P < 0.01 or P < 0.05) decrease of absolute and relative kidney weight were detected in all POLYCAN groups compared with vehicle control. In addition, serum BUN and creatinine level in all POLYCAN groups were significantly (P < 0.01 or P < 0.05) lower than vehicle control and the percentage of degenerative regions significantly (P < 0.01) decreased in all POLYCAN groups. As the results of CDDP-induced ARF process, dramatic decrease of the BW, increase of the kidney weight, serum BUN, and creatinine level were detected in vehicle control group compared with sham control group. The changes by CDDP-induced ARF process in POLYCAN groups were significantly and dose-dependently improved compared with vehicle control group. Therefore, POLYCAN has enough potential to develop as a new agent of prevention or treatment for ARF. PMID:23738131

  6. Protective effect of pomegranate flower extract against gentamicin-induced renal toxicity in male rats

    PubMed Central

    Sadeghi, Ferdos; Nematbakhsh, Mehdi; Noori-Diziche, Ali; Eshraghi-Jazi, Fatemeh; Talebi, Ardeshir; Nasri, Hamid; Mansouri, Azam; Dehghani, Aghdas; Saberi, Shadan; Shirdavani, Soheila; Ashrafi, Farzaneh

    2015-01-01

    Introduction: Gentamicin (GM) as an antibiotic is used in clinic. However, its administration is limited by side effects such as nephrotoxicity. Herbal extracts could be used in therapeutic approaches. Objectives: The present study was planned to investigate whether pomegranate flower extract (PFE) could ameliorate GM-induced renal toxicity in male rats. Materials and Methods: Twenty eight male Wistar rats were divided into 5 groups. Groups 1 and 2 respectively received PFE 25 and 50 mg/kg for 9 days. Groups 3, 4 and 5 received saline, PFE 25 mg/kg, and PFE 50 mg/kg for 9 days, respectively, and GM (100 mg/kg/day) was administered from day 3 on. Blood samples were obtained, and after sacrificing the animals, the kidneys were removed for histopathology investigations. Results: GM alone increased the serum levels of creatinine (Cr) and blood urea nitrogen (BUN), and tissue damage and kidney weight (P < 0.05). However, administration of low dose of PFE accompanied with GM decreased these markers significantly (P < 0.05). Low dose of PFE also ameliorated weight loss induced by GM (P < 0.05). Conclusion: It is concluded that PFE 25 mg/kg is the effective dose to ameliorate nephrotoxicity induced by GM. PMID:26060837

  7. Protective effect of pomegranate flower extract against gentamicin-induced renal toxicity in male rats.

    PubMed

    Sadeghi, Ferdos; Nematbakhsh, Mehdi; Noori-Diziche, Ali; Eshraghi-Jazi, Fatemeh; Talebi, Ardeshir; Nasri, Hamid; Mansouri, Azam; Dehghani, Aghdas; Saberi, Shadan; Shirdavani, Soheila; Ashrafi, Farzaneh

    2015-01-01

    Gentamicin (GM) as an antibiotic is used in clinic. However, its administration is limited by side effects such as nephrotoxicity. Herbal extracts could be used in therapeutic approaches. The present study was planned to investigate whether pomegranate flower extract (PFE) could ameliorate GM-induced renal toxicity in male rats. Twenty eight male Wistar rats were divided into 5 groups. Groups 1 and 2 respectively received PFE 25 and 50 mg/kg for 9 days. Groups 3, 4 and 5 received saline, PFE 25 mg/kg, and PFE 50 mg/kg for 9 days, respectively, and GM (100 mg/kg/day) was administered from day 3 on. Blood samples were obtained, and after sacrificing the animals, the kidneys were removed for histopathology investigations. GM alone increased the serum levels of creatinine (Cr) and blood urea nitrogen (BUN), and tissue damage and kidney weight (P < 0.05). However, administration of low dose of PFE accompanied with GM decreased these markers significantly (P < 0.05). Low dose of PFE also ameliorated weight loss induced by GM (P < 0.05). It is concluded that PFE 25 mg/kg is the effective dose to ameliorate nephrotoxicity induced by GM.

  8. Titanium nanoparticle inhalation induces renal fibrosis in mice via an oxidative stress upregulated transforming growth factor-β pathway.

    PubMed

    Huang, Kuo-Tong; Wu, Cheng-Tien; Huang, Kuo-How; Lin, Wei-Chou; Chen, Chang-Mu; Guan, Siao-Syun; Chiang, Chih-Kang; Liu, Shing-Hwa

    2015-03-16

    Titanium dioxide nanoparticles (Nano-TiO2) are gradually being used extensively in clinical settings, industry, and daily life. Accumulation studies showed that Nano-TiO2 exposure is able to cause injuries in various animal organs, including the lung, liver, spleen, and kidney. However, it remains unclear whether exposure of Nano-TiO2 by inhalation causes renal fibrosis. Here, we investigated the role of reactive oxygen species (ROS)/reactive nitrogen species (RNS) related signaling molecules in chronic renal damage after Nano-TiO2 inhalation in mice. Mice were treated with Nano-TiO2 (0.1, 0.25, and 0.5 mg/week) or microparticle-TiO2 (0.5 mg/week) by nonsurgical intratracheal instillation for 4 weeks. The results showed that Nano-TiO2 inhalation increased renal pathological changes in a dose-dependent manner. No renal pathological changes were observed in microparticle-TiO2-instilled mice. Nano-TiO2 (0.5 mg/week) possessed the ability to precipitate in the kidneys, determined by transmission electron microscopy and increased serum levels of blood urea nitrogen. The expressions of markers of ROS/RNS and renal fibrosis markers, including nitrotyrosine, inducible nitric oxide synthase, hypoxia inducible factor-1α (HIF-1α), heme oxygenase 1, transforming growth factor-β (TGFβ), and collagen I, determined by immunohistochemical staining were increased in the kidneys. Furthermore, Nano-TiO2-induced renal injury could be mitigated by iNOS inhibitor aminoguanidine and ROS scavenger N-acetylcysteine treatment in transcription level. The in vitro experiments showed that Nano-TiO2 significantly and dose-dependently increased the ROS production and the expressions of HIF-1α and TGFβ in human renal proximal tubular cells, which could be reversed by N-acetylcysteine treatment. Taken together, these results suggest Nano-TiO2 inhalation might induce renal fibrosis through a ROS/RNS-related HIF-1α-upregulated TGF-β signaling pathway.

  9. Targeting renal purinergic signalling for the treatment of lithium-induced nephrogenic diabetes insipidus.

    PubMed

    Kishore, B K; Carlson, N G; Ecelbarger, C M; Kohan, D E; Müller, C E; Nelson, R D; Peti-Peterdi, J; Zhang, Y

    2015-06-01

    Lithium still retains its critical position in the treatment of bipolar disorder by virtue of its ability to prevent suicidal tendencies. However, chronic use of lithium is often limited by the development of nephrogenic diabetes insipidus (NDI), a debilitating condition. Lithium-induced NDI is due to resistance of the kidney to arginine vasopressin (AVP), leading to polyuria, natriuresis and kaliuresis. Purinergic signalling mediated by extracellular nucleotides (ATP/UTP), acting via P2Y receptors, opposes the action of AVP on renal collecting duct (CD) by decreasing the cellular cAMP and thus AQP2 protein levels. Taking a cue from this phenomenon, we discovered the potential involvement of ATP/UTP-activated P2Y2 receptor in lithium-induced NDI in rats and showed that P2Y2 receptor knockout mice are significantly resistant to Li-induced polyuria, natriuresis and kaliuresis. Extension of these studies revealed that ADP-activated P2Y12 receptor is expressed in the kidney, and its irreversible blockade by the administration of clopidogrel bisulphate (Plavix(®)) ameliorates Li-induced NDI in rodents. Parallel in vitro studies showed that P2Y12 receptor blockade by the reversible antagonist PSB-0739 sensitizes CD to the action of AVP. Thus, our studies unravelled the potential beneficial effects of targeting P2Y2 or P2Y12 receptors to counter AVP resistance in lithium-induced NDI. If established in further studies, our findings may pave the way for the development of better and safer methods for the treatment of NDI by bringing a paradigm shift in the approach from the current therapies that predominantly counter the anti-AVP effects to those that enhance the sensitivity of the kidney to AVP action. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

  10. Targeting Renal Purinergic Signalling for the Treatment of Lithium-induced Nephrogenic Diabetes Insipidus

    PubMed Central

    Kishore, B. K.; Carlson, N. G.; Ecelbarger, C. M.; Kohan, D. E.; Müller, C. E.; Nelson, R. D.; Peti-Peterdi, J.; Zhang, Y.

    2015-01-01

    Lithium still retains its critical position in the treatment of bipolar disorder by virtue of its ability to prevent suicidal tendencies. However, chronic use of lithium is often limited by the development nephrogenic diabetes insipidus (NDI), a debilitating condition. Lithium-induced NDI is due to resistance of the kidney to arginine vasopressin (AVP), leading to polyuria, natriuresis and kaliuresis. Purinergic signalling mediated by extracellular nucleotides (ATP/UTP), acting via P2Y receptors, opposes the action of AVP on renal collecting duct (CD) by decreasing the cellular cAMP and thus AQP2 protein levels. Taking a cue from this phenomenon, we discovered the potential involvement of ATP/UTP-activated P2Y2 receptor in lithium-induced NDI in rats, and showed that P2Y2 receptor knockout mice are significantly resistant to Li-induced polyuria, natriuresis and kaliuresis. Extension of these studies revealed that ADP-activated P2Y12 receptor is expressed in the kidney, and its irreversible blockade by the administration of clopidogrel bisulfate (Plavix®) ameliorates Li-induced NDI in rodents. Parallel in vitro studies showed that P2Y12 receptor blockade by the reversible antagonist PSB-0739 sensitizes CD to the action of AVP. Thus, our studies unraveled the potential beneficial effects of targeting P2Y2 or P2Y12 receptors to counter AVP resistance in lithium-induced NDI. If established in further studies, our findings may pave the way for the development of better and safer methods for the treatment of NDI by bringing a paradigm shift in the approach from the current therapies that predominantly counter the anti-AVP effects to those that enhance the sensitivity of the kidney to AVP action. PMID:25877068

  11. Renal and antibacterial effects induced by myotoxin I and II isolated from Bothrops jararacussu venom.

    PubMed

    Barbosa, P S F; Martins, A M C; Havt, A; Toyama, Daniela O; Evangelista, J S A M; Ferreira, D P P; Joazeiro, P P; Beriam, Luis O S; Toyama, Marcos H; Fonteles, M C; Monteiro, H S A

    2005-09-15

    Bothrops jararacussu myotoxin I (BthTx-I; Lys 49) and II (BthTX-II; Asp 49) were purified by ion-exchange chromatography and reverse phase HPLC. In this work we used the isolated perfused rat kidney method to evaluate the renal effects of B. jararacussu myotoxins I (Lys49 PLA2) and II (Asp49 PLA2) and their possible blockage by indomethacin. BthTX-I (5 microg/ml) and BthTX-II (5 microg/ml) increased perfusion pressure (PP; ct120=110.28+/-3.70 mmHg; BthTX I=171.28+/-6.30*mmHg; BthTX II=175.50+/-7.20*mmHg), renal vascular resistance (RVR; ct120=5.49+/-0.54 mmHg/ml.g(-1)min(-1); BthTX I=8.62+/-0.37*mmHg/ml g(-1)min(-1); BthTX II=8.9+/-0.36*mmHg/ml g(-1)min(-1)), urinary flow (UF; ct(120)=0.14+/-0.01ml g(-1)min(-1); BthTX I=0.32+/-0.05*ml g(-1)min(-1); BthTX II=0.37+/-0.01*ml g(-1)min(-1)) and glomerular filtration rate (GFR; ct120=0.72+/-0.10 ml g(-1)min(-1); BthTX I=0.85+/-0.13*ml g(-1)min(-1); BthTX II=1.22+/-0.28*ml g(-1)min(-1)). In contrast decreased the percent of sodium tubular transport (%TNa(+); ct(120)=79,76+/-0.56; BthTX I=62.23+/-4.12*; BthTX II=70.96+/-2.93*) and percent of potassium tubular transport (%TK(+);ct120=66.80+/-3.69; BthTX I=55.76+/-5.57*; BthTX II=50.86+/-6.16*). Indomethacin antagonized the vascular, glomerular and tubular effects promoted by BthTX I and it's partially blocked the effects of BthTX II. In this work also evaluated the antibacterial effects of BthTx-I and BthTx-II against Xanthomonas axonopodis. pv. passiflorae (Gram-negative bacteria) and we observed that both PLA2 showed antibacterial activity. Also we observed that proteins Also we observed that proteins chemically modified with 4-bromophenacyl bromide (rho-BPB) decrease significantly the antibacterial effect of both PLA2. In conclusion, BthTx I and BthTX II caused renal alteration and presented activity antimicrobial. The indomethacin was able to antagonize totally the renal effects induced by BthTx I and partially the effects promoted by BthTx II, suggesting involvement of

  12. Amelioration of Doxorubicin-Induced Cardiac and Renal Toxicity by Oxycarotenoid Lutein and Its Mechanism of Action.

    PubMed

    Sindhu, Edakkadath Raghavan; Nithya, Thattaruparambil Raveendran; Binitha, Ponnamparambil Purushothaman; Kuttan, Ramadasan

    2016-01-01

    We set out to determine the effect of oxycarotenoid lutein on reducing cardiac and renal toxicity induced by doxorubicin (DXR). We started with oral administration in rats of lutein for 15 d before administering DXR (30 mg/kg body weight, intraperitoneally, in a single dose). Animals in all groups were sacrificed 24 h after DXR administration. Serum markers of cardiac injury lactate dehydrogenase, creatine phosphokinase, serum glutamate oxaloacetate transaminase, and serum glutamate pyruvate transaminase increased drastically after DXR but decreased after lutein treatment (p < 0.001). Elevated serum urea and creatinine in DXR-treated rats were reduced by lutein treatment (p < 0.001). Lutein increased superoxide dismutase, catalase, glutathione peroxidase, and glutathione levels in cardiac and renal tissues of DXR-treated rats. Pretreatment of lutein reduced DXR-induced rise of oxidative stress markers including lipid peroxidation, tissue hydroperoxides, and conjugated dienes in cardiac and renal tissue. These findings were supported by electrocardiogram measurements and histopathological analyses. Results confirmed the protection of lutein against cardiac and renal toxicity induced by DXR in rats.

  13. Differential effects of grape juice on gastric emptying and renal function from cisplatin-induced acute adverse toxicity.

    PubMed

    Ko, J-L; Tsai, C-H; Liu, T-C; Lin, M-Y; Lin, H-L; Ou, C-C

    2016-08-01

    Grape skin and seeds contain large amounts of phytochemicals such as polyphenols, resveratrol, and proanthocyanidins, which possess antioxidant activities. Cisplatin is widely used in the treatment of cancer. High doses of cisplatin have also been known to produce acute adverse effects. The aim of this study was to investigate the protective effects of antioxidant properties of whole grape juice (with skin and seeds) on cisplatin-induced acute gastrointestinal tract disorders and nephrotoxicity in Wistar rats. Gastric emptying is significantly increased in whole grape juice-pretreated rats when compared to cisplatin treatment alone. The expression of ghrelin mRNA of stomach is increased in rats with whole grape juice. However, pretreatment with whole grape juice did not reduce renal function markers in acute renal toxicity. No significant changes were recorded in the oxidative stress/antioxidant status parameters of any study group. In contrast, pretreatment with whole grape juice slightly improved tubular cell vacuolization, tubular dilatation, and cast formation in renal tubules. These results show that consumption of whole grape juice induces somewhat beneficial effects in preventing cisplatin-mediated dyspepsia but does not offer protection against cisplatin-induced acute renal toxicity.

  14. Vasopressin-induced natriuresis in the conscious rat: role of blood pressure, renal prostaglandin synthesis and the peptide ANF.

    PubMed Central

    Lote, C J; Thewles, A; Wood, J A

    1989-01-01

    1. The response to arginine vasopressin (AVP) at doses of 5 and 10 pmol (100 g body weight)-1 h-1 was studied in conscious rats during the infusion of 1% (w/v) dextrose at 11.6 ml h-1 with and without pre-treatment with indomethacin. 2. In the absence of indomethacin AVP infusion induced dose-related increases in sodium output that were positively correlated with increases in mean arterial blood pressure (MAP) and plasma atrial natriuretic factor (ANF) immunoreactivity. Increases in renal prostaglandin E2 (PGE2) synthesis were also associated with AVP infusion. 3. Indomethacin pre-treatment abolished the AVP-induced increases in renal PGE2 synthesis and also the dose-related differences in ANF immunoreactivity. Increases in MAP and sodium output were unaffected at the 10 pmol (100 g body weight)-1 h-1 dose of AVP and only slightly attenuated for the 5 pmol (100 g body weight)-1 h-1 dose. 4. For both series AVP induced marked falls in glomerular filtration rate (GFR) but only small transient falls in effective renal plasma flow. The observed falls in GFR support the view that the natriuresis is due to changes in tubular handling and not in the filtered load of sodium. 5. It is concluded that the natriuresis elicited by AVP is closely related to the pressor action of the hormone but renal PGE2 synthesis and plasma ANF are not responsible for mediating this response. PMID:2533261

  15. HIF Prolyl-Hydoxylase-2 Senses High Salt Intake to Increase Hypoxia Inducible Factor-1α Levels in the Renal Medulla

    PubMed Central

    Wang, Zhengchao; Zhu, Qing; Xia, Min; Li, Pin-Lan; Hinton, Shante J.; Li, Ningjun

    2010-01-01

    High salt induces the expression of transcription factor hypoxia-inducible factor (HIF)-1α and its target genes in the renal medulla, which is an important renal adaptive mechanism to high salt intake. HIF prolyl hydroxylase domain-containing proteins (PHDs) have been identified as major enzymes to promote the degradation of HIF-1α. PHD2 is the predominant isoform of PHDs in the kidney and primarily expressed in the renal medulla. The present study tested the hypothesis that PHD2 responds to high salt and mediates high salt-induced increase in HIF-1α levels in the renal medulla. In normotensive rats, high salt intake (4% NaCl, 10 days) significantly inhibited PHD2 expressions and enzyme activities in the renal medulla. Renal medullary overexpression of PHD2 transgene significantly decreased HIF-1α levels. PHD2 transgene also blocked high salt-induced activation of HIF-1α target genes heme oxygenase-1 and nitric oxide synthase-2 in the renal medulla. In Dahl salt-sensitive hypertensive rats, however, high salt intake did not inhibit the expression and activities of PHD2 in the renal medulla. Correspondingly, renal medullary HIF-1α levels were not up-regulated by high salt intake in these rats. After transfection of PHD2 shRNA, HIF-1α and its target genes were significantly up-regulated by high salt intake in Dahl S rats. Overexpression of PHD2 transgene in the renal medulla impaired renal sodium excretion after salt loading. These data suggest that high salt intake inhibits PHD2 in the renal medulla, thereby upregulating the HIF-1α expression. The lack of PHD-mediated response to high salt may represent a pathogenic mechanism producing salt sensitive hypertension. PMID:20308610

  16. Vasodysfunction That Involves Renal Vasodysfunction, Not Abnormally Increased Renal Retention of Sodium, Accounts for the Initiation of Salt-Induced Hypertension

    PubMed Central

    Morris, R. Curtis; Schmidlin, Olga; Sebastian, Anthony; Tanaka, Masae; Kurtz, Theodore W.

    2016-01-01

    Prevailing theory holds that abnormally large increases in renal salt retention and cardiac output are early pathophysiologic events mediating initiation of most instances of salt-induced hypertension. This theory has come under increasing scrutiny because it is based on studies that lack measurements of sodium balance and cardiac output obtained during initiation of salt-loading in proper normal controls, i.e., salt-resistant subjects with normal blood pressure. Here we make the case for a “vasodysfunction” theory for initiation of salt-induced hypertension: In response to an increase in salt intake, a subnormal decrease in total peripheral resistance that involves a subnormal decrease in renal vascular resistance, in the absence of abnormally large increases in sodium retention and cardiac output, is the hemodynamic abnormality that usually mediates initiation of salt-induced increases in blood pressure (BP). It is the failure to normally decrease vascular resistance in response to salt loading that enables a normal increase of cardiac output to initiate the salt-induced increase in blood pressure. This theory is based on the results of properly controlled studies which consistently demonstrate that in salt-sensitive subjects, salt-loading initiates increased BP through a hemodynamic mechanism that: 1) does not usually involve early increases in sodium retention and cardiac output greater than those which occur with salt-loading in normal controls, and 2) usually involves an early failure to decrease vascular resistance to the same extent as that observed during salt-loading in normal controls. Multiple mechanisms including disturbances in nitric oxide and sympathetic nervous system activity likely underlie this subnormal vasodilatory response to salt that usually precedes and initiates salt-induced hypertension. PMID:26927006

  17. Differential roles of hydrogen peroxide and hydroxyl radical in cisplatin-induced cell death in renal proximal tubular epithelial cells.

    PubMed

    Baek, Su Mi; Kwon, Chae Hwa; Kim, Jae Ho; Woo, Jae Suk; Jung, Jin Sup; Kim, Yong Keun

    2003-09-01

    Reactive oxygen species (ROS) have been suggested as important mediators of cisplatin-induced acute renal failure in vivo. However, our previous studies have shown that cisplatin-induced cell death in vitro could not be prevented by scavengers of hydrogen peroxide and hydroxyl radical in rabbit renal cortical slices. This discrepancy may be attributed to differential roles of ROS in necrotic and apoptotic cell death. We therefore examined, in this study, the roles of ROS in necrosis and apoptosis induced by cisplatin in primary cultured rabbit proximal tubule. Cisplatin induced necrosis at high concentrations over a few hours and apoptosis at much lower concentrations over longer periods. Necrosis induced by high concentration of cisplatin was prevented by a cell-permeable superoxide scavenger (tiron), hydrogen peroxide scavengers (catalase and pyruvate), and antioxidants (Trolox and deferoxamine), whereas hydroxyl radical scavengers (dimethythiourea and thiourea) did not affect the cisplatin-induced necrosis. However, apoptosis induced by lower concentration of cisplatin was partially prevented by tiron and hydroxyl radical scavengers but not by hydrogen peroxide scavengers and antioxidants. Cisplatin-induced apoptosis was mediated by the signaling pathway that is associated with cytochrome c release from mitochondria and caspase-3 activation. These effects were prevented by tiron and dimethylthiourea but not by catalase. Dimethylthiourea produced a significant protection against cisplatin-induced acute renal failure, and the effect was associated with an inhibition of apoptosis. These results suggest that hydrogen peroxide is involved in the cisplatin-induced necrosis, whereas hydroxyl radical is responsible for the cisplatin-induced apoptosis. The protective effects of hydroxyl radical scavengers are associated with an inhibition of cytochrome c release and caspase activation.

  18. [Protective effect of Angelica sinensis polysaccharides on subacute renal damages induced by D-galactose in mice and its mechanism].

    PubMed

    Fan, Yan-ling; Xia, Jie-yu; Jia, Dao-yong; Zhang, Meng-si; Zhang, Yan-yan; Wang, Lu; Huang, Guo-ning; Wang, Ya-ping

    2015-11-01

    To explore the protective effect of Angelica sinensis polysaccharides(ASP) on subacute renal damages induced by D-galactose in mice and its mechanism. Male C57BL/6J mice were randomly divided into 3 groups, with 10 mice in each group. The D-galactose model group was subcutaneously injected with D-galactose (120 mg x kg(-1)), qd x 42; the ASP + D-galactose model group was intraperitoneally injected with ASP since the 8th day of the replication of the D-galactose model, qd x 35; and the normal control group was subcutaneously injected with saline at the same dose