lu-208075 and Kidney-Diseases

The objective of this study is to determine if ambrisentan (ET. Male 12-week-old humanized sickle mice (HbSS) and their genetic controls (HbAA) were treated with vehicle, HU, ambrisentan, or HU with ambrisentan for 2 weeks and renal structure and function were assessed.. Vehicle treated HbSS mice exhibited significant proteinuria compared to vehicle treated HbAA mice. HbSS mice also displayed significantly elevated plasma ET-1 concentrations and decreased urine osmolality compared to HbAA controls. Proteinuria was significantly lower in both HU and ambrisentan treated animals compared to vehicle treated HbSS mice; however, there was no additional improvement in HbSS mice treated with combined ambrisentan and HU. The combination of HU and ambrisentan resulted in significantly lower KIM-1 excretion, glomerular injury, and interstitial inflammation than HU alone.. These findings indicate that HU and ET

Topics: Anemia, Sickle Cell; Animals; Antisickling Agents; Disease Models, Animal; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Humans; Hydroxyurea; Kidney Diseases; Male; Mice; Phenylpropionates; Pyridazines

BackgroundThe pathogenesis of idiopathic nephrotic syndrome (INS) remains unclear, although recent studies suggest endothelin 1 (ET-1) and CD80 of podocytes are involved. We investigated the potential of antagonist to ET-1 receptor type A (ETRA) as therapeutic agent through the suppression of CD80 in a rat model of INS.MethodsPuromycin aminonucleoside (PAN) was injected to Wister rats to induce proteinuria: some were treated with ETRA antagonist and others were treated with 0.5% methylcellulose. Blood and tissue samples were collected. Quantitative PCR was used to determine the expression of Toll-like receptor-3 (TLR-3), nuclear factor-κB (NF-κB), CD80, talin, ETRA, and ET-1 in the kidney. To confirm the level of CD80 protein expression, immunofluorescence staining and western blot analysis of the renal tissue were performed.ResultsAmount of proteinuria in the treatment group was significantly lower than the other groups. The same-day body weight, serum creatinine values, and blood pressure were not significantly different. ETRA antagonist restores podocyte foot process effacement as well as the aberrant expression of TLR-3, nuclear factor-κB (NF-κB), and CD80 in PAN-injured kidneys.ConclusionsThe ETRA antagonist may be promising drug for INS as it showed an antiproteinuric effect. Its action was considered to be through suppression of CD80 expression on podocytes.

Topics: Animals; B7-1 Antigen; Blood Pressure; Body Weight; Creatinine; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Female; Kidney; Kidney Diseases; Kidney Glomerulus; Nephrosis; Nephrotic Syndrome; NF-kappa B; Phenylpropionates; Podocytes; Proteinuria; Puromycin Aminonucleoside; Pyridazines; Rats; Rats, Wistar; Receptor, Endothelin A; Toll-Like Receptor 3

Sickle cell disease (SCD)-associated nephropathy is a major source of morbidity and mortality in patients because of the lack of efficacious treatments targeting renal manifestations of the disease. Here, we describe a long-term treatment strategy with the selective endothelin-A receptor (ET

Topics: Anemia, Sickle Cell; Animals; Disease Models, Animal; Endothelin A Receptor Antagonists; Female; Humans; Kidney Diseases; Male; Mice; Phenylpropionates; Pyridazines; Time Factors

Tacrolimus is a potent immunosuppressive agent mainly used for allogeneic solid organ transplantation. Although usage of tacrolimus led to a significant increase in short-term allograft survival, the long-term morbidity remains high. Endothelin-1 (ET-1) is reported to be associated with increased vascular resistance, CNI-induced nephrotoxicity and chronic rejection.. In the present study, we first detected the serum and renal ET-1 level of rats treated by tacrolimus and found strong positive correlations were existed between the ET-1 level and the tacrolimus dosage and treated time. Furthermore, we studied the protective effect of ambrisentan in liver transplantation rats when co-administrated with tacrolimus. Healthy inbred male Wistar and Sprague-Dawley (SD) rats were used in this study. The post-operative general condition, transplantation survival time, hepatic aminotransferase, serum IFN-γ and level kidney injury biochemical index were recorded and compared to evaluate the immune response and outcomes in the recipient rats after liver transplantation.. Our results indicate that ambrisentan prevents the changes of ET-1 content in rats of non-operative treatment group and reduced the nephrotoxicity in the rats with liver transplantation. Rats from ambrisentan co-administration group exhibited good postoperative condition and prolonged survival.. Ambrisentan reverted some effects induced by tacrolimus in the kidney and indicated a positive potential for therapeutic benefit.

Topics: Animals; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Male; Phenylpropionates; Pyridazines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Tacrolimus; Treatment Outcome