Urotensin receptor antagonist palosuran attenuates cyclosporine-a-induced nephrotoxicity in rats

Abstract

Background. Cyclosporine-A (CsA) is widely used for immunosuppressive therapy in renal transplantation. Nephrotoxicity is the main dose-limiting undesirable consequence of CsA. Urotensin II (U-II), a novel peptide with a powerful influence on vascular biology, has been added to the list of potential renal vascular regulators. Upregulation of the urotensin receptors and elevation of plasma U-II levels are thought to possibly play a role in the etiology of renal failure. Objectives. The present study examines this hypothesis by evaluating renal function and histology with regard to the potential role of U-II and its antagonist, palosuran, in the pathogenesis of CsA-induced nephrotoxicity in rats. Material and methods. Male Sprague-Dawley rats were treated with CsA (15 mg/kg, for 21 days, intraperitoneally) or CsA + palosuran (300 mg/kg, for 21 days). Renal function was measured and histopathology, U-II immunostaining and protein detection with western blotting of the kidneys were performed. Results. Cyclosporine-A administration caused a marked decline in creatinine clearance (Ccr). Fractional sodium excretion (FE Na) tended to increase in the CsA-treated rats. Plasma U-II levels decreased in the CsAtreated rats. Cyclosporine-A treatment resulted in a marked deterioration in renal histology and an increase in the expression of U-II protein in the kidneys. Palosuran's improvement of renal function manifested as a significant decrease in serum creatinine levels and a significant increase in urine creatinine levels, resulting in a marked increase in Ccr. Palosuran produced a significant normalization of kidney histology and prevented an increase in U-II expression. Conclusions. Cyclosporine-A-induced renal impairment was accompanied by an increase in U-II expression in kidneys and a contrary decrease in systemic U-II levels. Palosuran improved the condition of rats suffering from renal dysfunction by preventing the decrease in renal U-II expression without affecting the systemic levels of U-II. The protective effect of palosuran in CsA nephrotoxicity is possibly independent of its U-II receptor antagonism.

Long-Term Protection of CHBP Against Combinational Renal Injury Induced by Both Ischemia–Reperfusion and Cyclosporine A in Mice

“…Survived TECs participate in alleviating injury and promoting repair ( 6 ) via dedifferentiating and entering cell cycle within a few hours post injury ( 7 ). Cyclosporine A (CsA) as an immunosuppressant was used after kidney transplantation to reduce acute rejection and early graft losses ( 8 ). However, CsA has not improved long-term graft survival due to its nephrotoxicity ( 9 ), characterized by tubulointerstitial fibrosis and afferent arteriolar hyalinosis ( 10 ).…”

Prepubertal Ve Postpubertal Sıçanların Genital Sistem Organlarında Ürotensin 2 Reseptörünün Karşılaştırılması

“…Bu etkilerinin yanı sıra ÜT 2 güçlü anjiojenik etkilidir (13) ve bunlara ek olarak ÜT 2 insülin salınımını da inhibe etmektedir (13). Bu nedenlerle ÜT 2 kalp yetersizliği, yüksek tansiyon ve preeklampsi gibi kardiyovasküler sistem hastalıklarıyla, diyabetes mellitus gibi endokrin sistem hastalıklarıyla, çeşitli böbrek ve karaciğer hastalıklarıyla ve noröpsikiyatrik hastalıklarla ilişkilendirilmiştir (14)(15)(16). Yapılan çeşitli çalışmalarda vücuttaki ÜT 2 konsantrasyonlarının kalp, karaciğer ve renal hastalıklarda, ateroskleroz ve hipertansiyon gibi kardiyovasküler hastalıklarda ve diyabetes mellitusta yükseldiği gösterilmiştir (6,(17)(18)(19)(20)(21)(22).…”