Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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Advances in Clinical and Experimental Medicine

2019, vol. 28, nr 10, October, p. 1393–1401

doi: 10.17219/acem/104544

Publication type: original article

Language: English

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

Murat Olukman1,A,D, Cenk Can1,C, Deniz Coşkunsever1,B, Yiğit Uyanikgil2,B, Türker Çavuşoğlu3,B, Eser Sözmen3,B, Soner Duman2,E, Fatma Gül Çelenk3,C, Sibel Ülker1,D,F

1 Department of Medical Pharmacology, Faculty of Medicine, Ege University, Izmir, Turkey

2 Department of Medical Biochemistry, Faculty of Medicine, Ege University, Izmir, Turkey

3 Department of Histology and Embriology, Faculty of Medicine, Ege University, Izmir, Turkey

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 (FENa) tended to increase in the CsA-treated rats. Plasma U-II levels decreased in the CsA-treated 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.
Conclusion. 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.

Key words

nephrotoxicity, urotensin-II, cyclosporine-A, palosuran, experiment

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