Abstract
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. 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. 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. 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. 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.
Highlights
Cyclosporine-A (CsA) is a calcineurine inhibitor that is widely used for immunosuppressive therapy in renal transplantation patients.[1]
Cyclosporine-A-induced renal impairment was accompanied by an increase in Urotensin II (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
Summary
Cyclosporine-A (CsA) is a calcineurine inhibitor that is widely used for immunosuppressive therapy in renal transplantation patients.[1]. Nephrotoxicity is the main dose-limiting undesirable consequence of CsA treatment, which may lead to irreversible damage in both glomerular and tubular structures. Urotensin II (U-II), a novel peptide with potent influences on vascular biology, was added to the list of potential renal vascular regulators. This peptide has been defined as the most potent vasoconstrictor to date and is a ligand for the Gq protein U-II receptor (UTR), originally known as the GPR14 receptor.[7] Urotensin II and UTR are expressed in a large number of tissues and organs[8,9] and pharmacological studies have shown that U-II plays a potent vasoactive role in the cardiovascular system.[10,11] In addition to its potent direct vascular actions, U-II contributes to the control of renal function[12,13,14,15] and, is involved in cardiorenal disease states. 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
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