postulated protective role of lacidipine and verapamil against cyclosporin A-induced nephrotoxicity and its relation to P-glycoprotein expression in rat kidney

ABSTRACT

Cyclosporin-A [CsA] has markedly improved the results of transplantation and its use is extended to include autoimmune and primary renal diseases. However, the major limitation of its use is its nephrotoxicity. P-glycoprotein [P-gp] is a transmembrane efflux pump for hydrophobic, potentially toxic compounds, including CsA. CsA has been shown to increase P-gp expression in tubular and endothelial cells. Aim of Work The aim of the present study was to elucidate the protective effect of the calcium channel blockers lacidipine and verapamil against CsA-induced nephrotoxicity and the relation of this protective effect to P-gp expression in rat kidney. This study included 7 groups, each containing 7 rats oral saline group. intraperitoneal [IP] saline group, CsA [25 mg/kg/] group rats received CsA IP for 14 days, lacidipine [1 mg/kg/d] group rats received lacidipine orally for 17 days, concomitant lacidipine and CsA group rats received lacidipine for 3 days and concomitant with CsA for another 14 days, yerapamil [0.1 mg/kg/d] group rats received erapamil i.p for 17 days and concomitant verapamil and CsA group rats received verapamil for 3 days and concomitant with CsA for another 14 days Serum creatinine, histopathological and immunostaining for P-gp for rat kidneys were done for all rats. This study revealed that CsA significantly raised serum creatinine, produced vacuolization and necrosis in tubular cells and increased P-gp expression. Kidneys treated with lacidipine alone revealed no significant changes biochemically and histologically. When lacidipine was given with CsA, it significantly protected the kidneys against CsA-induced nephrotoxicity and increased expression of P-gp in kidneys. Verapamil alone caused mild nephrotoxicity in the form of vacuolization and increased serum creatinine level. It also inhibited P-gp expression in rat kidneys. Verapamil given with CsA significantly ameliorated CsA nephrotoxicity and decreased P-gp expression. lacidipine had protective effect against CsA nephrotoxicity more than verapamil. Hemodynamic effect is the main effect and moreover, lacidipine may protect via P-gp over- expression