Study of the potential role of candesartan, selenium, or rosiglitazone in the amelioration of cyclosporine-induced nephrotoxicity in rats

ABSTRACT

The clinical utility of cyclosporine A [CsA] as an immunosuppressive agent has been significantly limited by the frequent occurrence of chronic nephropathy. This study was designed to investigate the possible role of candesartan or selenium in the amelioration of CsA-induced chronic nephropathy in rats. Furthermore, to delineate the possible, if any, modulatory role of rosiglitazone in this pathological status. Fifty male albino rats weighing 180-220 g were used in the present study. Rats were divided into five groups, each of ten rats. Group I, injected subcutaneously [SC] by olive oil and received also 2% gum acacia daily through a gastric tube. Group II injected with CsA SC daily for 6 weeks and received also 2% gum acacia orally daily for 6 weeks. Group III, IV, and V received the same dose of CsA concomitantly with candesartan, selenium, or rosiglitazone respectively through a gastric tube daily for 6 weeks. Administration of CsA to rats for six weeks resulted in significant high levels of plasma renin activity, serum urea, and creatinine. It also, caused a significant decrease in creatinine clearance, renal contents of glutathione [GSH], glutathione peroxidase [GPx], superoxide dismutase [SOD], catalase, and accompanied by high levels of malondialdehyde [MDA], proteinuria, and urinary N-acetyl-beta-D-glucosaminidase [NAG] activity. The histopathological studies revealed arteriolopathy and fibrosis. Concomitant administration of candesartan or rosiglitazone with CsA significantly reduced proteinuria and attenuated glomerulosclerosis. Also, they improved the renal function as evidenced by significantly lower concentrations of serum creatinine, serum urea, urinary NAG activity and improved natriuresis and creatinine clearance. These beneficial effects were accompanied by significant increase in renal contents of GSH, GPx, SOD, and catalase with reduced levels of MDA. Furthermore, concomitant administration of selenium with CsA significantly reduced proteinuria and glomerulosclerosis, improved creatinine clearance, and lowered concentrations of serum creatinine, urea nitrogen, and urinary NAG activity. Also, concomitant administration of selenium elevated GSH level, GPx activity, and reduced MDA level significantly. The results of the present study demonstrated that concomitant administration of candesartan, selenium, or rosiglitazone with CsA attenuates its structural and functional changes in a rat model of chronic CsA-induced nephropathy. Our findings provide a potential rationale for the use of candesartan or rosiglitazone alone or combined with selenium in future clinical studies