Amelioration of cyclosporine nephrotoxicity by irbesartan, A selective AT1 receptor antagonist

Abstract

Cyclosporine A (CsA), a fungal undecapeptide, is the most common immunosuppressive drug used in organ transplantation and autoimmune diseases. However, nephrotoxicity is the major adverse effect of CsA use. The molecular mechanisms of CsA nephrotoxicity are not well characterized, but more recent studies suggest an involvement of angiotensin II (ANG II) and reactive oxygen species in the development of cyclosporine nephrotoxicity. Induction of heat shock proteins (HSPs) is one of the best-described cellular responses to heat stress, hypoxia, and exposure to oxidants. HSPs have beneficial roles in protein processing and protection against cell injury. There is emerging evidence that ANG II induces oxidative stress in vitro and in vivo. This study was thus designed to investigate the role of Angiotensin II type I (AT1) receptor antagonist, irbesartan, on CsA-induced nephrotoxicity. Five groups of rats were employed in this study: group 1 served as control, group 2 rats were treated with CsA (20 mg kg(-1), subcutaneously for 21 days), and groups 3, 4, and 5 received CsA along with irbesartan (10, 25, and 50 mg kg(-1), perorally 24 hr before and 21 days concurrently), respectively. Renal function was assessed by measuring serum creatinine, blood urea nitrogen, creatinine, and urea clearance. The renal oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels, and enzymatic activity of catalase, glutathione reductase, and superoxide dismutase. Renal morphological alterations were assessed by histopathological examination. CsA administration for 21 days resulted in a marked renal oxidative stress and significantly deranged the renal functions as well as renal morphology. All these factors were significantly improved by irbesartan (50 mg kg(-1)) treatment. HSP72, HSP47, and HSP25 were clearly induced and expressed in CsA-treated animals. The induction and expression of HSP25 was markedly protected by treatment with irbesartan, whereas the induction and expression of HSP47 and HSP72 remained unaltered with the irbesartan treatment. These results clearly demonstrate the pivotal role of ANG II-induced oxidative stress and therapeutic potential of AT, receptor antagonist in ameliorating CsA-induced nephrotoxicity.