Effects of Cyclosporin A and Mycophenolate Mofetil on Expression of Transforming Growth Factor-beta 1 and Endothelin-1 Following Renal Ischemia-reperfusion in Rats

Han, Byoung Geun; Song, Ki Hak; Lee, Jae Myoung; Yang, Jae Won; Choi, Jung Wook; Kim, Jung Kwon; Choi, Seung Ok

Abstract

PURPOSE
Nephrotoxicity of cyclosporin A (CsA) remains a major obstacle for the clinical use of this potent immunosuppressant. It is likely that the transforming growth factor-beta(TGF-beta) and endothelin-1 (ET-1) play a central role in initiation and/or progression of CsA induced nephropathy in renal ischemia-reperfusion injury. It is proposed that the new immunosuppressive drug mycophenolate mofetil (MMF) reduces the incidence of acute rejection in comparison with azathioprine. Thus, the aim of the present study was to analyze the expression of TGF-beta and ET-1 in renal ischemia-reperfusion injured rats and to see the effect of CsA or MMF on the expression of these mediators. Effects of coadministration of CsA and MMF were also evaluated. METHODS: Sprague-Dawley rats (N=60) performed right nephrectomy were classified into five groups according to experimental methods. Control group underwent right nephrectomy. After the right nephrectomy, to induce renal ischemia, the left renal vascular pedicle was occluded for 30 minutes with vascular clamps in all experimental groups. After 30 minutes, the clamps were removed to undergo reperfusion. In control group, ischemic injury wasn't done. CsA group was administered CsA (10 mg/kg/ day, S.C) after the operation. CsA and MMF group was coadministered CsA (10 mg/kg/day, S.C) and MMF (10 mg/kg/day, P.O). MMF group was administered MMF (10 mg/kg/day, P.O). After 7 days, the left kidney was removed and processed for histological, immunohistochemical, immunofluorescent and molecular analyses for TGF-beta 1 and histological, immunohistochemical, immunofluorescent analyses for ET-1. RESULTS: The immunohistochemical and immunofluorescent expression density for TGF-beta1 in CsA group was higher than control and other experimental groups. The immunohistochemical and immunofluorescent expression density and mRNA production for ET-1 in CsA group was higher than control and other experimental groups. The expression density for TGF-beta1 and ET-1 in CsA and MMF group was less than in CsA group. The expression density for TGF-beta 1 and ET-1 in MMF group was less than in CsA group and CsA and MMF group, was similar to ischemia-reperfusion group. CONCLUSION: These results suggest that MMF does not seem to have nephrotoxic effects, and seems to have a reno-protective effect from CsA induced nephrotoxicity in the ischemia-reperfusion model. The present study might partially explain that MMF is going to contribute to the improvement of the survival rate of the transplanted kidney associated with acute and/or chronic rejection and to the reduction of CsA dosage and its complications.