BACKGROUND: Chronic cyclosporine A (CsA) nephrotoxicity is manifested by renal dysfunction, progressive histopathological kidney lesions characterized by afferent arteriolopathy, and tubulointerstitial fibrosis. In addition to the direct toxic effect of CsA, many other etiological factors such as angiotensin II, transforming growth factor (TGF)-β, and macrophage infiltration are involved in this pathogenesis. This study investigated the hypothesis that concomitant administration of mizoribine (MZR) and angiotensin II receptor blockade (ARB) may prevent CsA nephrotoxicity in rats. METHODS: Sprague-Dawley male rats were divided into the following seven groups: group 1, treated with CsA; group 2, treated with CsA + MZR; group 3, treated with CsA + valsartan (Val); group 4, treated with CsA + MZR + Val; group 5, treated with MZR; group 6, treated with Val; and group 7, controls (n = 5 each). Renal histopathology and the effect of CsA-induced nephrotoxicity on inflammatory mediators were evaluated. RESULTS: Results of this study demonstrated that ARB administration significantly decreased arteriolopathy and that in comparison with monotherapy, concomitant administration of MZR and ARB further decreased arteriolopathy, fibrosis, macrophage infiltration, and TGF-β1 mRNA expression associated with CsA nephrotoxicity. CONCLUSION: These findings indicate that MZR and ARB combination treatment provides synergistic protective effects against chronic CsA nephrotoxicity.
BACKGROUND: Chronic cyclosporine A (CsA) nephrotoxicity is manifested by renal dysfunction, progressive histopathological kidney lesions characterized by afferent arteriolopathy, and tubulointerstitial fibrosis. In addition to the direct toxic effect of CsA, many other etiological factors such as angiotensin II, transforming growth factor (TGF)-β, and macrophage infiltration are involved in this pathogenesis. This study investigated the hypothesis that concomitant administration of mizoribine (MZR) and angiotensin II receptor blockade (ARB) may prevent CsAnephrotoxicity in rats. METHODS: Sprague-Dawley male rats were divided into the following seven groups: group 1, treated with CsA; group 2, treated with CsA + MZR; group 3, treated with CsA + valsartan (Val); group 4, treated with CsA + MZR + Val; group 5, treated with MZR; group 6, treated with Val; and group 7, controls (n = 5 each). Renal histopathology and the effect of CsA-induced nephrotoxicity on inflammatory mediators were evaluated. RESULTS: Results of this study demonstrated that ARB administration significantly decreased arteriolopathy and that in comparison with monotherapy, concomitant administration of MZR and ARB further decreased arteriolopathy, fibrosis, macrophage infiltration, and TGF-β1 mRNA expression associated with CsAnephrotoxicity. CONCLUSION: These findings indicate that MZR and ARB combination treatment provides synergistic protective effects against chronic CsAnephrotoxicity.