The effect of α-melanocyte-stimulating hormone on renal tubular cell apoptosis and tubulointerstitial fibrosis in cyclosporine A nephrotoxicity

Background. The pathogenesis of cyclosporine A (CsA)-induced nephrotoxicity has been known to be secondary to hemodynamic changes, but increasing evidence indicates that CsA has a direct toxicity to renal tubular cells, leading to their apoptosis and tubulointerstitial fibrosis. This study evaluated the mechanism for CsA-induced tubular cell apoptosis, tubulointerstitial fibrosis and its associated proteins, and the therapeutic effects of a-melanocyte-stimulating hormone (MSH) on them. Methods. Male Sprague-Dawley rats fed with a low-sodium diet were divided into three treatment groups: group A (vehicle-injected group), group B (CsA 15 mg/kg-injected group), and group C(CsA+ alpha-MSH-injected group). After 42 days, creatinine clearance; blood CsA level; apoptosis; inflammation and tubulointerstitial fibrosis in renal tissue; and the expression of Bax, Bcl(2), Fas, FasL, and transforming growth factor (TGF)-beta protein were determined. Results. CsA-induced tubular cell apoptosis; cellular infiltration; and increase of Fas, Bax, TGF-beta protein expression with significant tubulointerstitial fibrosis, and reduced Bcl(2) protein expression. alpha-MSH treatment prevented the Bax and TGF-beta protein increase and induced Bcl(2) protein increase, together with reduction of apoptosis, inflammation, and tubulointerstitial fibrosis. Conclusions. These findings suggest that chronic CsA nephrotoxicity is related to Bax and Bcl(2)-related apoptosis pathways, and that alpha-MSH can attenuate the CsA-induced tubulointerstitial fibrosis as well as tubular cell apoptosis.