alpha-Melanocyte stimulating hormone (MSH) decreases cyclosporine A induced apoptosis in cultured human proximal tubular cells

The pathogenesis of chronic cyclosporine A (CsA) nephrotoxicity has not bee n elucidated, but apoptosis is thought to play an important role in CsA ind uced tubular atrophy. Recently Fas-Fas ligand system mediated apoptosis has been frequently reported in many epithelial cells as well as in T lymphocy tes. We investigated the ability of CsA to induce apoptosis in cultured hum an proximal tubular epithelial cells and also the effect of alpha -MSH on t hem. Fas, Fas ligand, and an intracellular adaptor protein, Fas-associating protein with death domain (FADD) expression, and poly-ADP ribose polymeras e (PARP) cleavage were also studied. CsA induced apoptosis in cultured tubu lar epithelial cells demonstrated by increased number of TUNEL positive cel ls and it was accompanied by a significant increase in Fas mRNA and Fas lig and protein expressions. FADD and the cleavage product of PARP also increas ed, indicating the activation of caspase. In alpha -MSH co-treated cells, a poptosis markedly decreased with downregulation of Fas, Fas ligand and FADD expressions and also the cleavage product of PARP. In conclusion, these da ta suggest that tubular cell apoptosis mediated by Fas system may play a ro le in tubular atrophy in chronic CsA nephrotoxicity and pretreatment of alp ha -MSH may have a some inhibitory effect on CsA induced tubular cell apopt osis.