Cyclosporine A inhibits the adaptive responses to hypertonicity: A potential mechanism of nephrotoxicity

Cell survival in the hypertonic environment of the renal medulla is depende nt on the intracellular accumulation of protective organic solutes through the induction of genes whose transcriptional regulation is mediated in part by interaction between osmotic response elements and the transcription nuc lear factor of activated T lymphocyte 5. It is shown that cyclosporine A (C sA) prevents the nuclear translocation of the transcription nuclear factor of activated T lymphocyte 5 and inhibits osmotic response element-mediated reporter gene expression. The expression of miRNA for hypertonicity-induced genes (aldose reductase. betaine/gamma-amino-n-butyric acid transporter 1, and heat shock protein 70) is also decreased in the medulla of CsA-treated rats. CsA inhibits the increase of betaine/gamma-amino-n-butyric acid tran sporter 1 and heat shock protein 70 mRNA in osmotically stressed MDCK cells , blocks cell proliferation under isotonic conditions, and augments hyperto nicity-induced apoptosis. Histologic examination of the kidneys of CsA-trea ted rats shows a marked increase in apoptosis in the renal medulla where hy pertonicity normally prevails. The data are consistent with calcineurin-med iated induction of hypertonic stress-response genes, and they suggest that CsA nephrotoxicity may in part result from inhibition of the adaptive respo nses to hypertonicity occurring during the urinary concentrating mechanism.