Specific disruption of renal function and gene transcription by cyclosporin A.

Abstract

The effects of cyclosporin A (CsA) are cell-specific, ranging from its immunosuppressive action on cells of the immune system to a variety of nonimmunologic toxic side effects. The predominant undesirable side effects of CsA occur in the kidney. Although many toxic renal effects of CsA have been described, the molecular basis of the nephrotoxicity is unknown. Elucidation of the molecular basis for the renal action of CsA may shed light on the function of cyclophilin in nonimmune cell types. The present study demonstrates that CsA selectively reduces the gluconeogenic capacity of rat proximal tubules via a decrease in activity of phosphoenolpyruvate carboxykinase (GTP:oxaloacetate carboxy-lyase (transphosphorylating), E.C. 4.1.1.32; PEPCK). The decrease in renal PEPCK activity occurs within 3 days and reflects a corresponding reduction in renal PEPCK mRNA abundance. This, in turn, is due to a selective inhibition of renal PEPCK gene transcription. Expression of several other renal genes is unaffected by CsA, as is expression of the PEPCK gene in liver. Thus, the effects of CsA are organ-specific and do not represent a general cytotoxic effect on proximal tubule cells. These results suggest that selective inhibition of the activity of a transcription factor(s) required for expression of specific genes in renal tubules may play a role in CsA-induced nephrotoxicity.