J. Biol. Chem., Vol. 267, Issue 19, 13768-13771, Jul, 1992
Specific disruption of renal function and gene transcription by cyclosporin A
SM Morris Jr, D Kepka-Lenhart, RL McGill, NP Curthoys and S Adler
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pennsylvania.
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.
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