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Specific disruption of renal function and gene transcription by cyclosporin A
S M Morris1, D Kepka-Lenhart, R L McGill
1Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pennsylvania.
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.
Insights
Cyclosporin A (CsA) impairs kidney function by reducing gluconeogenesis in rat proximal tubules. This occurs due to CsA inhibiting the transcription of the phosphoenolpyruvate carboxykinase (PEPCK) gene.
Area of Science:
- Nephrology
- Molecular Pharmacology
- Biochemistry
Background:
- Cyclosporin A (CsA) is known for immunosuppression but also causes significant kidney toxicity.
- The molecular mechanisms underlying CsA-induced nephrotoxicity remain largely unknown.
- Understanding CsA's renal effects may reveal cyclophilin's role in non-immune cells.
Purpose of the Study:
- To investigate the molecular basis of CsA-induced nephrotoxicity.
- To determine how CsA affects kidney function at the cellular and molecular level.
- To examine CsA's impact on gluconeogenesis and specific gene expression in rat kidneys.
Main Methods:
- Treatment of rats with CsA.
- Measurement of gluconeogenic capacity in isolated rat proximal tubules.
- Assay of phosphoenolpyruvate carboxykinase (PEPCK) activity and mRNA levels.
- Analysis of other renal and liver gene expression.
Main Results:
- CsA selectively reduced the gluconeogenic capacity of rat proximal tubules.
- CsA decreased PEPCK activity and mRNA abundance within 3 days.
- The reduction in PEPCK was due to selective inhibition of renal PEPCK gene transcription.
- CsA did not affect the expression of other renal genes or PEPCK gene in the liver, indicating organ specificity.
Conclusions:
- CsA-induced nephrotoxicity involves the selective inhibition of PEPCK gene transcription in renal tubules.
- This effect is organ-specific and not a general cytotoxic effect.
- Inhibition of transcription factors regulating renal-specific genes may contribute to CsA nephrotoxicity.