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Cyclophilin D knockout protects the mouse kidney against cyclosporin A-induced oxidative stress
Jelena Klawitter1,2, Jost Klawitter1, Alexander Pennington1
1Clinical Research and Development, Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado.
Abstract:
Mitochondrial dysfunction and oxidative stress have been implicated in cyclosporin A (CsA)-induced nephrotoxicity. CsA interacts with cyclophilin D (CypD), an essential component of the mitochondrial permeability transition pore and regulator of cell death processes. Controversial reports have suggested that CypD deletion may or may not protect cells against oxidative stress-induced cell death. In the present study, we treated wild-type (WT) mice and mice lacking CypD [peptidylprolyl isomerase F knockout (Ppif) mice] with CsA to test the role and contribution of CypD to the widely described CsA-induced renal toxicity and oxidative stress. Our results showed an increase in the levels of several known uremic toxins as well as the oxidative stress markers PGF2α and 8-isoprostane in CsA-treated WT animals but not in Ppif animals. Similarly, a decline in S-adenosylmethionine and the resulting methylation potential indicative of DNA hypomethylation were observed only in CsA-treated WT mice. This confirms previous reports of the protective effects of CypD deletion on the mouse kidney mediated through a stronger resistance of these animals to oxidative stress and DNA methylation damage. However, a negative effect of CsA on the glycolysis and overall energy metabolism in Ppif mice also indicated that additional, CypD-parallel pathways are involved in the toxic effects of CsA on the kidney. In summary, CsA-mediated induction of oxidative stress is associated with CypD, with CypD deletion providing a protective effect, whereas the reduction of energy production observed upon CsA exposure did not depend on the animals' CypD status.
Insights
Cyclosporin A (CsA) causes kidney damage via oxidative stress, which is prevented by deleting cyclophilin D (CypD). However, CsA
Area of Science:
- Nephrology
- Mitochondrial Biology
- Toxicology
Background:
- Cyclosporin A (CsA) is known to induce nephrotoxicity, involving mitochondrial dysfunction and oxidative stress.
- Cyclophilin D (CypD) plays a role in mitochondrial permeability and cell death, but its specific involvement in CsA nephrotoxicity is debated.
- Previous studies have yielded conflicting results regarding the protective effects of CypD deletion against oxidative stress.
Purpose of the Study:
- To investigate the role of CypD in CsA-induced nephrotoxicity and oxidative stress in vivo.
- To determine whether CypD deletion protects against CsA-induced renal damage and DNA hypomethylation.
- To elucidate the contribution of CypD to CsA's effects on energy metabolism.
Main Methods:
- Treatment of wild-type (WT) and CypD knockout (Ppif-/-) mice with CsA.
- Measurement of uremic toxins, oxidative stress markers (PGF2α, 8-isoprostane), S-adenosylmethionine, and DNA methylation potential.
- Assessment of glycolysis and energy metabolism in kidney tissues.
Main Results:
- CsA treatment increased uremic toxins and oxidative stress markers in WT mice, but not in Ppif-/- mice.
- CsA-induced decline in S-adenosylmethionine and DNA hypomethylation were observed only in WT mice.
- CsA negatively impacted glycolysis and energy metabolism in Ppif-/- mice, suggesting CypD-independent pathways.
Conclusions:
- CypD deletion confers protection against CsA-induced oxidative stress and DNA methylation damage in the mouse kidney.
- The protective effect is mediated by enhanced resistance to oxidative stress and DNA damage in CypD-deficient mice.
- CsA's detrimental effects on kidney energy production occur independently of CypD status, indicating parallel toxic pathways.
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