| First Author | Klawitter J | Year | 2019 |
| Journal | Am J Physiol Renal Physiol | Volume | 317 |
| Issue | 3 | Pages | F683-F694 |
| PubMed ID | 31188033 | Mgi Jnum | J:283507 |
| Mgi Id | MGI:6380901 | Doi | 10.1152/ajprenal.00417.2018 |
| Citation | Klawitter J, et al. (2019) Cyclophilin D knockout protects the mouse kidney against cyclosporin A-induced oxidative stress. Am J Physiol Renal Physiol 317(3):F683-F694 |
| abstractText | 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 PGF2alpha 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. |
