N-acetylcysteine ameliorates cisplatin-induced renal senescence and renal interstitial fibrosis through sirtuin1 activation and p53 deacetylation.

The mechanism underlying the development of chronic kidney disease (CKD) after acute kidney injury (AKI) remains unclear. Maladaptive repair has been considered an important mechanism of CKD post AKI. Renal tubular cells under maladaptive repair have characteristics of premature senescence. These premature senescent cells can generate profibrotic factors that promote organ fibrosis. The purpose of this study was to investigate whether cisplatin induces premature renal senescence and the role of premature renal senescence in the progression of CKD post AKI. As oxidative stress is a major cause of senescence, we further evaluated whether antioxidant therapy could protect renal tubular cells from cisplatin-induced premature senescence and retard the progression of CKD post AKI. The molecular mechanism of this protection was also investigated. We found that cisplatin induced premature renal senescence in vitro and in vivo. In a multiple-cisplatin-treatment murine model, renal interstitial fibrosis was accompanied by premature renal senescence. N-acetylcysteine (NAC), an antioxidant, attenuated premature senescence and decreased renal fibrosis, and its effects were dependent on sirtuin1 (SIRT1) activation and p53 deacetylation. These results indicate that cisplatin can induce premature renal senescence, which is associated with the development of CKD post cisplatin-induced AKI. SIRT1 activation and p53 deacetylation might be identified as potential targets for attenuating premature renal senescence and retarding the progression of CKD post AKI.