N-acetylcysteine ameliorates cisplatin-induced renal senescence and renal interstitial fibrosis through sirtuin1 activation and p53 deacetylation
N-acetylcysteine ameliorates cisplatin-induced renal senescence and renal interstitial fibrosis through sirtuin1 activation and p53 deacetylation
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N-乙酰半胱氨酸通过 Sirtuin1 激活和 p53 脱乙酰化改善顺铂诱导的肾衰老和肾间质纤维化
DOI：
10.1016/j.freeradbiomed.2018.11.006
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发表时间：
2019-01-01
影响因子：
7.4
通讯作者：
Wang, Jun
中科院分区：
文献类型：
--
作者：
Li, Caizhen;Xie, Na;Wang, Jun
急性肾损伤（阿基）后发生慢性肾病（CKD）的潜在机制尚不清楚。适应不良修复被认为是阿基后CKD的重要机制。肾小管细胞在适应不良的修复状态下具有早衰的特征。这些过早衰老的细胞可以产生促进器官纤维化的促纤维化因子。本研究的目的是研究顺铂是否诱导肾脏过早衰老以及肾脏过早衰老在阿基后CKD进展中的作用。由于氧化应激是衰老的主要原因，我们进一步评估了抗氧化治疗是否可以保护肾小管细胞免受顺铂诱导的过早衰老并延缓阿基后CKD的进展。并对这种保护作用的分子机理进行了探讨。我们发现顺铂在体外和体内均能诱导肾脏过早衰老。在多次顺铂治疗的小鼠模型中，肾间质纤维化伴随着过早的肾衰老。N-乙酰半胱氨酸（NAC），一种抗氧化剂，衰减早衰和减少肾纤维化，其作用依赖于sirtuin 1（SIRT 1）激活和p53去乙酰化。这些结果表明，顺铂可诱导肾脏过早衰老，这与顺铂诱导的阿基后CKD的发展相关。SIRT 1激活和p53去乙酰化可能被确定为减轻肾早衰和延缓阿基后CKD进展的潜在靶点。
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.