National Clinical Research Center of Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
National Clinical Research Center of Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
Free Radic Biol Med. 2019 Jan;130:512-527. doi: 10.1016/j.freeradbiomed.2018.11.006. Epub 2018 Nov 15.
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.
急性肾损伤（AKI）后慢性肾脏病（CKD）的发病机制尚不清楚。适应性修复被认为是 AKI 后 CKD 的重要机制。适应性修复下的肾小管细胞具有早衰的特征。这些早衰的细胞可以产生促进器官纤维化的促纤维化因子。本研究旨在探讨顺铂是否诱导急性肾损伤后肾脏的过早衰老以及过早衰老在 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 AKI 后 CKD 的进展。还研究了这种保护的分子机制。我们发现顺铂在体外和体内诱导了急性肾损伤后的过早衰老。在多次顺铂治疗的小鼠模型中，肾间质纤维化伴随着急性肾损伤后的过早衰老。N-乙酰半胱氨酸（NAC），一种抗氧化剂，可减轻过早衰老和减少肾纤维化，其作用依赖于沉默信息调节因子 1（SIRT1）的激活和 p53 的去乙酰化。这些结果表明，顺铂可诱导急性肾损伤后的过早衰老，这与顺铂诱导的 AKI 后 CKD 的发生有关。SIRT1 的激活和 p53 的去乙酰化可能被确定为减轻急性肾损伤后过早衰老和延缓 CKD 进展的潜在靶点。
