SQSTM1/p62对p53的调控在糖尿病肾小管上皮细胞衰老中的作用

The accumulation of senescent cells in the kidney is both an important feature and pathogenic factor of Diabetic Kidney Disease (DKD), and the activation of p53 pathway is the key pathogenic event underlying. However, the upstream mechanism responsible for p53 activation has not been elucidated yet. Relevant researches along with our previous studies have found that the progression of DKD is associated with a decreased autophagy level and extensive cellular accumulation of autophage adaptor protein SQSTM1/p62. A recent study has shown that p53 could regulate autophagy through its interaction with SQSTM1/p62 in breast cancer cells. p53 and SQSTM1/p62 are both proteins with multiple functional domains, and we hypothesize that the p53-p62 interaction might also participate in p53-mediated cellular senescence. This project plans to elucidate the following questions using both in vitro and in vivo experiments in renal tubular epithelial cells:(1) Whether SQSTM1/p62 could regulate cellular senescence through its interaction or direct binding with p53; (2) Exploring the binding domain of SQSTM1/p62 with p53; (3) Whether the p53-p62 interaction participates in Diabetes-induced kidney senescence. It is of crucial importance in further understanding of the particular mechanisms of Diabetes related renal aging and searching potential interventions by achieving these aims.

衰老细胞在肾脏蓄积是糖尿病肾脏病（DKD）的重要特征和致病因素，P53通路活化是其中关键环节，但肾脏P53通路活化的上游机制尚未完全阐明。相关研究及申请人前期研究发现，DKD伴有肾脏自噬能力降低及自噬适配蛋白SQSTM1/p62在肾脏广泛蓄积。新近研究发现，在乳腺癌细胞P53可通过与SQSTM1/p62的直接结合进而调控SQSTM1/p62介导的细胞自噬。P53与SQSTM1/p62均为具有多种功能域的蛋白分子，二者之间的结合能否参与调控P53及其介导的细胞衰老目前尚不清楚。本项目以肾小管上皮细胞为研究对象，旨在探讨下列三方面问题：①SQSTM1/p62能否通过与P53的相互作用调控细胞衰老；②探索SQSTM1/p62分子上介导二者结合的结构功能域；③二者之间的相互作用是否参与DKD肾脏衰老的发生发展。完成本项目对于深入理解DKD肾脏衰老的具体机制以及寻找可能的干预措施均具有重要意义。

衰老细胞在肾脏蓄积是糖尿病肾病（DKD）的重要特征和致病因素。p53通路活化是细胞衰老的关键环节，但其上游机制尚未完全阐明。而申请人前期研究发现，DKD伴有肾脏自噬能力降低以及自噬适配蛋白SQSTM1/p62的广泛蓄积。新近研究发现，乳腺癌细胞中p53可通过与p62直接结合进而调控p62介导的细胞自噬。p53和SQSTM1/p62都是具有多种功能域的蛋白分子，二者之间的相互作用能否调控p53及其介导的细胞衰老尚不清楚。在这项研究中，我们利用人近端小管上皮细胞(HK-2)，重点研究了SQSTM1/p62和p53之间的相互作用。结果表明SQSTM1/p62可通过激活MDM2的转录，增强MDM2与p53的相互作用，从而促进p53的泛素化，改善细胞衰老。综上所述，SQSTM1/p62在糖尿病肾病中是肾脏衰老的关键调控因子。