自噬适配蛋白SQSTM1/p62在糖尿病足细胞胰岛素抵抗中的作用及机制

Glomerular podocytes insulin resistance is a key pathogenic event responsible for diabetes-induced podocytes injury, while the precise mechanism is not fully elucidated. Related studies, along with our previous studies, have evidenced that diabetic podocytes exhibited impaired cellular autophagy, which was accompanied with elevated cellular accumulation of autophagy adaptor SQSTM1/p62. Recent studies also suggested that besides mediating autophagy flux, SQSTM1/p62 could directly bind to and interact with other signal transduction proteins, therefore exerting the regulatory effects on several cellular signal pathways including mTOR and NF-κB pathways. The mTOR and NF-κB are known regulators of cellular insulin signals. Based on these findings, we hypothesized that cellular accumulation of SQSTM1/p62 in diabetic podocytes might be involved in the pathogenesis of podocytes insulin resistance. The present study aims to investigate the role of SQSTM1/p62 in the pathogenesis of podocytes insulin resistance. Furthermore, whether mTOR and NF-κB pathways might act as the downstream players underlying SQSTM1/p62-mediated insulin resistance will also be explored. The present study might be of significance in both deepening the current understanding of podocyte insulin resistance, and exploring novel intervening target for diabetic kidney disease as well.

肾小球足细胞胰岛素抵抗是糖尿病肾脏病发生发展的关键环节，具体机制一直未能完全阐明。国内外相关研究及申请人前期研究发现，糖尿病环境诱导的足细胞损伤伴有自噬能力下降，以及自噬适配蛋白SQSTM1/p62在胞浆内的蓄积。除介导细胞自噬流外，新近研究发现SQSTM1/p62还可依赖其蛋白分子上的结构功能域，对包括mTOR和NF-κB通路在内的多种信号通路发挥调控作用。而二者是已知的胰岛素信号传递的调控因子。因此糖尿病环境下足细胞SQSTM1/p62的蓄积，很可能通过mTOR和NF-κB通路参与足细胞胰岛素抵抗的发生。本项目拟采用体内试验和体外实验相结合的方法重点探讨：①SQSTM1/p62在足细胞胰岛素抵抗中的作用；②mTOR和NF-κB通路是否是SQSTM1/p62诱导足细胞胰岛素抵抗的下游机制。完成本项目对于深入理解足细胞胰岛素抵抗的机制，以及寻找可能的干预措施均具有重要意义。

肾小球足细胞胰岛素抵抗是糖尿病肾病的重要特征和致病因素，其具体机制尚未完全阐明。申请人前期研究发现SQSTM1/p62能够参与肾小球足细胞胰岛素抵抗，同时伴随着线粒体功能受损，而肾小管上皮细胞（HK-2）是肾脏中最耗能的细胞类型，在能量代谢失衡下氧化磷酸化水平的改变对肾小管上皮细胞的影响最为显著，参与整个肾脏的稳态调节。SQSTM1/p62是具有多种功能域的蛋白分子，是否能调控线粒体氧化磷酸化尚不清楚。在这项研究中，我们利用人近端小管上皮细胞(HK-2)，建立急性肾损伤（AKI）模型，重点研究了SQSTM1/p62在线粒体氧化磷酸化中的作用。结果表明SQSTM1/p62可通过激活ATF2的转录，增强线粒体核糖体蛋白MRPL12的表达，从而增加线粒体氧化磷酸化，改善细胞供能。综上所述，SQSTM1/p62在AKI中是调节肾脏氧化磷酸化的关键因子。