PKCα介导的EGFR降解在糖尿病肾病足细胞损伤中的作用及机制

发布时间：2018-04-05 04:13

本文选题：人足细胞　切入点：PKCα　出处：《华中科技大学》2015年博士论文

【摘要】：目前,虽然已经有大量研究表明PKCα及EGFR参与糖尿病肾病的发生发展但二者在高糖刺激下足细胞损伤中的作用机制及二者有无相关性尚不明确。我们的研究发现：1.在糖尿病肾病患者肾小球可见PKCα表达明显增多,EGFR表达下降；2.在糖尿病大鼠肾皮质组织裂解液,细胞膜亚成分及脂筏区PKCα表达增多,EGFR表达下降；3.高糖刺激下体外人足细胞全细胞裂解液,细胞膜中EGFR表达下调,PKCα表达上调,伴随有足细胞标志蛋白synaptopodin表达的下调及足细胞损伤标志蛋白desmin表达上调；4.高糖环境下,EGFR在足细胞中发生了泛素化修饰,并且随着高糖刺激时间延长,EGFR泛素化水平不断上升：5.给予PKCα特异性抑制剂后可阻止高糖介导的足细胞全细胞裂解液中EGFR泛素化水平的上调及随后的EGFR表达水平下降；6.PKCα或泛素活化酶E1抑制剂可阻断高糖诱导的EGFR内吞与胞膜上表达的下调：7.阻断溶酶体降解途径和蛋白酶体降解途径可逆转高糖诱导的EGFR降解与足细胞损伤。综上所述,PKCα可能通过介导EGFR泛素化,内吞及降解参与糖尿病肾病中足细胞损伤；另外,我们的研究第一次在糖尿病肾病足细胞中,将PKCα与EGFR相互联系起来,这将代表糖尿病相关足细胞和肾小球损伤的新机制。
[Abstract]:At present , although a large number of studies have shown that PKC伪 and EGFR are involved in the development of diabetic nephropathy , both the mechanism of action of PKC 伪 and EGFR in diabetic nephropathy is unclear .
2 . The expression of PKC伪 in renal cortex of diabetic rats increased and the expression of EGFR was decreased .
3 . Under the stimulation of high glucose , the expression of EGFR in human foot cells in vitro was down regulated and the expression of PKC伪 was up - regulated .
4 . In the high - sugar environment , EGFR has a ubiquitination modification in the foot cells , and the level of EGFR ubiquitination increases as the stimulation time of the high sugar increases : 5 . After the PKC alpha - specific inhibitor is administered , the up - regulation of the EGFR ubiquitination level in the high - sugar - mediated whole cell lysis solution and the subsequent decrease of the EGFR expression level can be prevented ;
6 . The downregulation of high glucose - induced EGFR endocytosis and cell membrane expression can be blocked by PKC伪 or ubiquitin - activating enzyme E1 inhibitor : 7 . blocking lysosomal degradation pathway and proteasome degradation pathway can reverse high glucose - induced EGFR degradation and foot cell damage .

In conclusion , PKC伪 may participate in the pathogenesis of diabetic nephropathy by mediating the ubiquitination , endocytosis and degradation of EGFR ;
In addition , our study , for the first time in diabetic nephropathy , associates PKC伪 with EGFR , which represents a new mechanism for diabetic - associated foot cells and glomerular injury .

【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R587.2;R692.9

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