Ezrin下调致尿磷增加及足细胞损伤，且影响Ezrin泛素化的Nedd4-2上游激酶SGK3在慢性肾病（CKD）小鼠肾内缺失，然而，SGK3缺失介导Ezrin泛素化在CKD中磷代谢紊乱和蛋白尿发生的分子机制不明。我们发现：沉默SGK3致Ezrin泛素化和降解增加，Na-P协同转运子2a(Npt2a)水平降低及足突融合。本项目拟：1.探讨SGK3对泛素连接酶Nedd4-2与Ezrin的相互关系以及对Ezrin泛素化的影响，阐明SGK3下调时Ezrin降解的分子机制；2.在细胞和整体水平下调SGK3以及设计阻遏Ezrin与Nedd4-2结合的肽段干预，探讨Ezrin泛素化对Ezrin/Npt2a及Ezrin/足糖萼蛋白（足细胞标志蛋白）复合物命运转归、分布、活性及尿磷、尿蛋白的影响，阐明CKD中肾小管排磷增加与蛋白尿发生的分子机制。本研究结果将为CKD发病机制提供新线索并为其防治提供分子药靶。

SGK3 is the protein kinase of E3 ubiquitin ligase Nedd4-2, which mediates Ezrin ubiquitination. Down-regulation of Ezrin leads to the increase of phosphaturia and podocyte damage.The expression of SGK3 is decreased in chronic kidney diseases (CKD). However, little is known about the detail molecular mechanism of SGK3 deficiency on Ezrin ubiquitination and its role in phosphorus disturbance and proteinuria of CKD. Previously we have found that lacking of SGK3 leads to increased Ezrin ubiquitination and degradation, decreased sodium-phosphate cotransporter iia (Npt2a) level, as well as fusion of podocytes foot processes. Current project aims at: 1. Investigating the effect of SGK3 deficiency on Ezrin ubiquitination and the interaction of Ezrin and Nedd4-2, to clarify the molecular mechanism of Ezrin degradation mediated by SGK3 deficiency; 2. Knocking down SGK3, synthesizing small peptides to intervene the combination of Nedd4-2 and Ezrin in vitro and in vivo, analyzing the influence of Ezrin ubiquitination on the turnover of Ezrin/Npt2a and Ezrin/ podocalyxin complex, the urinary excretion of poshphate and protein, thus to explore the molecular mechanism of increased phosphaturia and proteinuria in CKD. The expecting results will provide new clues to the CKD pathogenesis and provide molecular drug targets for prevention and therapy of CKD.