E3泛素连接酶HUWE1参与调节肾小管间质纤维化的分子机制研究

肾小管间质纤维化是慢性肾脏病发展的重要病理过程，也是反映肾功能下降程度的主要决定因素。由E3泛素连接酶介导的特定蛋白质降解对不同疾病发生发展的影响是近年来医学研究的热点，但是有关E3连接酶对肾小管间质纤维化的研究较少。本课题的前期研究表明，E3泛素连接酶HUWE1在小鼠肾小管间质纤维化模型中表达明显降低；HUWE1与表皮生长因子受体EGFR之间存在直接相互作用，上调HUWE1的表达可促进EGFR降解；血管紧张素II (AngII) 显著上调HUWE1的mRNA表达。本课题将利用动物和细胞实验，围绕以下层面进行深入研究：1) HUWE1-EGFR直接相互作用以及介导后者泛素化降解的分子机制；2) HUWE1-EGFR相互作用对肾小管间质纤维化的影响；3) AngII对HUWE1表达的转录调控机制。深入探讨E3连接酶介导的泛素化降解对肾小管间质纤维化的影响，可为今后开发治疗策略奠定理论基础。

Renal fibrosis, particularly tubulointerstitial fibrosis, is the common final outcome of almost all progressive chronic kidney diseases. Renal tubulointerstitial fibrosis is also a reliable predictor of prognosis and a major determinant of renal insufficiency. Ubiquitin E3 ligases are involved in various diseases by mediating the specific protein degradation. However, the study of ubiquitin E3 ligases in renal tubulointerstitial fibrosis is very rare. The preliminary data from our proposed project has shown that the expression of ubiquitin E3 ligase HUWE1 was significantly decreased in the mice model of unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis, and the mRNA expression of HUWE1 was upregulated by Angiotensin II (AngII) in vitro. Of the interest, the data from our preliminary study indicated the interaction between HUWE1 and epidermal growth factor receptor (EGFR)，which is key molecular related to renal fibrosis. Based on these preliminary data, we’ll further study the three aspects in the future: 1) the mechanism mediating the interaction of HUWE1 and EGFR, and mechanism of HUWE1-mediated EGFR ubiquitylation and degradation; 2) the effect of the interaction of HUWE1 and EGFR on renal tubulointerstitial fibrosis; 3) the mechanism of AngII on HUWE1 transcriptional expression. The findings of our study will demonstrate the effects of E3 ligases mediated protein degradation on renal tubulointerstitial fibrosis.