自噬相关蛋白FIP-200调控肾缺血再灌注损伤中肾小管上皮细胞凋亡的作用及机制研究

Though ischemia reperfusion injury (IRI) has been considered as one of the leading causes of acute kidney injury (AKI), the underling mechanisms of its effect remain perplexing. Previous studies demonstrated that the unbalance between autophagy and apoptosis might contribute to the injury of renal tubular epithelial cells induced by IRI, since autophagy might possess anti-apoptosis ability at the early stage of renal IRI outburst. On the other hand, HMGB-1 is capable in mediating autophagy with the combination of Beclin-1 competitively, followed by bonding to PI3KC3 complex, resulting in an increased production of PI3KC3 complex. Moreover, our previous studies indicated that FIP-200, a FAK family-interacting protein of 200 kDa, is competent in regulating the translocation of HMGB-1 from nuclear to cytoplasm. Taken together, we assumed that FIP-200 mediates its anti-apoptosis and pro-authophagy effects on renal tubular epithelial cells via promoting the translocation of HMGB-1 and, formation of Beclin-1-PI3KC3 complex at the early stage of renal IRI. Therefore, we planned to conduct this study in vitro and vivo, to elucidate the effects of FIP-200 on HMGB-1 translocation, formation of Beclin-1-PI3KC3 complex, induction of autophagy, and relieving of apoptosis in renal IRI, with the ultimate aim to disclose the underling mechanism of it, which might provide a potential therapeutic target for clinics in dealing with AKI patients.

肾缺血再灌注损伤(IRI)是导致急性肾损伤(AKI) 的重要诱因，但其机制复杂。既往研究发现自噬与凋亡在肾IRI致肾小管上皮细胞损伤时发挥着重要的作用，早期肾IRI所诱发的自噬可对抗凋亡。高迁移率族蛋白1(HMGB-1)可竞争性结合Beclin-1，级联促进Beclin-1-调控因子III型磷脂酰肌醇3激酶(PI3KC3)复合体生成而诱发自噬。我们发现粘着斑激酶家族相互作用蛋白(FIP-200)可促进HMGB-1转位，因此提出“FIP-200可能在肾IRI早期促进HMGB-1转位，从而生成Beclin-1-PI3KC3复合体，诱发自噬且抗肾小管上皮细胞凋亡，最终减轻肾IRI”的科学假说。本课题拟研究FIP-200在肾IRI中对HMGB-1转位、Beclin-1-PI3KC3复合体的生成、肾小管上皮细胞自噬以及凋亡的影响，阐明FIP-200对肾IRI的作用与机制，寻找AKI防治的新靶点。

肾缺血再灌注损伤(IRI)是导致急性肾损伤(AKI) 的重要诱因，但其机制复杂。既往研究发现自噬与凋亡在肾IRI致肾小管上皮细胞损伤时发挥着重要的作用，早期肾IRI所诱发的自噬可对抗凋亡。高迁移率族蛋白1(HMGB1)可竞争性结合Beclin-1，级联促进Beclin-1-调控因子III型磷脂酰肌醇3激酶(PI3KC3)复合体生成而诱发自噬。本项目按计划研究自噬相关蛋白FIP-200在肾IRI中的作用及其与自噬、凋亡信号通路的关系。项目执行相对顺利，观察FIP200flox/flox-Ggt基因敲除小鼠在肾IRI中的表型与变化，阐明缺氧条件下FIP-200调控HMGB1核内转位的直接作用靶点是赖氨酸的乙酰化ε亚基群，成功验证“FIP-200可能在肾IRI早期促HMGB1转位生成Beclin-1-PI3KC3复合体诱发自噬而抗肾小管上皮细胞凋亡，最终减轻肾IRI”的科学假说。本课题研究FIP-200在肾IRI中对HMGB1转位、Beclin-1-PI3KC3复合体的生成、肾小管上皮细胞自噬以及凋亡的影响，阐明FIP-200对肾IRI的作用与机制，寻找AKI防治的新靶点。