FADD负性调控细胞自噬：脂质导致肾小管损伤的新机制

肥胖及脂代谢紊乱是CKD的重要危险因素，但脂质导致肾损伤的机制仍不清楚。FADD在死亡受体介导的细胞凋亡中十分重要，同时也具有众多非凋亡的生物学功能。前期工作发现在脂质处理的肾小管上皮细胞（RTEC）及肥胖小鼠和CKD患者肾组织，FADD表达上调。过表达FADD抑制了RTEC自噬并加剧了脂质诱导的细胞凋亡；而沉默FADD则上调了ATG5，提示FADD可能通过抑制ATG5介导的自噬参与了脂质引起的RTEC损伤。此外，生物信息学分析显示转录因子Oct-1与FADD启动子区有四个结合位点，脂质处理也增加了Oct-1表达，而过表达Oct-1则上调了FADD。因而推测：脂质可能通过Oct-1上调FADD表达，后者通过下调ATG5而抑制自噬，加剧了肾小管细胞损伤，促进了CKD的发生。本课题将在动物、细胞和分子水平探讨FADD在脂质引起的肾小管损伤中的作用及机制，为临床治疗脂代谢相关的肾损伤提供新靶点。

Obesity and dyslipidemia are the major risk factors for the development of chronic kidney disease (CKD), but the mechanism remains unclear. As a key adaptor protein transmitting apoptotic signals mediated by the death receptors, FADD also functions in many non-apoptotic pathological and physiological processes. Data from our preliminary study and online database revealed that the expression of FADD was significantly up-regulated in kidneys of CKD patients, obese animals, and renal tubular epithelial cell (RTEC) treated with the oxidized lipid of oxLDL. Furthermore, we found that overexpression of FADD inhibited the autophagy of RTECs and worsened cell apoptosis. In contrast, silencing FADD promoted cell apoptosis in line with enhanced autophagy in RTECs, suggesting that FADD was involved in lipid-induced tubular injury possibly through regulation of autophagy. Further preliminary study and some known concept indicated that FADD could directly regulate autophagy gene ATG5. Additionally, preliminary data and bioinformatics analysis suggested that transcription factor Oct-1 could be a key regulator of FADD in lipid-induced renal tubular injury. Therefore, we hypothesized that Oct-1-regulated FADD might mediate lipid-induced renal tubular injury via suppressing ATG5 and autophagy. In the present proposal, employing the models of animal, cell and molecule, we will fully investigate the functions of FADD in lipid-induced kidney injury, providing new targets for the treatment of lipid disorder-related kidney injury.