MTDH-RXR/PPARα-脂肪酸β氧化障碍通路介导糖尿病肾脏病肾小管上皮细胞脂毒性的机制研究

肾小管上皮细胞（RTECs）脂肪酸β氧化障碍导致脂毒性是糖尿病肾脏病（DKD）发生发展的关键因素，但发生机制未明。我们前期报道：MTDH可诱导DKD足细胞凋亡、促进RTECs炎症反应及间质纤维化，但这些病理作用是否由脂毒性介导尚不清楚。我们近期预实验结果提示：MTDH参与RTECs脂质沉积及脂毒性损伤过程，可能与MTDH的“LXXLL”基序结构竞争性抑制异二聚体RXR/PPARα对辅激活因子的募集，阻碍PPARα对脂肪酸β氧化相关酶及蛋白的转录作用有关。据此，我们提出：MTDH通过调控RXR/PPARα-脂肪酸β氧化障碍通路介导DKD中RTECs脂毒性。本项目拟利用基因打靶、超声微泡基因转导、染色质免疫沉淀等技术，以MTDH对PPARα活性调控为切入点，从体内、外体深入探讨MTDH抑制脂肪酸β氧化介导DKD肾小管脂毒性的分子机制，对发现DKD新发病机制及治疗靶点具有重要意义。

Renal tubular epithelial cells (RTECs) lipotoxicity due to fatty acid β-oxidation dysfunction is one of the most important mechanisms of diabetic kidney disease (DKD). However, the underling mechanism remains unclear. Previously, we reported that MTDH induced podocyte apoptosis in DKD as well as promoted RTECs inflammation and interstitial fibrosis. However, it is unclear that whether these pathological effects of MTDH are related to lipotoxicity. Recently, we found that MTDH involved in RTECs lipid deposition and lipotoxicity, which may result from the inhibition of coactivator recruit to the heterodimer of RXR/PPARα by the LXXLL motif of MTDH and thus prevents transcription of genes related in fatty acid β oxidation. We hypothesize that MTDH induces renal tubular epithelial cells lipotoxicity via regulating RXR/PPARα-mediated fatty acid oxidation dysfunction in diabetic kidney disease. In this study, we will take the regulation of PPARα activity by MTDH as a breakthrough point and clarify the molecular mechanism of MTDH induced RTECs lipotoxicity in DKD in vitro and in vivo, using technologies such as gene targeting, ultrasound microbubbles mediated gene transduction, chromatin immunoprecipitation. This study is of great significance for the discovering the new pathogenesis and looking for the potential therapeutic targets of DKD.