SESN2通过调控肾小管上皮细胞外泌体分泌抑制糖尿病肾小管间质纤维化的机制研究

肾小管上皮细胞损伤是糖尿病肾脏疾病（DKD）肾小管间质纤维化（TIF）重要的起始因素，理想的治疗靶点应在改善肾小管上皮细胞损伤的同时减轻其对肾间质其他细胞的影响。既往研究提示损伤的肾小管上皮细胞可通过外泌体与肾间质成纤维细胞“对话”促进TIF，抑制损伤肾小管上皮细胞外泌体分泌可减轻TIF，但何种因素调控肾小管上皮细胞外泌体分泌尚不清楚。我们前期研究表明应激反应蛋白SESN2可改善肾小管上皮细胞损伤，预实验发现过表达SESN2通过下调外泌体分泌关键基因SNAP23抑制肾小管上皮细胞外泌体分泌；共培养实验提示过表达SESN2可通过减少白蛋白诱导的肾小管上皮细胞外泌体分泌，减轻其对肾间质成纤维细胞活化的促进作用。本课题将通过体内外实验，采用分子生物学相关技术手段，探讨SESN2通过抑制DKD过程中肾小管上皮细胞外泌体分泌从而改善TIF的机制，为延缓DKD提供新的治疗靶点。

Renal tubular epithelial cells injury is an important predisposing factor for tubulointerstitial fibrosis (TIF) during diabetic kidney disease (DKD). The ideal therapeutic target should reduce renal tubular epithelial cells injury and their influence on other interstitium cells at the same time. Previous studies have suggested that injured renal tubular epithelial cells promote TIF by crosstalk with renal interstitial fibroblasts through exosomes. Meanwhile, inhibiting the secretion of exosomes from injured renal tubular epithelial cells reduce TIF. However, it is still unclear which factor regulates exsomes release. Our previous studies have shown that the stress response protein SESN2 reduced renal tubular epithelial cells injury. The preliminary experiment showed that overexpressing SESN2 inhibited the release of exosomes from renal tubular epithelial cells through down-regulating SNAP23, the key gene of exosomes secretion. Co-culture experiments suggested that compared those co-cultured with albumin-induced renal tubular epithelial cells, co-cultured with albumin-induced and SESN2 overexpressed renal tubular epithelial cells reduced interstitial fibroblasts activation, which may because SESN2 reduce exosomes release. We will explore the mechanism by which SESN2 alleviates TIF by inhibiting injured renal tubular epithelial cells derived exosomes release during DKD through in vivo and in vitro experiments. This study will provide a new therapeutic target for DKD.