STC-1调控AMPK/SIRT3通路在抑制BNIP3介导糖尿病肾小管间质损伤中的作用与机制

Diabetic kidney disease (DKD) is a common secondary renal disease, which is also the leading cause of ESRD. Tubulo-interstitial injury has proved to be an important pathological mechanism of DKD. Our previous study shown that the unusual expression of STC-1 has a close relationship with tubulo-interstitial injury,and it is a biomarker to predict the progression of tubulointerstitial fibrosis. We found that mitochondria are closely related to the pathophysiological function of the tubule cells and the production of mitochondrial ROS, which is the core of the damage and apoptosis of tubule cells in DKD. the underlying mechanism remains largely elusive. BNIP3 knockout could attenuate the tubulo-interstitial injury compare to the wild type, however, the underlying mechanism remains largely elusive. In this proposal, we will perform in vitro and in vivo studies to dissect the role of STC-1/AMPK/SIRT3 signaling pathway in the pathophysiological function of tubulointerstitial fibrosis under the stimulation of high glucose and AngII; To explore the role of intervention of BNIP3 in delaytion the progression of CKD by interfere with mitochondrial function. The goal of this proposal is to dissect the role and underlying mechanisms of STC-1/BNIP3 in tubulo-interstitial damage in order to provide scientific and experimental direction for the treatment of DKD in future.

糖尿病肾病（DKD）是常见的继发性肾脏病，也是引起终末期肾病的主要病因。肾小管间质纤维化在DKD发病中的作用日益受到重视。我们前期研究发现斯钙素-1(STC-1)异常表达同DKD疾病进展密切相关，是预测小管间质损伤程度的生物标志物；线粒体影响小管细胞病理生理功能及ROS产生，是引起DKD小管损伤与凋亡的核心环节；BNIP3基因敲除小鼠予以STZ造模DKD，同野生型小鼠相比小管间质纤维化水平显著降低，但其具体机制不明。本项目采用动物及细胞分子生物学技术，体内外研究DKD状态下高葡萄糖（HG）、AngII通过抑制STC-1/AMPK/SIRT3通路激活在DKD小管间质损伤中的作用与机制，探讨下调BNIP3影响线粒体功能干预DKD进展及其相关机理。旨在揭示STC-1/BNIP3通过影响促纤维化因子表达在DKD小管间质损伤中的分子发病机制，为DKD诊疗提供新的干预靶点。

糖尿病肾病（DKD）是常见的继发性肾脏病，也是引起终末期肾病的主要病因。肾小管间质纤维化在DKD发病中的作用日益受到重视。本课题发现斯钙素-1(STC-1)异常表达同DKD疾病进展密切相关，是预测小管间质损伤程度的生物标志物；细胞及动物实验证实线粒体影响小管细胞病理生理功能及ROS 产生，是引起DKD小管损伤与凋亡的核心环节，外源性补充STC-1 可以改善 db/db小鼠肾脏氧化应激与细胞凋亡；体外试验中，高葡萄糖处理的bumpt细胞通过STC-1激活AMPK/SIRT3 途径抑制BNIP3表达，减轻氧化应激及细胞凋亡。在临床研究中，通过检测DKD患者STC-1血清浓度发现，高浓度组与低浓度组患者相比，预后更好，一方面表明血清 STC-1可能预测 DKD进展，另一方面证实额外补充STC-1可能成为治疗DKD患者的潜在药物。本课题发现DKD状态下，精氨酸甲基转移酶-1参与内质网应激和肾小管上皮细胞-间充质转化的新机制；消退素D1在高糖状态下，可抑制NF-κ B的激活， 减轻炎症反应对肾小管间质的损伤；通过代谢组学，首次发现 5-羟基己酸可以作为预测DKD进展的早期标志物；初步证实脂联素治疗减轻DKD大鼠肾脏组织病理学损伤，降低血糖水平，维持稳定的动物体重，促进小管细胞活性，抑制细胞凋亡和自噬体的形成，同时可增加线粒体质量、线粒体 DNA含量和线粒体膜体内外电位。上述研究为DKD诊治提供了新的角度和治疗靶点。