补体旁路途径活化通过影响肾脏神经酰胺代谢参与糖尿病肾病发病机制的研究

糖尿病肾病是慢性肾脏病的重要病因，发病机制尚不明晰，近年包括申请者在内的研究发现补体活化和肾脏异位脂质沉积是其重要组成部分。申请者前期通过对患者血、尿、肾组织标本和基因敲除动物研究发现：补体旁路途径活化在本病发病机制中发挥重要作用，脂质组学研究提示补体旁路途径活化可能介导了肾脏脂质特别是神经酰胺的异位沉积，转录组学研究提示神经酰胺合酶3可能是上述过程中关键脂质调控蛋白。结合既往研究提示补体与氧化应激、内质网应激、脂代谢之间存在复杂的交叉对话，我们提出如下科学假说：补体旁路途径活化介导氧化应激和内质网应激，导致肾脏异位脂质沉积特别是神经酰胺沉积，其中关键脂质调控蛋白神经酰胺合酶3促进神经酰胺合成，介导肾小管上皮细胞损伤从而参与本病发生发展。本课题拟从临床、动物和细胞研究深入探索补体旁路途径介导的肾脏脂质特别是神经酰胺异位沉积、进而参与本病发病，有助于深入揭示本病发病机制及探索潜在的治疗靶点。

Diabetic kidney disease (DKD) is becoming the leading cause of chronic kidney disease. The pathogenesis of DKD is not fully clear. Previous studies, including those of the applicant’s, found that complement activation and ectopic lipid deposition of kidneys are the important aspects. Our previous studies, from plasma, urine and renal tissues of DKD patients and gene knockout animal models, found that complement activation, especially via the alternative pathway, played an important role in the pathogenesis of DKD. The lipidomics study suggested that activation of the alternative complement pathway mediates ectopic lipid, especially ceramide, deposition in kidneys. The transcriptomics study suggested that ceramide synthase 3 (CerS3) is the key lipid regulatory protein in the abovementioned process. Combined with previous studies that complex cross-talks exist among complement activation, oxidative stress, endoplasmic reticulum stress and lipid metabolism, we proposed the following scientific hypothesis: complement alternative pathway activation mediates oxidative stress and endoplasmic reticulum stress, which leads to local ectopic lipid deposition in kidneys, especially ceramide deposition, in which the key lipid regulatory protein CerS3 promotes ceramide synthesis, mediates injuries of renal tubular epithelial cells and ultimately leads to kidney damage in diabetes. In the current project, we aim to further explore, from clinical research, animal experiments and in vitro experiments, the cellular and molecular mechanism of ectopic lipid deposition, especially ceramide deposition, in kidneys mediated by the activation of complement alternative pathway in the pathophysiological process of DKD. These will further reveal the pathogenesis of DKD and explore potential therapeutic targets.