Sha Qian, Lyu Jinxiu, Zhao Meng, Li Haijuan, Guo Mengzhe, Sun Qiang
Department of Pharmacy, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.
Front Genet. 2020 Dec 11;11:616435. doi: 10.3389/fgene.2020.616435. eCollection 2020.
Diabetic nephropathy (DN) is one of the most common diabetic complications, which is the major course of end-stage renal disease (ESRD). However, the systematical molecular characterizations during DN pathogenesis and progression has not been not well understood. To identify the fundamental mediators of the pathogenesis and progression of DN. we performed a combination RNASeq, proteomics, and metabolomics analyses of both patients' derived kidney biopsy samples and kidneys from DN model. As a result, molecular changes of DN contain extracellular matrix accumulation, abnormal activated inflamed microenvironment, and metabolism disorders, bringing about glomerular sclerosis and tubular interstitial fibrosis. Specificity, Further integration analyses have identified that the linoleic acid metabolism and fatty-acids β-oxidation are significantly inhibited during DN pathogenesis and progression, the transporter protein ABCD3, the fatty acyl-CoA activated enzymes ACOX1, ACOX2, and ACOX3, and some corresponding metabolites such as 13'-HODE, stearidonic acid, docosahexaenoic acid, (±)10(11)-EpDPA were also significantly reduced. Our study thus provides potential molecular mechanisms for DN progression and suggests that targeting the key enzymes or supplying some lipids may be a promising avenue in the treatment of DN, especially advanced-stage DN.
糖尿病肾病（DN）是最常见的糖尿病并发症之一，是终末期肾病（ESRD）的主要病因。然而，DN发病机制和进展过程中的系统分子特征尚未完全明确。为了确定DN发病机制和进展的基本介质，我们对患者的肾活检样本和DN模型的肾脏进行了RNA测序、蛋白质组学和代谢组学分析。结果显示，DN的分子变化包括细胞外基质积聚、异常激活的炎症微环境和代谢紊乱，导致肾小球硬化和肾小管间质纤维化。具体而言，进一步的整合分析表明，在DN发病机制和进展过程中，亚油酸代谢和脂肪酸β氧化显著受到抑制，转运蛋白ABCD3、脂肪酰辅酶A激活酶ACOX1、ACOX2和ACOX3以及一些相应的代谢物如13'-HODE、硬脂酸、二十二碳六烯酸、（±）10（11）-EpDPA也显著减少。因此，我们的研究为DN进展提供了潜在的分子机制，并表明靶向关键酶或提供某些脂质可能是治疗DN，尤其是晚期DN的一条有前景的途径。
