Journal of Molecular Histology ( IF 2.9 ) Pub Date : 2020-08-16 , DOI: 10.1007/s10735-020-09904-6 Xiang Wang 1, 2 , Qiling Liu 1 , Deqin Kong 1 , Zi Long 1 , YuFang Guo 2 , Shuang Wang 2 , Rui Liu 1 , Chunxu Hai 1
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Abstract
Diabetic nephropathy (DN), a serious complication of hyperglycemia, is one of the most common causes of end-stage renal disease (ESRD). Glomerular podocyte injury is a major mechanism that leads to DN. However, the mechanisms underlying podocyte injury are ambiguous. In this study, we sought to investigate the contribution of SET domain-containing protein 6 (SETD6) to the pathogenesis of podocyte injury induced by glucose (GLU) and palmitic acid (PA), as well as the underlying mechanisms. Our results showed that GLU and PA treatment significantly decreased SETD6 expression in mouse podocytes. Besides, Cell Counting Kit-8 (CCK-8) and flow cytometry assay demonstrated that silencing of SETD6 silence obviously enhanced cell viability, and suppressed apoptosis in GLU and PA-induced podocytes. We also discovered that downregulation of SETD6 suppressed GLU and PA-induced ROS generation and podocyte mitochondrial dysfunction. Nrf2-Keap1 signaling pathway was involved in the effect of SETD6 on mitochondrial dysfunction. Taken together, silencing of SETD6 protected mouse podocyte against apoptosis and mitochondrial dysfunction through activating Nrf2-Keap1 signaling pathway. Therefore these data provide new insights into new potential therapeutic targets for DN treatment.
Graphic abstract
中文翻译：
SETD6的下调通过激活Nrf2-Keap1信号通路在糖尿病肾病中保护足细胞免受高葡萄糖和棕榈酸诱导的细胞凋亡以及线粒体功能障碍。
摘要
糖尿病肾病（DN）是高血糖症的严重并发症，是终末期肾脏疾病（ESRD）的最常见原因之一。肾小球足细胞损伤是导致DN的主要机制。但是，足细胞损伤的机制尚不清楚。在这项研究中，我们试图研究含SET结构域的蛋白6（SETD6）对葡萄糖（GLU）和棕榈酸（PA）诱导的足细胞损伤的发病机制的作用，以及潜在的机制。我们的结果表明，GLU和PA处理可显着降低小鼠足细胞中SETD6的表达。此外，Cell Counting Kit-8（CCK-8）和流式细胞仪检测表明，SETD6沉默的沉默明显增强了细胞活力，并抑制了GLU和PA诱导的足细胞的凋亡。我们还发现SETD6的下调抑制了GLU和PA诱导的ROS生成以及足细胞线粒体功能障碍。Nrf2-Keap1信号通路参与SETD6对线粒体功能障碍的影响。总之，沉默SETD6可通过激活Nrf2-Keap1信号通路保护小鼠足细胞免于凋亡和线粒体功能障碍。因此，这些数据为DN治疗的新潜在治疗靶点提供了新见识。
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