基因敲除
脂肪组织
移植
纤维化
褐色脂肪组织
生物
运行x1
基因沉默
内分泌学
异位表达
内科学
小RNA
糖尿病肾病
癌症研究
医学
肾
细胞生物学
干细胞
细胞凋亡
基因
造血
生物化学
作者
Yudan Zhang,Yingying Cai,Hongbin Zhang,Jiajun Zhang,Yanmei Zeng,Cunxia Fan,Shaozhou Zou,Chunyan Wu,Shu Fang,Ping Li,Xiaochun Lin,Ling Wang,Meiping Guan
标识
DOI:10.1016/j.metabol.2021.154916
摘要
Adipose tissue is a major source of circulating microRNAs (miRNAs) that can regulate target genes in distant organs. However, the role of brown adipose tissue (BAT) in diabetic kidney disease (DKD) is still unknown. We studied the original BAT miR-30b targeting two key fibrotic regulators, Runt-related transcription factor 1 (Runx1) and snail family zinc finger 1 (Snail1), to combat DKD.First, we transplanted healthy BAT from normal mouse donors into diabetic mice (induced by a high-fat diet and streptozotocin injection). In vitro, we observed extracellular vesicles (EVs) secreted from brown adipocytes. AgomiR-30b was directly administered to the BAT of diabetic mice twice weekly for 4 consecutive weeks. Next, the role of Runx1 in DKD was determined by using siRUNX1 or pCMV-RUNX1 in HK-2 cells and in diabetic mice treated with AAV9-U6-shRunx1 or AAV9-EF1a-Runx1.BAT transplantation reactivated endogenous BAT activity in diabetic mice, increased circulating miR-30b levels and significantly ameliorated DKD. In TGFβ1-treated HK-2 cells, miR-30b expression was significantly suppressed. miR-30b overexpression markedly decreased fibronectin and downregulated Runx1 and Snail1 expression, while silencing of miR-30b had the opposite effects. Next, Runx1 knockdown and overexpression mimicked the above phenotype of miR-30b mimics and inhibitors, respectively, both in vitro and in vivo. Moreover, Runx1 promoted TGFβ1-induced fibrosis by upregulating the PI3K pathway.BAT-derived miRNAs might be a promising target for kidney protection in diabetes mellitus.
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