Brown adipose tissue transplantation ameliorates diabetic nephropathy through the miR-30b pathway by targeting Runx1.
Brown adipose tissue transplantation ameliorates diabetic nephropathy through the miR-30b pathway by targeting Runx1.
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DOI：
10.1016/j.metabol.2021.154916
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发表时间：
2021-10
期刊：
影响因子：
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通讯作者：
Yudan Zhang;Yingying Cai;Hongbin Zhang;Jiajun Zhang;Yanmei Zeng;Cunxia Fan;Shaozhou Zou;Chunyan Wu
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文献类型：
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作者：
Yudan Zhang;Yingying Cai;Hongbin Zhang;Jiajun Zhang;Yanmei Zeng;Cunxia Fan;Shaozhou Zou;Chunyan Wu
目的脂肪组织是循环 microRNA (miRNA) 的主要来源，可调节远处器官中的靶基因。然而，棕色脂肪组织（BAT）在糖尿病肾病（DKD）中的作用仍不清楚。我们研究了针对两个关键纤维化调节因子 Runt 相关转录因子 1 (Runx1) 和蜗牛家族锌指 1 (Snail1) 的原始 BAT miR-30b，以对抗 DKD。方法首先，我们将来自正常小鼠供体的健康 BAT 移植到糖尿病小鼠中（通过高脂饮食和注射链脲佐菌素诱导）。在体外，我们观察到棕色脂肪细胞分泌的细胞外囊泡（EV）。 AgomiR-30b 直接给予糖尿病小鼠的 BAT，每周两次，连续 4 周。接下来，通过在 HK-2 细胞和经 AAV9-U6-shRunx1 或 AAV9-EF1a-Runx1 治疗的糖尿病小鼠中使用 siRUNX1 或 pCMV-RUNX1 来确定 Runx1 在 DKD 中的作用。 结果 BAT 移植重新激活了糖尿病小鼠的内源性 BAT 活性，增加了循环 miR-30b 水平，并显着改善了 DKD。在 TGFβ1 处理的 HK-2 细胞中，miR-30b 表达显着受到抑制。 miR-30b 过表达显着降低纤连蛋白并下调 Runx1 和 Snail1 表达，而 miR-30b 沉默则产生相反的效果。接下来，Runx1 敲低和过表达在体外和体内分别模拟了 miR-30b 模拟物和抑制剂的上述表型。此外，Runx1通过上调PI3K通路促进TGFβ1诱导的纤维化。结论BAT衍生的miRNA可能是糖尿病肾脏保护的一个有前景的靶点。
ObjectiveAdipose 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.MethodsFirst, 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.ResultsBAT 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.ConclusionBAT-derived miRNAs might be a promising target for kidney protection in diabetes mellitus.