MiR-4756 promotes albumin-induced renal tubular epithelial cell epithelial-to-mesenchymal transition and endoplasmic reticulum stress via targeting Sestrin2
MiR-4756 promotes albumin-induced renal tubular epithelial cell epithelial-to-mesenchymal transition and endoplasmic reticulum stress via targeting Sestrin2
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MiR-4756 通过靶向 Sestrin2 促进白蛋白诱导的肾小管上皮细胞上皮间质转化和内质网应激
DOI：
10.1002/jcp.27107
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发表时间：
2019-03-01
影响因子：
5.6
通讯作者：
Xue, Yaoming
中科院分区：
文献类型：
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作者：
Jia, Yijie;Zheng, Zongji;Xue, Yaoming
越来越多的证据表明，蛋白尿促进糖尿病肾病(DKD)的进展，并诱导肾小管上皮细胞向间充质细胞转化(EMT)和内质网(ER)应激，但其机制尚不清楚。在我们以前的研究中，我们发现在2型糖尿病伴大量白蛋白尿的患者尿胞外小泡中miR-4756水平升高。在初步研究中，我们发现miR-4756可能来源于肾小管上皮细胞，但其作用尚未阐明。白蛋白刺激显著增加HK-2细胞miR-4756水平。此外，miR-4756模拟白蛋白刺激的HK-2细胞EMT和内质网应激，miR-4756抑制剂抑制这些事件。然后我们发现miR-4756靶向Sestrin2的3‘非翻译区，并直接抑制Sestrin2的表达。此外，Sestrin2过表达可消除miR-4756过表达所诱导的EMT和内质网应激。此外，miR-4756的过表达增加了ERK1/2的活性，降低了5‘一磷酸激活的蛋白激酶的活性。因此，我们的研究提供了证据表明miR-4756通过Sestrin2加速了DKD的进程，提示靶向miR-4756可能是治疗DKD的一种新策略。
Accumulating evidence indicates that proteinuria promotes the progression of diabetic kidney disease (DKD) and induces renal epithelial tubular cell epithelial-to-mesenchymal transition (EMT) and endoplasmic reticulum (ER) stress, but the mechanism remains unclear. In our previous research, we found that miR-4756 levels were increased in the urinary extracellular vesicles of type 2 diabetes mellitus patients with macroalbuminuria. In a preliminary study, we found that miR-4756 may be derived from renal tubular epithelial cells, but its role has not been elucidated. Albumin stimulation significantly increased miR-4756 levels in HK-2 cells. In addition, an miR-4756 mimic accelerated albumin-stimulated HK-2 cell EMT and ER stress, and an miR-4756 inhibitor suppressed these events. We then found that miR-4756 targeted the 3 '-untranslated region (UTR) of Sestrin2 and directly suppressed Sestrin2 expression. Furthermore, the induction of EMT and ER stress by the overexpression of miR-4756 was abolished by Sestrin2 overexpression. Moreover, the overexpression of miR-4756 increased ERK1/2 activation and decreased 5 ' monophosphate-activated protein kinase activation. Thus, our study provides evidence that miR-4756 accelerates the process of DKD through Sestrin2, suggesting that targeting miR-4756 may be a novel strategy for DKD treatment.