Bai Xiaoyan, Geng Jian, Zhou Zhanmei, Tian Jianwei, Li Xiao
Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, 510515, China.
Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Sci Rep. 2016 Feb 3;6:20475. doi: 10.1038/srep20475.
MicroRNA-130b (miR-130b) downregulation has been identified in diabetes, but the role and mechanisms for miR-130b in mediating renal tubulointerstitial fibrosis in diabetic nephropathy (DN) remain unknown. We demonstrated that plasma miR-130b downregulation exhibited clinical and biological relevance as it was linked to increased serum creatinine, β2-microglobulin and proteinuria, increased Snail expression and tubulointerstitial fibrosis in renal biopsies of DN patients. MiR-130b inhibitor caused Snail upregulation and enhanced molecular features of epithelial-to-mesenchymal transition (EMT) in high glucose (30 mM) cultured NRK-52E cells. In contrast, miR-130b mimic downregulated Snail expression and increased epithelial hallmarks. Notably, Snail was identified as an miR-130b direct target and inversely correlated with E-CADHERIN expression. Furthermore, the miR-130b-dependent effects were due to Snail suppression that in turn deregulated E-CADHERIN, VIMENTIN, COLLAGEN IV and α-smooth muscle actin (α-SMA), key mediators of EMT. These effects were reproduced in streptozotocin-induced diabetic rats. Thus, we propose a novel role of the miR-130b-SNAIL axis in fostering EMT and progression toward increased tubulointerstitial fibrosis in DN. Detection of plasma miR-130b and its association with SNAIL can be extrapolated to quantifying the severity of renal tubulointerstitial fibrosis. Targeting miR-130b could be evaluated as a potential therapeutic approach for DN.
在糖尿病中已发现微小RNA-130b（miR-130b）表达下调，但miR-130b在介导糖尿病肾病（DN）肾小管间质纤维化中的作用及机制仍不清楚。我们发现，血浆miR-130b表达下调具有临床和生物学相关性，因为它与DN患者肾活检中血清肌酐、β2微球蛋白和蛋白尿增加、Snail表达增加以及肾小管间质纤维化有关。miR-130b抑制剂可导致高糖（30 mM）培养的NRK-52E细胞中Snail上调，并增强上皮-间质转化（EMT）的分子特征。相反，miR-130b模拟物可下调Snail表达并增加上皮标志物。值得注意的是，Snail被确定为miR-130b的直接靶点，且与E-钙黏蛋白表达呈负相关。此外，miR-130b依赖性效应是由于Snail受到抑制，进而使EMT的关键介质E-钙黏蛋白、波形蛋白、IV型胶原和α-平滑肌肌动蛋白（α-SMA）失调所致。这些效应在链脲佐菌素诱导的糖尿病大鼠中也得到了验证。因此，我们提出miR-130b-SNAIL轴在促进DN中的EMT及肾小管间质纤维化进展方面具有新作用。检测血浆miR-130b及其与SNAIL的关联可用于推断肾小管间质纤维化的严重程度。靶向miR-130b可作为DN的一种潜在治疗方法进行评估。
