MicroRNA-130b improves renal tubulointerstitial fibrosis via repression of Snail-induced epithelial-mesenchymal transition in diabetic nephropathy.
MicroRNA-130b improves renal tubulointerstitial fibrosis via repression of Snail-induced epithelial-mesenchymal transition in diabetic nephropathy.
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MicroRNA-130b通过抑制蜗牛诱导的上皮 - 间质转变来改善肾小管间质纤维化。
DOI：
10.1038/srep20475
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发表时间：
2016-02-03
影响因子：
4.6
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Bai X;Geng J;Zhou Z;Tian J;Li X
MicroRNA-130b （miR-130b）下调已在糖尿病中被发现，但miR-130b在糖尿病肾病（DN）中介导肾小管间质纤维化的作用和机制尚不清楚。我们证明血浆miR-130b下调具有临床和生物学相关性，因为它与肾病患者肾活检中血清肌酐、β2-微球蛋白和蛋白尿升高、Snail表达增加和小管间质纤维化有关。MiR-130b抑制剂引起高糖（30 mM）培养的NRK-52E细胞的Snail上调和上皮-间质转化（EMT）的分子特征增强。相反，miR-130b模拟下调的Snail表达和增加的上皮标记。值得注意的是，Snail被鉴定为miR-130b的直接靶点，并且与E-CADHERIN的表达呈负相关。此外，mir -130b依赖性效应是由于蜗牛抑制，进而解除了E-CADHERIN， VIMENTIN， COLLAGEN IV和α-平滑肌肌动蛋白（α-SMA），这些是EMT的关键介质。这些影响在链脲佐菌素诱导的糖尿病大鼠中重现。因此，我们提出了miR-130b-SNAIL轴在促进EMT和DN中向增加的小管间质纤维化进展中的新作用。血浆miR-130b的检测及其与SNAIL的关联可以推断量化肾小管间质纤维化的严重程度。靶向miR-130b可以作为一种潜在的DN治疗方法进行评估。
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.