Urology Department, Cangzhou Central Hospital, No. 16 Xinhua Road, Hebei, 061000, People's Republic of China.
Hum Cell. 2018 Jan;31(1):22-32. doi: 10.1007/s13577-017-0180-z. Epub 2017 Jul 13.
It has been reported that transforming growth factor-β1 (TGF-β1) signaling plays an important role in the development of diabetic nephropathy (DN). The nuclear transcription co-repressor Ski-related novel protein N (SnoN) is a critical negative regulator of TGF-β1/Smad signal pathway, involving in tubule epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) accumulation, and tubulointerstitial fibrosis. In this study, we focused on miR-23a as a regulator of SnoN. Our purpose is to study the effects of miR-23a on high glucose (HG)-induced EMT process and ECM deposition in HK2 cells. We found that miR-23a was up-regulated in renal tissues of diabetic patients and HG-induced HK2 cells. Besides, the high level of miR-23a was closely associated with decreased SnoN expression. Knockdown of miR-23a increased SnoN expression and in turn suppressed HG-induced EMT and renal fibrogenesis. Introduction of miR-23a decreased SnoN expression and enhanced the profibrogenic effects of HG on HK2 cells. Next, bioinformatics analysis predicted that the SnoN was a potential target gene of miR-23a. Luciferase reporter assay demonstrated that miR-23a could directly target SnoN. We demonstrated that overexpression of SnoN was sufficient to inhibit HG-induced EMT and renal fibrogenesis in HK2 cells. Furthermore, down-regulation of SnoN partially reversed the protective effect of miR-23a knockdown on HG-induced EMT and renal fibrogenesis in HK2 cells. Collectively, miR-23a and SnoN significantly impact on the progression of HG-induced EMT and renal fibrogenesis in vitro, and they may represent novel targets for the prevention strategies of renal fibrosis in the context of DN.
已有报道称转化生长因子-β1（TGF-β1）信号通路在糖尿病肾病（DN）的发展中起着重要作用。核转录共抑制因子Ski 相关 novel protein N（SnoN）是 TGF-β1/Smad 信号通路的关键负调控因子，参与小管上皮-间充质转化（EMT）、细胞外基质（ECM）积聚和小管间质纤维化。在本研究中，我们将重点关注 microRNA-23a（miR-23a）作为 SnoN 的调节因子。我们的目的是研究 miR-23a 对高糖（HG）诱导的 HK2 细胞 EMT 过程和 ECM 沉积的影响。我们发现 miR-23a 在糖尿病患者的肾脏组织和 HG 诱导的 HK2 细胞中上调。此外，miR-23a 的高水平与 SnoN 表达的降低密切相关。miR-23a 的敲低增加了 SnoN 的表达，进而抑制了 HG 诱导的 EMT 和肾纤维化。引入 miR-23a 降低了 SnoN 的表达，并增强了 HG 对 HK2 细胞的促纤维化作用。接下来，生物信息学分析预测 SnoN 是 miR-23a 的潜在靶基因。荧光素酶报告基因检测证实 miR-23a 可直接靶向 SnoN。我们证实 SnoN 的过表达足以抑制 HG 诱导的 HK2 细胞 EMT 和肾纤维化。此外，SnoN 的下调部分逆转了 miR-23a 敲低对 HG 诱导的 EMT 和肾纤维化的保护作用。综上所述，miR-23a 和 SnoN 显著影响 HG 诱导的 EMT 和肾纤维化的进展，它们可能代表了 DN 背景下预防肾纤维化的新靶点。
