NDRG2 knockdown promotes fibrosis in renal tubular epithelial cells through TGF-β1/Smad3 pathway
NDRG2 knockdown promotes fibrosis in renal tubular epithelial cells through TGF-β1/Smad3 pathway
复制标题
NDRG2敲低通过TGF-β1/Smad3途径促进肾小管上皮细胞纤维化
DOI：
10.1007/s00441-017-2643-7
复制
发表时间：
2017-09-01
影响因子：
3.6
通讯作者：
Yang, Jinjian
中科院分区：
文献类型：
--
作者：
Jin, Zhibo;Gu, Chaohui;Yang, Jinjian
肾纤维化是各种慢性肾脏疾病进展为终末期肾脏疾病的共同病理途径，其特征在于肾小管萎缩、成纤维细胞/肌成纤维细胞活化和细胞外基质（ECM）过度沉积。N-Myc下游调节基因2（NDRG 2）与大鼠肝纤维化相关。然而，NDRG 2在肾纤维化中的生物学功能仍不清楚。因此，我们研究NDRG 2对肾纤维化的影响以及NDRG 2在TGF-β 1诱导的肾小管上皮细胞（HK-2）中的潜在机制。我们的研究结果表明，TGF-β 1下调NDRG 2 mRNA和蛋白质在HK-2细胞的表达。此外，NDRG 2敲低显著降低TGF-β 1诱导的E-钙粘蛋白的蛋白质和mRNA，并增加TGF-β 1诱导的α-SMA、波形蛋白、Snail、Col-I、Col-III和FN的蛋白质和mRNA表达水平;这被NDRG 2过表达逆转。此外，NDRG 2沉默显著增加了Smad 3（p-Smad 3）的磷酸化水平，其被NDRG 2过表达降低，尽管这些对p-Smad 2和Smad 7的蛋白表达没有影响。此外，SIS 3，一种Smad 3磷酸化的特异性抑制剂，部分逆转NDRG 2敲低对TGF-β 1诱导的HK-2细胞中上皮间质转化（EMT）标志物和ECM组分的蛋白和mRNA表达的影响。总之，我们的研究结果表明，NDRG 2敲低促进肾纤维化，通过其对蛋白质和mRNA表达的EMT标志物和ECM组分的影响，通过调节下游Smad 3信号通路在肾小管上皮细胞。调节NDRG 2的表达可能为肾纤维化提供新的治疗方法。
Renal fibrosis is a common pathological pathway of various chronic kidney diseases progressing to end-stage renal disease and is characterized by tubular atrophy, fibroblast/myofibroblast activation and excessive deposition of extracellular matrix (ECM). N-Myc downstream-regulated gene-2 (NDRG2) is reported to be associated with liver fibrosis in rats. However, the biological function of NDRG2 in renal fibrosis remains unclear. Therefore, we investigate the effect of NDRG2 on renal fibrosis and the underlying mechanism of NDRG2 in TGF-beta 1-induced renal tubular epithelial cells (HK-2). Our results show that TGF-beta 1 down-regulates NDRG2 mRNA and protein expression in HK-2 cells. Moreover, NDRG2 knockdown dramatically reduces the TGF-beta 1-induced protein and mRNA of E-cadherin and increases the TGF-beta 1-induced protein and mRNA expression level of alpha-SMA, Vimentin, Snail, Col-I, Col-III and FN; this is reversed by NDRG2 overexpression. Furthermore, NDRG2 silencing significantly increases the phosphorylation level of Smad3 (p-Smad3), which is decreased by NDRG2 overexpression, although these have no effect on the protein expression of p-Smad2 and Smad7. In addition, SIS3, a specific inhibitor of Smad3 phosphorylation, partly reverses the effect of NDRG2 knockdown on the protein and mRNA expression of epithelial-mesenchymal transition (EMT) markers and ECM components in TGF-beta 1-induced HK-2 cells. Taken together, our results indicate that NDRG2 knockdown promotes renal fibrosis through its effect on the protein and mRNA expression of EMT markers and ECM components by regulating the downstream Smad3 signaling pathway in renal tubular epithelial cells. Modulation of NDRG2 expression might provide a new therapy for renal fibrosis.