Xu Ping, Guan Mei-Ping, Bi Jian-Gang, Wang Dan, Zheng Zong-Ji, Xue Yao-Ming
Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Endocrinology and Metabolism, Second Affiliated Hospital of Jinan University, Shenzhen, Guangdong, China.
Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Cell Signal. 2017 Feb;31:96-104. doi: 10.1016/j.cellsig.2017.01.012. Epub 2017 Jan 7.
Tubulointerstitial fibrosis (TIF) plays an important role in the progression of renal fibrosis in diabetic nephropathy (DN). Accumulating evidence supports a crucial effect of early growth response factor 1 (Egr1) on renal fibrosis in DN, but the underlying mechanisms are not entirely clear. Here, we explored the aggravating role of Egr1 and identified microRNA-181a-5p (miR-181a-5p) as an upstream regulator of Egr1 in TIF of DN. We demonstrated that overexpression of Egr1 enhanced, whereas small interfering RNA targeting Egr1 decreased the expressions of transforming growth factor β1 (TGF-β1) and fibrosis-related genes including fibronectin and collagen I in human proximal tubule cell line (HK-2) cells. We then found that miR-181a-5p expression was down-regulated, accompanied by the corresponding up-regulation of Egr1, TGF-β1, fibronectin and collagen I in renal tissues of type 2 diabetic Otsuka-Long-Evans-Tokushima-Fatty rats with DN, and that the expression of miR-181a-5p was negatively correlated with the level of Egr1 in HK-2 cells treated with high glucose. Furthermore, we identified that miR-181a-5p directly suppressed Egr1 to decrease the expressions of TGF-β1, fibronectin and collagen I in HK-2 cells through targeting the 3' untranslated region of Egr1. The functional relevance of miR-181a-5p-induced Egr1 decrease was supported by inhibition and overexpression of miR-181a-5p in HK-2 cells. Thus, we concluded that aberrant Egr1 expression, which can be suppressed by miR-181a-5p directly, plays a crucial role in the progression of renal TIF in DN. This study indicates that targeting miR-181a-5p may be a novel therapeutic approach of DN.
肾小管间质纤维化（TIF）在糖尿病肾病（DN）肾纤维化进展中起重要作用。越来越多的证据支持早期生长反应因子1（Egr1）对DN肾纤维化有关键作用，但其潜在机制尚不完全清楚。在此，我们探讨了Egr1的加重作用，并确定微小RNA - 181a - 5p（miR - 181a - 5p）是DN的TIF中Egr1的上游调节因子。我们证明，Egr1的过表达增强了人近端肾小管细胞系（HK - 2）中转化生长因子β1（TGF -β1）以及包括纤连蛋白和I型胶原在内的纤维化相关基因的表达，而靶向Egr1的小干扰RNA则降低了这些基因的表达。然后我们发现，在患有DN的2型糖尿病大冢 - 朗 - 伊文斯 - 德岛 - 肥胖大鼠的肾组织中，miR - 181a - 5p表达下调，同时Egr1、TGF -β1、纤连蛋白和I型胶原相应上调，并且在高糖处理的HK - 2细胞中，miR - 181a - 5p的表达与Egr1水平呈负相关。此外，我们确定miR - 181a - 5p通过靶向Egr1的3'非翻译区直接抑制Egr1，从而降低HK - 2细胞中TGF -β1、纤连蛋白和I型胶原的表达。HK - 2细胞中miR - 181a - 5p的抑制和过表达支持了miR - 181a - 5p诱导Egr1降低的功能相关性。因此，我们得出结论，可被miR - 181a - 5p直接抑制的异常Egr1表达在DN的肾TIF进展中起关键作用。本研究表明，靶向miR - 181a - 5p可能是DN的一种新型治疗方法。
