Let-7d miRNA prevents TGF-β1-induced EMT and renal fibrogenesis through regulation of HMGA2 expression.
TGF-β1-induced epithelial to mesenchymal transition (EMT) process of tubular epithelial cells plays a leading role in the occurrence and progression of renal fibrosis as seen in diabetic nephropathy (DN). High mobility group AT-hook 2 (HMGA2) is considered to be involved in TGF-β1-mediated EMT via multifactorial mechanisms. Specific microRNAs (miRNAs) are closely associated with EMT, and here we focused on let-7d miRNA as a regulator of HMGA2. This study aims to investigate the effects of HMGA2 on EMT process induced by TGF-β1 using small interfering RNA (siRNA) technique in vitro, and further explore the potential role of let-7d miRNA during renal fibrosis in DN. We demonstrated that siRNA targeting HMGA2 was sufficient to inhibit TGF-β1-induced EMT and fibrogenesis in rat kidney tubular epithelial cells (NRK52E). Furthermore, let-7d expression was significantly reduced by TGF-β1 stimulation, we focused on let-7d and found that overexpression of let-7d down-regulated the expression of HMGA2 and in turn suppressed TGF-β1-induced EMT and renal fibrogenesis. Inhibition of let-7d increased HMGA2 expression and enhanced the profibrogenic effects of TGF-β1 on NRK-52E cells. Consistent with the above observations in vitro, let-7d expression was also decreased in the kidneys of unilateral ureter obstruction model, accompanied by the correspondingly increased expression of HMGA2 and fibrotic genes in this model. Collectively, HMGA2 and let-7d miRNA significantly impact on the progression of TGF-β1-induced EMT and fibrogenesis both in vitro and in vivo, and they may represent novel targets for the prevention strategies of renal fibrosis in the context of DN.
Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Endocrinology, Jingzhou First People's Hospital, Yangtze University, Jingzhou, Hubei, China.
Ya
Y
Wang
Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Ying
Y
Le
Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Jun-Yu
JY
Xue
Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Zong-Ji
ZJ
Zheng
Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: xymbright@126.com.
Yao-Ming
YM
Xue
D000818:Animals; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000150:complications / Q000473:pathology; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005355:Fibrosis; D005786:Gene Expression Regulation; D025743:HMGA2 Protein / Q000235:genetics*; D007687:Kidney Tubules, Proximal / Q000473:pathology*; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology / Q000502:physiology*; D014517:Ureteral Obstruction
D025743:HMGA2 Protein; C548145:MIRNLET7 microRNA, rat; D035683:MicroRNAs; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1
Epithelial to mesenchymal transition; HMGA2; Kidney tubular epithelial cells; Let-7d; Renal fibrogenesis