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Mol Cell Endocrinol. 2014 Jul 5;392(1-2):163-72. doi: 10.1016/j.mce.2014.05.018. Epub 2014 Jun 2.

miR-21 overexpression enhances TGF-β1-induced epithelial-to-mesenchymal transition by target smad7 and aggravates renal damage in diabetic nephropathy.

Author information

  • 1Metabolic Disease Center, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China; Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China; Department of Endocrine and Metabolism, Capital Medical University, Beijing, China; Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China.
  • 2Metabolic Disease Center, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China; Department of Endocrine and Metabolism, Capital Medical University, Beijing, China. Electronic address: gaoyb111@hotmail.com.
  • 3Metabolic Disease Center, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
  • 4Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
  • 5Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
  • 6Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China. Electronic address: jinkui.yang@gmail.com.

Abstract

Epithelial-to-mesenchymal transition (EMT) plays an important role in renal interstitial fibrosis (RIF) with diabetic nephropathy (DN). Smad7 (a inhibitory smad), a downstream signaling molecules of TGF-β1, represses the EMT. The physiological function of miR-21 is closely linked to EMT and RIF. However, it remained unclear whether miR-21 over-expression affected TGF-β1-induced EMT by regulating smad7 in DN. In this study, real-time RT-PCR, cell transfection, luciferase reporter gene assays, western blot and confocal microscope were used, respectively. Here, we found that miR-21 expression was upregulated by TGF-β1 in time- and concentration -dependent manner. Moreover, miR-21 over-expression enhanced TGF-β1-induced EMT(upregulation of a-SMA and downregulation of E-cadherin) by directly down-regulating smad7/p-smad7 and indirectly up-regulating smad3/p-smad3, accompanied by the decrease of Ccr and the increase of col-IV, FN, the content of collagen fibers, RTBM, RTIAW and ACR. Meantime, the siRNA experiment showed that smad7 can directly regulate a-SMA and E-cadherin expression. More importantly, miR-21 inhibitor can not only inhibit EMT and fibrosis but also ameliorate renal structure and function. In conclusion, our results demonstrated that miR-21 overexpression can contribute to TGF-β1-induced EMT by inhibiting target smad7, and that targeting miR-21 may be a better alternative to directly suppress TGF-β1-mediated fibrosis in DN.

KEYWORDS:

Diabetic nephropathy; Epithelial-to-mesenchymal transition; MicroRNA(miR); Renal interstitial fibrosis; TGF-β1

PMID:
24887517
DOI:
10.1016/j.mce.2014.05.018
[PubMed - indexed for MEDLINE]
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