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J Mol Med (Berl). 2016 Mar;94(3):291-300. doi: 10.1007/s00109-015-1340-9. Epub 2015 Oct 3.

TGF-β induces miR-30d down-regulation and podocyte injury through Smad2/3 and HDAC3-associated transcriptional repression.

Author information

1
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210016, China.
2
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210016, China. wangsencao@nju.edu.cn.
3
The Key lab of Jiangsu molecular Medicine, Nanjing University School of Medicine, Nanjing, 210091, China. wangsencao@nju.edu.cn.
4
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210016, China. liuzhihong@nju.edu.cn.

Abstract

The microRNA-30 family plays important roles in maintaining kidney homeostasis. Patients with focal segmental glomerulosclerosis (FSGS) have reduced miR-30 levels in glomerulus. TGF-β represses miR-30s in kidney podocytes, which leads to cytoskeleton damage and podocyte apoptosis. In this study, we investigated the mechanism by which TGF-β represses miR-30d in vitro. The human miR-30d promoter contains multiple copies of Smad binding element-like sequences. A fragment of 150 base pairs close to the transcription start site was negatively regulated by TGF-β to a similar extent as the 1.8 kb promoter, which was blocked by histone-deacetylase inhibition. TGF-β specifically enhanced HDAC3 expression. Knockdown of HDAC3 by shRNA or a selective inhibitor RGFP966 significantly relieved the repression of miR-30d mRNA and the promoter transcription. TGF-β promoted HDAC3 association with Smad2/3 and NCoR and caused their accumulation at the putative Smad binding site on the miR-30d promoter, which was prohibited by TSA or RGFP966. Furthermore, TSA or RGFP966 treatment reversed TGF-β-induced up-regulation of miR-30d targets Notch1 and p53 and alleviated the podocyte cytoskeleton damage and apoptosis. Taken together, these findings pinpoint that TGF-β represses miR-30d through a Smad2/3-HDAC3-NCoR repression complex and provide novel insights into a potential target for the treatment of podocyte injury-associated glomerulopathies. Key message: MiR-30d promoter is negatively regulated by TGF-β. TGF-β down-regulates miR-30 through Smad signaling pathway. HDAC3 and NCoR are recruited by Smad2/3 to mediate miR-30d repression by TGF-β. HDAC3 acts as a critical player in TGF-β-induced miR-30d repression and podocyte injuries.

KEYWORDS:

HDAC3; Podocyte; Smad; TGF-β; Transcriptional repression; miR-30d

PMID:
26432290
DOI:
10.1007/s00109-015-1340-9
[Indexed for MEDLINE]

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