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Journal of Molecular Medicine

, Volume 94, Issue 3, pp 291–300 | Cite as

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

  • Lin Liu
  • Wenjun Lin
  • Qin Zhang
  • Wangsen CaoEmail author
  • Zhihong LiuEmail author
Original Article

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

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

Notes

Acknowledgments

This work was supported by research grants from National Basic Research Program of China 973 Program No.2012CB517606, National Nature Science Foundation of China (81271301 and 81470940), and the Major International (Regional) Joint Research Project (81320108007).

Conflict of interest

The authors declare that they have no competing interests.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.National Clinical Research Center of Kidney Diseases, Jinling HospitalNanjing University School of MedicineNanjingChina
  2. 2.The Key lab of Jiangsu molecular MedicineNanjing University School of MedicineNanjingChina

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