Journal
JOURNAL OF MOLECULAR MEDICINE-JMM
Volume 94, Issue 3, Pages 291-300Publisher
SPRINGER
DOI: 10.1007/s00109-015-1340-9
Keywords
TGF-beta; miR-30d; HDAC3; Smad; Podocyte; Transcriptional repression
Funding
- National Basic Research Program of China 973 Program [2012CB517606]
- National Nature Science Foundation of China [81271301, 81470940]
- Major International (Regional) Joint Research Project [81320108007]
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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-beta represses miR-30s in kidney podocytes, which leads to cytoskeleton damage and podocyte apoptosis. In this study, we investigated the mechanism by which TGF-beta 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-beta to a similar extent as the 1.8 kb promoter, which was blocked by histone-deacetylase inhibition. TGF-beta 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-beta 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-beta-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-beta 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-beta. TGF-beta down-regulates miR-30 through Smad signaling pathway. HDAC3 and NCoR are recruited by Smad2/3 to mediate miR-30d repression by TGF-beta. HDAC3 acts as a critical player in TGF-beta-induced miR-30d repression and podocyte injuries.
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