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

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.