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Inhibition of the processing of miR-25 by HIPK2-Phosphorylated-MeCP2 induces NOX4 in early diabetic nephropathy

Title
Inhibition of the processing of miR-25 by HIPK2-Phosphorylated-MeCP2 induces NOX4 in early diabetic nephropathy
Authors
Oh H.J.Kato M.Deshpande S.Zhang E.Sadhan D.Lanting L.Wang M.Natarajan R.
Ewha Authors
오형중
SCOPUS Author ID
오형중scopus
Issue Date
2016
Journal Title
Scientific Reports
ISSN
2045-2322JCR Link
Citation
vol. 6
Publisher
Nature Publishing Group
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Phosphorylated methyl-CpG binding protein2 (p-MeCP2) suppresses the processing of several microRNAs (miRNAs). Homeo-domain interacting protein kinase2 (HIPK2) phosphorylates MeCP2, a known transcriptional repressor. However, it is not known if MeCP2 and HIPK2 are involved in processing of miRNAs implicated in diabetic nephropathy. p-MeCP2 and HIPK2 levels were significantly increased, but Seven in Absentia Homolog1 (SIAH1), which mediates proteasomal degradation of HIPK2, was decreased in the glomeruli of streptozotocin injected diabetic mice. Among several miRNAs, miR-25 and its precursor were significantly decreased in diabetic mice, whereas primary miR-25 levels were significantly increased. NADPH oxidase4 (NOX4), a target of miR-25, was significantly increased in diabetic mice. Protein levels of p-MeCP2, HIPK2, and NOX4 were increased in high glucose (HG)-or TGF-β-treated mouse glomerular mesangial cells (MMCs). miR-25 (primary, precursor, and mature) and mRNA levels of genes indicated in the in vivo study showed similar trends of regulation in MMCs treated with HG or TGF-β. The HG-or TGF-β-induced upregulation of p-MeCP2, NOX4 and primary miR-25, but downregulation of precursor and mature miR-25, were attenuated by Hipk2 siRNA. These results demonstrate a novel role for the SIAH1/HIPK2/MeCP2 axis in suppressing miR-25 processing and thereby upregulating NOX4 in early diabetic nephropathy. © 2016 The Author(s).
DOI
10.1038/srep38789
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