Inhibition of the processing of miR-25 by HIPK2-Phosphorylated-MeCP2 induces NOX4 in early diabetic nephropathy.
Inhibition of the processing of miR-25 by HIPK2-Phosphorylated-MeCP2 induces NOX4 in early diabetic nephropathy.
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DOI：
10.1038/srep38789
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发表时间：
2016-12-12
影响因子：
4.6
通讯作者：
Natarajan R
中科院分区：
文献类型：
--
作者：
Oh HJ;Kato M;Deshpande S;Zhang E;Das S;Lanting L;Wang M;Natarajan R
磷酸化甲基CpG结合蛋白2(p-MeCP2)抑制了几个microRNAs(MiRNAs)的加工。同源域相互作用蛋白激酶2(HIPK2)使已知的转录抑制因子MeCP2磷酸化。然而，目前尚不清楚MeCP2和HIPK2是否参与了与糖尿病肾病有关的miRNAs的加工。注射链脲佐菌素的糖尿病小鼠肾小球P-MeCP2和HIPK2水平显著升高，而介导HIPK2蛋白酶体降解的七缺失同源蛋白1(SIAH1)水平降低。在几个miRNAs中，miR-25及其前体在糖尿病小鼠中显著降低，而初级miR-25水平显著升高。作为miR-25靶点的NADPH氧化酶4(NOX4)在糖尿病小鼠中显著增加。高糖(HG)或转化生长因子-β处理的小鼠肾小球系膜细胞(MMC)中p-MeCP2、HIPK2和NOX4的蛋白水平增加。体内研究表明，在HG或转化生长因子-β处理的MMC中，miR-25(初级、前体和成熟)基因和mR-NA水平的调控趋势相似。Hipk2siRNA可减弱HG或转化生长因子-β诱导的p-MeCP2、NOX4和原代miR-25表达上调，而前体和成熟miR-25表达下调。这些结果表明，在早期糖尿病肾病中，SIAH1/HIPK2/MeCP2轴在抑制miR-25加工从而上调NOX4方面发挥了新的作用。
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.
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影响因子：
4.3
作者：
Calzado, Marco A.;De La Vega, Laureano;Schmitz, M. Lienhard
通讯作者：
Schmitz, M. Lienhard
影响因子：
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通讯作者：
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12.4
作者：
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通讯作者：
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影响因子：
64.8
作者：
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通讯作者：
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