title: Inhibition of the processing of miR-25 by HIPK2-Phosphorylated-MeCP2 induces NOX4 in early diabetic nephropathy.
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.
authors.affiliation: Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, California, USA.|Ewha Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital, South Korea.
authors.forename: Hyung Jung
authors.initials: HJ
authors.lastname: Oh
authors.affiliation: Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, California, USA.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, California, USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Deshpande
authors.affiliation: Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, California, USA.|Tsingua University, Beijing, China.
authors.forename: Erli
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, California, USA.
authors.forename: Sadhan
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, California, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Lanting
authors.affiliation: Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, California, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, California, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Natarajan
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000494:pharmacology; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D000074663:NADPH Oxidase 4 / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; C558895:MIRN25 microRNA, mouse; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D035683:MicroRNAs; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D000074663:NADPH Oxidase 4; C422943:Nox4 protein, mouse; C484442:Siah1a protein, mouse; D044767:Ubiquitin-Protein Ligases; C492003:Hipk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D005947:Glucose