title: MicroRNA-218 promotes high glucose-induced apoptosis in podocytes by targeting heme oxygenase-1.
abstract: Emerging evidence has demonstrated that microRNAs (miRNAs) play a mediatory role in the pathogenesis of diabetic nephropathy. In this study, we found that miR-218 was upregulated in high glucose (HG) treated podocytes, which are essential components of the glomerular filtration barrier and a major prognostic determinant in diabetic nephropathy. Additionally, up-regulation of miR-218 was accompanied by an increased rate of podocyte death and down-regulation in the level of nephrin, a key marker of podocytes. However, inhibition of miR-218 exerted the opposite effect. In addition, the dual-luciferase reporter assay showed that miR-218 directly targeted the 3'-untranslated region of heme oxygenase-1 (HO-1), and further study confirmed an increase of HO-1 in HG-treated podocytes transfected with anti-miR-218. Knockdown of HO-1 blocked the anti-apoptotic effect of anti-miR-218. Furthermore, inhibition of miR-218 was associated with decreased expression of the known pro-apoptotic molecule p38-mitogen-activated protein kinase (p38-MAPK) activation. Following preconditioning with SB203580, an inhibitor of p38-MAPK, the stimulatory effect of HG on podocyte apoptosis was strikingly ameliorated. These findings suggested that miR-218 accelerated HG-induced podocyte apoptosis through directly down-regulating HO-1 and facilitating p38-MAPK activation.
authors.affiliation: Department of Nephrology, Xi'an Central Hospital, Xi'an, 710003, China. Electronic address: haiboyangsea@163.com.
authors.forename: Haibo
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Nephrology, Tongchuan Mining Central Hospital, Tongchuan, 727000, China.
authors.forename: Qingjun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Xi'an Central Hospital, Xi'an, 710003, China.
authors.forename: Sutong
authors.initials: S
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050199:Podocytes / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C547684:MIRN218 microRNA, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; C113267:nephrin; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose
keywords: Cell apoptosis; Diabetic nephropathy; HO-1; Podocyte; miRNAs