title: Metadherin facilitates podocyte apoptosis in diabetic nephropathy.
abstract: Apoptosis, one of the major causes of podocyte loss, has been reported to have a vital role in diabetic nephropathy (DN) pathogenesis, and understanding the mechanisms underlying the regulation of podocyte apoptosis is crucial. Metadherin (MTDH) is an important oncogene, which is overexpressed in most cancers and responsible for apoptosis, metastasis, and poor patient survival. Here we show that the expression levels of Mtdh and phosphorylated p38 mitogen-activated protein kinase (MAPK) are significantly increased, whereas those of the microRNA-30 family members (miR-30s) are considerably reduced in the glomeruli of DN rat model and in high glucose (HG)-induced conditionally immortalized mouse podocytes (MPC5). These levels are positively correlated with podocyte apoptosis rate. The inhibition of Mtdh expression, using small interfering RNA, but not Mtdh overexpression, was shown to inhibit HG-induced MPC5 apoptosis and p38 MAPK pathway, and Bax and cleaved caspase 3 expression. This was shown to be similar to the effects of p38 MAPK inhibitor (SB203580). Furthermore, luciferase assay results demonstrated that Mtdh represents the target of miR-30s. Transient transfection experiments, using miR-30 microRNA (miRNA) inhibitors, led to the increase in Mtdh expression and induced the apoptosis of MPC5, whereas the treatment with miR-30 miRNA mimics led to the reduction in Mtdh expression and apoptosis of HG-induced MPC5 cells in comparison with their respective controls. Our results demonstrate that Mtdh is a potent modulator of podocyte apoptosis, and that it represents the target of miR-30 miRNAs, facilitating podocyte apoptosis through the activation of HG-induced p38 MAPK-dependent pathway.
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou 510280, China.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Liu
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou 510280, China.
authors.forename: Fen-Fen
authors.initials: FF
authors.lastname: Peng
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou 510280, China.
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Li
authors.affiliation: Department of Nephrology, NanFang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xiao-Wen
authors.initials: XW
authors.lastname: Chen
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou 510280, China.
authors.forename: Wang-Qiu
authors.initials: WQ
authors.lastname: Gong
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou 510280, China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Chen
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou 510280, China.
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou 510280, China.
authors.forename: Pei-Lin
authors.initials: PL
authors.lastname: Li
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou 510280, China.
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Li
authors.affiliation: Department of Emergency, ZhuJiang Hospital, Southern Medical University, Guangzhou 510280, China.
authors.forename: Zhao-Zhong
authors.initials: ZZ
authors.lastname: Xu
authors.affiliation: Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou 510280, China.
authors.forename: Hai-Bo
authors.initials: HB
authors.lastname: Long
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D008954:Models, Biological; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D016601:RNA-Binding Proteins
chemical_list: D005947:Glucose; D008565:Membrane Proteins; D035683:MicroRNAs; D048051:p38 Mitogen-Activated Protein Kinases; C483038:Mtdh protein, mouse; D016601:RNA-Binding Proteins