title: NADPH oxidase-mediated upregulation of connexin43 contributes to podocyte injury.
abstract: The gap junction protein connexin43 (Cx43) was markedly increased in podocytes in a rat model of nephrosis induced by puromycin. However, the mechanisms and roles of the altered Cx43 in podocytes are still unclear. Given that oxidative stress mediates podocyte injury under a variety of pathological situations, we examined the possible involvement of an oxidative stress-related mechanism in the regulation of Cx43. Incubation of podocytes with puromycin led to a time- and concentration-dependent loss of cell viability, which was preceded by an elevation in Cx43 levels. Concomitantly, puromycin also induced NOX4 expression and promoted superoxide (O(2)(·-)) generation. Inhibition of NADPH oxidase with apocynin and diphenyleneiodonium chloride or addition of the superoxide dismutase mimetic tempol completely abrogated, whereas the O(2)(·-) donors menadione and 2,3-dimethoxy-1,4-naphthoquinone reproduced, the effects of puromycin on Cx43 expression and cell injury. Further analysis demonstrated that treatment of podocytes with several structurally different gap-junction inhibitors significantly attenuated the cytotoxicity of puromycin. Our results thus indicate that NADPH oxidase-mediated upregulation of Cx43 contributes to podocyte injury.
authors: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan.
authors: Qiaojing
authors: Q
authors: Yan
authors: Kun
authors: K
authors: Gao
authors: Yuan
authors: Y
authors: Chi
authors: Kai
authors: K
authors: Li
authors: Ying
authors: Y
authors: Zhu
authors: Yigang
authors: Y
authors: Wan
authors: Wei
authors: W
authors: Sun
authors: Hiroyuki
authors: H
authors: Matsue
authors: Masanori
authors: M
authors: Kitamura
authors: Jian
authors: J
authors: Yao
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009861:Onium Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D011691:Puromycin / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000098:Acetophenones; D000964:Antimetabolites, Antineoplastic; D018031:Connexin 43; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D009861:Onium Compounds; D013113:Spin Labels; D013481:Superoxides; D011691:Puromycin; C007517:diphenyleneiodonium; C056165:acetovanillone; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C001803:tempol