title: Induction of glia maturation factor-beta in proximal tubular cells leads to vulnerability to oxidative injury through the p38 pathway and changes in antioxidant enzyme activities.
abstract: Proteinuria is an independent risk factor for progression of renal diseases. Glia maturation factor-beta (GMF-beta), a 17-kDa brain-specific protein originally purified as a neurotrophic factor from brain, was induced in renal proximal tubular (PT) cells by proteinuria. To examine the role of GMF-beta in PT cells, we constructed PT cell lines continuously expressing GMF-beta. The PT cells overexpressing GMF-beta acquired susceptibility to cell death upon stimulation with tumor necrosis factor-alpha and angiotensin II, both of which are reported to cause oxidative stress. GMF-beta overexpression also promoted oxidative insults by H2O2, leading to the reorganization of F-actin as well as apoptosis in non-brain cells (not only PT cells, but also NIH 3T3 cells). The measurement of intracellular reactive oxygen species in the GMF-beta-overexpressing cells showed a sustained increase in H2O2 in response to tumor necrosis factor-alpha, angiotensin II, and H2O2 stimuli. The sustained increase in H2O2 was caused by an increase in the activity of the H2O2-producing enzyme copper/zinc-superoxide dismutase, a decrease in the activities of the H2O2-reducing enzymes catalase and glutathione peroxidase, and a depletion of the content of the cellular glutathione peroxidase substrate GSH. The p38 pathway was significantly involved in the sustained oxidative stress to the cells. Taken together, the alteration of the antioxidant enzyme activities, in particular the peroxide-scavenging deficit, underlies the susceptibility to cell death in GMF-beta-overexpressing cells. In conclusion, we suggest that the proteinuria induction of GMF-beta in renal PT cells may play a critical role in the progression of renal diseases by enhancing oxidative injuries.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Jun-ya
authors.initials: JY
authors.lastname: Kaimori
authors.forename: Masaru
authors.initials: M
authors.lastname: Takenaka
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakajima
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hamano
authors.forename: Masaru
authors.initials: M
authors.lastname: Horio
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugaya
authors.forename: Takahito
authors.initials: T
authors.lastname: Ito
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Kousaku
authors.initials: K
authors.lastname: Okubo
authors.forename: Enyu
authors.initials: E
authors.lastname: Imai
mesh_terms: D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D005434:Flow Cytometry; D020904:Glia Maturation Factor / Q000378:metabolism* / Q000502:physiology*; D005979:Glutathione Peroxidase / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017403:In Situ Hybridization; D007668:Kidney / Q000378:metabolism; D007684:Kidney Tubules / Q000166:cytology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007834:Lasers; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D013482:Superoxide Dismutase; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000199:Actins; D017304:Annexin A5; D000975:Antioxidants; D004396:Coloring Agents; D020904:Glia Maturation Factor; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D010100:Oxygen