Induction of Glia Maturation Factor-β in Proximal Tubular Cells Leads to Vulnerability to Oxidative Injury through the p38 Pathway and Changes in Antioxidant Enzyme Activities

• Published in: The Journal of biological chemistry 2003-08, Vol.278 (35), p.33519
• Main Authors: Jun-ya Kaimori, Masaru Takenaka, Hideaki Nakajima, Takayuki Hamano, Masaru Horio, Takeshi Sugaya, Takahito Ito, Masatsugu Hori, Kousaku Okubo, Enyu Imai
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M301552200

Proteinuria is an independent risk factor for progression of renal diseases. Glia maturation factor-β (GMF-β), 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-β in PT cells, we constructed PT cell lines continuously expressing GMF-β. The PT cells overexpressing GMF-β acquired susceptibility to cell death upon stimulation with tumor necrosis factor-α and angiotensin II, both of which are reported to cause oxidative stress. GMF-β overexpression also promoted oxidative insults by H 2 O 2 , 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-β-overexpressing cells showed a sustained increase in H 2 O 2 in response to tumor necrosis factor-α, angiotensin II, and H 2 O 2 stimuli. The sustained increase in H 2 O 2 was caused by an increase in the activity of the H 2 O 2 -producing enzyme copper/zinc-superoxide dismutase, a decrease in the activities of the H 2 O 2 -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-β-overexpressing cells. In conclusion, we suggest that the proteinuria induction of GMF-β in renal PT cells may play a critical role in the progression of renal diseases by enhancing oxidative injuries.