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

Abstract

Proteinuria is an independent risk factor for progression of renal diseases. Glia maturation factor-␤ (GMF-␤), 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-␤ in PT cells, we constructed PT cell lines continuously expressing GMF-␤. The PT cells overexpressing GMF-␤ acquired susceptibility to cell death upon stimulation with tumor necrosis factor-␣ and angiotensin II, both of which are reported to cause oxidative stress. GMF-␤ 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-␤-overexpressing cells showed a sustained increase in H 2 O 2 in response to tumor necrosis factor-␣, 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-␤-overexpressing cells. In conclusion, we suggest that the proteinuria induction of GMF-␤ in renal PT cells may play a critical role in the progression of renal diseases by enhancing oxidative injuries.In chronic nephropathies, proteinuria is reportedly one of the best predictors, independent of mean arterial blood pressure, for disease progression toward end-stage renal failure (1, 2). Microalbuminuria, which features a small quantity of albumin only (30 -300 mg/24 h), is known as an important early sign of diabetic nephropathy (3, 4) and of progressive renal function loss in a non-diabetic population (5). In experimental models, proteinuria caused tubular insults accompanying infiltration of macrophages and T lymphocytes into the kidney (6). Interstitial inflammation can trigger fibroblast proliferation and accumulation of extracellular matrix proteins, which may facilitate tubulointerstitial fibrosis, which is a hallmark of progression of renal disease. In cultured proximal tubular (PT) 1 cells activated by administration of albumin, a number of genes encoding vasoactive and inflammatory molecules, which have potentially toxic effects on the kidney, were transactivated (7). These results strongly suggest that altering the disposition of PT cells by proteinuria must be involved in the process of renal damage. However, the mechanisms by which proteinuria accelerates renal disease progression remain largely unknown.We recently found that the brain-specific glia maturation factor-␤ (GMF-␤) gene is ind...

Activation of the Signal Transducer and Activator of Transcription Signaling Pathway in Renal Proximal Tubular Cells by Albumin

“…Further investigation is needed, however, to clarify the precise mechanisms of ROS generation by NADPH oxidase after albumin overloading. Our results also indicate that the GPx and catalase activities changed within 10 min after albumin loading, suggesting that albumin could interfere with GPx and catalase activities by way of glia maturation factor-beta (54). The low activities of GPx and catalase could be responsible for the accumulation of the intracellular ROS after albumin ingestion into mProx24 cells.…”

Glia maturation factor overexpression in neuroblastoma cells activates glycogen synthase kinase-3β and caspase-3

“…Kaimori et al (Kaimori et al, 2003) demonstrated oxidative stress enhancing ability of GMF in the pathophysiology of a renal disease. Overexpression of GMF in proximal tubular cells leads to vulnerability to oxidative injury through p38 pathway and changes in antioxidant enzyme activities (Kaimori et al, 2003). A recent study by Baldwin et al (Baldwin et al, 2006) demonstrated that the transient overexpression of GMF in glioblastoma cells activated p38 MAPK signaling and also increased susceptibility of the tumor cells to cytotoxicity of cisplatin, a chemotherapeutic agent.…”

“…Overexpression of GMF in PC12 pheochromocytoma cells activates p38 MAP kinase and its downstream MAPKAP-kinase 2 (Zaheer and Lim, 1998). Kaimori et al (Kaimori et al, 2003) demonstrated oxidative stress enhancing ability of GMF in the pathophysiology of a renal disease. Overexpression of GMF in proximal tubular cells leads to vulnerability to oxidative injury through p38 pathway and changes in antioxidant enzyme activities (Kaimori et al, 2003).…”

Protection of glioblastoma cells from cisplatin cytotoxicity via protein kinase Cι-mediated attenuation of p38 MAP kinase signaling

“…However, retroviral transduction of U87MG cells followed by puromycin selection did not give any resistant cells while empty control vector did, suggesting that sustained high overexpression of GMFb is toxic to U87MG cells. This has been reported previously for other cell types, and is consistent with a proapoptotic function for GMFb (Kaimori et al, 2003). To circumvent this problem, U87MG cells were transiently transfected with the GMFb-expressing vector.…”