title: Oxidative stress mediates nephropathy in type Ia glycogen storage disease.
abstract: Glycogen storage disease type Ia (GSD-Ia) patients, deficient in glucose-6-phosphatase-alpha, manifest disturbed glucose homeostasis with long-term renal disease. We have previously shown that renal fibrosis in GSD-Ia is mediated by the angiotensin/transforming growth factor-beta1 (TGF-beta1) pathway, which also elicits renal damage through oxidative stress. In this study, we further elucidate the mechanism of renal disease by showing that renal expression of Nox-2, p22(phox), and p47(phox), components of NADPH oxidase, are upregulated in GSD-Ia mice compared with controls. Akt/protein kinase B, a downstream mediator of angiotensin II and TGF-beta1, is also activated, leading to phosphorylation and inactivation of the Forkhead box O family of transcription factors. This in turn triggers downregulation of superoxide dismutase and catalase (CAT) activities that have essential roles in oxidative detoxification in mammals. Renal oxidative stress in GSD-Ia mice is shown by increased oxidation of dihydroethidium and by oxidative damage of DNA. Importantly, renal dysfunction, reflected by elevated serum levels of blood urea nitrogen, reduced renal CAT activity, and increased renal fibrosis, is improved in GSD-Ia mice treated with the antioxidant drug tempol. These data provide the first evidence that oxidative stress is one mechanism that underlies GSD-Ia nephropathy.
authors.affiliation: Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Wai Han
authors.initials: WH
authors.lastname: Yiu
authors.forename: Paul A
authors.initials: PA
authors.lastname: Mead
authors.forename: Hyun Sik
authors.initials: HS
authors.lastname: Jun
authors.forename: Brian C
authors.initials: BC
authors.lastname: Mansfield
authors.forename: Janice Y
authors.initials: JY
authors.lastname: Chou
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003573:Cytochrome b Group / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005953:Glycogen Storage Disease Type I / Q000503:physiopathology*; D007674:Kidney Diseases / Q000188:drug therapy / Q000503:physiopathology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D003573:Cytochrome b Group; D008562:Membrane Glycoproteins; D013113:Spin Labels; D002374:Catalase; D013482:Superoxide Dismutase; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C515614:Cyba protein, mouse; C060505:neutrophil cytosolic factor 1; C001803:tempol