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Oxidative stress mediates nephropathy in type Ia glycogen storage disease
- Source :
- Laboratory Investigation. 90:620-629
- Publication Year :
- 2010
- Publisher :
- Elsevier BV, 2010.
-
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.
- Subjects :
- medicine.medical_specialty
Down-Regulation
Glycogen Storage Disease Type I
medicine.disease_cause
Article
Antioxidants
Pathology and Forensic Medicine
Nephropathy
Cyclic N-Oxides
Superoxide dismutase
Mice
Internal medicine
medicine
Renal fibrosis
Animals
Glycogen storage disease
Molecular Biology
Kidney
Membrane Glycoproteins
biology
Superoxide Dismutase
NADPH Oxidases
Cell Biology
Catalase
Cytochrome b Group
medicine.disease
Angiotensin II
Up-Regulation
Disease Models, Animal
Oxidative Stress
Endocrinology
medicine.anatomical_structure
NAD(P)H oxidase
NADPH Oxidase 2
biology.protein
Kidney Diseases
Spin Labels
Oxidative stress
Signal Transduction
Subjects
Details
- ISSN :
- 00236837
- Volume :
- 90
- Database :
- OpenAIRE
- Journal :
- Laboratory Investigation
- Accession number :
- edsair.doi.dedup.....45b9351e6c42efbfe6755f5ee403267b