title: Nephropathy and elevated BP in mice with podocyte-specific NADPH oxidase 5 expression.
abstract: NADPH oxidase (Nox) enzymes are a significant source of reactive oxygen species, which contribute to glomerular podocyte dysfunction. Although studies have implicated Nox1, -2, and -4 in several glomerulopathies, including diabetic nephropathy, little is known regarding the role of Nox5 in this context. We examined Nox5 expression and regulation in kidney biopsies from diabetic patients, cultured human podocytes, and a novel mouse model. Nox5 expression increased in human diabetic glomeruli compared with nondiabetic glomeruli. Stimulation with angiotensin II upregulated Nox5 expression in human podocyte cultures and increased reactive oxygen species generation. siRNA-mediated Nox5 knockdown inhibited angiotensin II-stimulated production of reactive oxygen species and altered podocyte cytoskeletal dynamics, resulting in an Rac-mediated motile phenotype. Because the Nox5 gene is absent in rodents, we generated transgenic mice expressing human Nox5 in a podocyte-specific manner (Nox5(pod+)). Nox5(pod+) mice exhibited early onset albuminuria, podocyte foot process effacement, and elevated systolic BP. Subjecting Nox5(pod+) mice to streptozotocin-induced diabetes further exacerbated these changes. Our data show that renal Nox5 is upregulated in human diabetic nephropathy and may alter filtration barrier function and systolic BP through the production of reactive oxygen species. These findings provide the first evidence that podocyte Nox5 has an important role in impaired renal function and hypertension.
authors.affiliation: Kidney Research Centre, Division of Nephrology, Department of Medicine, and.
authors.forename: Chet E
authors.initials: CE
authors.lastname: Holterman
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Thibodeau
authors.forename: Chelsea
authors.initials: C
authors.lastname: Towaij
authors.forename: Alex
authors.initials: A
authors.lastname: Gutsol
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Montezano
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Parks
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.forename: Christopher R J
authors.initials: CR
authors.lastname: Kennedy
mesh_terms: D000419:Albuminuria / Q000209:etiology; D000818:Animals; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003928:Diabetic Nephropathies / Q000209:etiology; D006801:Humans; D006973:Hypertension / Q000209:etiology*; D007674:Kidney Diseases / Q000209:etiology*; D007678:Kidney Glomerulus / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases / Q000235:genetics / Q000502:physiology*; D050199:Podocytes / Q000201:enzymology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases; C431571:NOX5 protein, human