Nephropathy and elevated BP in mice with podocyte-specific NADPH oxidase 5 expression

Holterman, C. E., Thibodeau, J.-F., Towaij, C., Gutsol, A., Montezano, A. C., Parks, R. J., Cooper, M. E., Touyz, R. M. and Kennedy, C. R.J. (2014) Nephropathy and elevated BP in mice with podocyte-specific NADPH oxidase 5 expression. Journal of the American Society of Nephrology, 25(4), pp. 784-797. (doi:10.1681/ASN.2013040371)

Full text not currently available from Enlighten.

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 (Nox5pod+). Nox5pod+ mice exhibited early onset albuminuria, podocyte foot process effacement, and elevated systolic BP. Subjecting Nox5pod+ 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cooper, Dr Mark and Montezano, Dr Augusto and Touyz, Professor Rhian
Authors: Holterman, C. E., Thibodeau, J.-F., Towaij, C., Gutsol, A., Montezano, A. C., Parks, R. J., Cooper, M. E., Touyz, R. M., and Kennedy, C. R.J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of the American Society of Nephrology
Publisher:American Society of Nephrology
ISSN:1046-6673
ISSN (Online):1533-3450
Related URLs:

University Staff: Request a correction | Enlighten Editors: Update this record