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.