Obesity and
insulin resistance-related
proteinuria is associated with oxidative stress and impaired tissue bioavailable
nitric oxide. Recent data suggest that
nicotinamide adenine dinucleotide phosphate oxidase-mediated oxidative injury to the proximal tubule, like that seen in the glomerulus, contributes to
proteinuria in
insulin-resistant states. The
vasodilator β-blocker
nebivolol reduces
nicotinamide adenine dinucleotide phosphate oxidase activity, increases bioavailable
nitric oxide, and improves
insulin sensitivity. To test the hypothesis that a treatment strategy that reduces oxidative stress and attenuates
obesity-associated increases in glomerular and proximal tubule derived
protein, we treated young Zucker obese (ZO) and age-matched Zucker lean male rats with
nebivolol (10 mg · kg(-1) · d(-1)) for 21 d. Compared with Zucker lean, ZO controls exhibited increased
proteinuria and γ-
glutamyl transpeptidase, reductions in systemic
insulin sensitivity in association with increased renal
renin, (
pro)renin receptor,
angiotensin II type 1 receptor, and
mineralocorticoid receptor immunostaining, oxidative stress, and glomerular tubular structural abnormalities that were substantially improved with in vivo
nebivolol treatment.
Nebivolol treatment also led to improvements in glomerular podocyte foot-process effacement and improvement in podocyte-specific
proteins (
nephrin and synaptopodin) as well as proximal tubule-specific
proteins (
megalin and
lysosomal-associated membrane protein-2) and proximal tubule ultrastructural remodeling in the ZO kidney. Our findings support the notion that
obesity and
insulin resistance lead to increased glomerulotubular oxidative stress and resultant glomerular and tubular sources of excess urine
protein. Furthermore, the results of this study suggest the beneficial effect of
nebivolol on
proteinuria was derived from improvements in weight and
insulin sensitivity and reductions in renal oxidative stress in a state of
obesity and
insulin resistance.