title: Nebivolol attenuates redox-sensitive glomerular and tubular mediated proteinuria in obese rats.
abstract: 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.
authors.affiliation: Diabetes and Cardiovascular Center, the University of Missouri-ColumbiaSchool of Medicine, Columbia, Missouri 65211, USA.
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Pulakat
authors.forename: Roger D
authors.initials: RD
authors.lastname: Tilmon
authors.forename: Camila
authors.initials: C
authors.lastname: Manrique
authors.forename: Guido
authors.initials: G
authors.lastname: Lastra
authors.forename: Vincent G
authors.initials: VG
authors.lastname: Demarco
authors.forename: Adam
authors.initials: A
authors.lastname: Whaley-Connell
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D004983:Ethanolamines / Q000494:pharmacology*; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D046529:Microscopy, Electron, Transmission; D019255:NADPH Oxidases / Q000378:metabolism; D000068577:Nebivolol; D009765:Obesity / Q000188:drug therapy; D010084:Oxidation-Reduction / Q000187:drug effects; D011507:Proteinuria / Q000188:drug therapy; D011897:Random Allocation; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species
chemical_list: D000959:Antihypertensive Agents; D001578:Benzopyrans; D004983:Ethanolamines; D017382:Reactive Oxygen Species; D000068577:Nebivolol; D019255:NADPH Oxidases