Nebivolol reduces proteinuria and renal NADPH oxidase-generated reactive oxygen species in the transgenic Ren2 rat.
OBJECTIVE
Renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system activation are crucial in the pathogenesis of hypertension, cardiovascular and renal disease. NADPH oxidase-mediated increases in reactive oxygen species (ROS) are an important mediator for RAAS-induced cardiovascular and renal injury. Increased levels of ROS can diminish the bioactivity of nitric oxide (NO), a critical modulator of RAAS effects on the kidney. Thereby, we hypothesized that in vivo nebivolol therapy in a rodent model of activated RAAS would attenuate glomerular damage and proteinuria through its actions to reduce NADPH oxidase activity/ROS and increase bioavailable NO.


METHODS
We utilized the transgenic Ren2 rat which displays heightened tissue RAAS, hypertension, and proteinuria. Ren2 rats (6-9 weeks of age) and age-matched Sprague-Dawley littermates were treated with nebivolol 10 mg/kg/day (osmotic mini-pump) for 21 days.


RESULTS
Ren2 rats exhibited increases in systolic blood pressure, proteinuria, kidney cortical tissue total NADPH oxidase activity and subunits (Rac1, p67(phox), and p47(phox)), ROS and 3-nitrotyrosine, as well as reductions in podocyte protein markers; each of these parameters improved with nebivolol treatment along with increases in renal endothelial NO synthase expression.


CONCLUSIONS
Our data suggest that nebivolol improves proteinuria through reductions in renal RAAS-mediated increases in NADPH oxidase/ROS and increases in bioavailable NO.
Whaley-Connell
Adam
A
The University of Missouri School of Medicine, Department of Internal Medicine, Division of Nephrology and Hypertension CE417, DC043.0, Five, Hospital Dr., Columbia, MO 65212, USA. whaleyconnella@health.missouri.edu
Habibi
Javad
J
Johnson
Megan
M
Tilmon
Roger
R
Rehmer
Nathan
N
Rehmer
Jenna
J
Wiedmeyer
Charles
C
Ferrario
Carlos M
CM
Sowers
James R
JR
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004983:Ethanolamines / Q000494:pharmacology*; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D000068577:Nebivolol; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism; D011507:Proteinuria / Q000188:drug therapy* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000959:Antihypertensive Agents; D001578:Benzopyrans; D004983:Ethanolamines; D017382:Reactive Oxygen Species; D000068577:Nebivolol; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019255:NADPH Oxidases; D012083:Renin