Sex Differences in Renal Nitric Oxide Synthase, NAD(P)H Oxidase, and Blood Pressure in Obese Zucker Rats

Abstract

By increasing renal oxidative stress, obesity may alter the protective effect of female sex on blood pressure (BP). The aim of this study was to determine whether female rats had altered expression and activity of renal nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] oxidase and nitric oxide synthase (NOS), enzymes important in superoxide and nitric oxide generation, respectively, and whether this relationship was altered in obesity. Male and female, lean and obese Zucker rats were fed progressively higher levels of NaCl over 54 days while BP was measured by radiotelemetry. Kidneys were harvested after euthanization. A total of 32 (n=8/body type/sex) Zucker rats were examined. On a high-salt diet (4% NaC1), male and obese rats had significantly higher mean arterial blood pressure relative to female and lean rats (mm Hg: lean male=108, lean female=99, obese male=129, and obese female=123) and reduced renal cortical NOS activity (determined by 2-way analysis of variance; P<0.05 for sex and body type). Immunoblotting revealed that cortical endothelial NOS protein abundance was reduced in obese but not in male rats. Surprisingly, lean female rats had the highest outer medullary protein levels of several NADPH oxidase subunits, including gp91phox, p47phox, and p67phox (% of lean male: 207, 196, and 151, respectively; P<0.01 for all). However, renal NADPH activity was not increased in lean females, but was significantly increased in obese rats of both sexes (P<0.05). High-NaCl diet increased BP modestly in obese females, but not at all in lean females, suggesting some loss of protection with obesity in female rats. Reduced cortical NOS activity (both in male and obese rats) and/or increased NADPH oxidase activity (obese rats) may have contributed to increased salt sensitivity of BP.