Oxidative and nitrosative stress have been implicated in high-
sodium diet (HSD)-related hypertensive renal injury. In this study, we investigated
angiotensin II type 2-receptor-mediated renoprotection in obese Zucker rats fed HSD. Obese Zucker rats were fed normal
sodium diet or HSD 4%, for 14 days, with/without
angiotensin II type 2-receptor agonist
C21, delivered subcutaneously via osmotic pump, 1 mg/kg per day. Compared with normal
sodium diet controls, HSD rats exhibited increase in cortical
nicotinamide adenine dinucleotide phosphate oxidase activity, urinary H2O2, and 8-isoprostanes, which were associated with severe glomerulosclerosis, interstitial
fibrosis, decline in estimated glomerular filtration rate, and an increase in urinary leak and activity of N-acetyl-β-D-
glucosaminidase, a lysosomal
enzyme and a marker of tubular damage. These changes were improved by
C21 treatment. Cortical expression of
endothelial nitric oxide synthase, phospho-
endothelial nitric oxide synthase (Ser(1177)), and plasma
nitrites were reduced after HSD intake, whereas nitrosative stress (3-nitrotyrosine) and enzymatic defense (
superoxide dismutase-to-
catalase activity) remained unaltered. However,
C21 preserved plasma
nitrites in HSD-fed obese Zucker rat.
C21 treatment reduced
protein-to-
creatinine,
albumin-to-
creatinine, as well as fractional excretion of
protein and
albumin in HSD-fed obese Zucker rat, which is independent of changes in
protein recycling receptors,
megalin, and
cubilin. HSD intake also altered renal excretory and reabsorptive capacity as evident by elevated plasma
urea nitrogen-to-
creatinine and fractional excretion of
urea nitrogen, and reduced urine-to-plasma
creatinine, which were modestly, but insignificantly, improved by
C21 treatment. Together results demonstrate that
angiotensin II type 2-receptor activation protects against HSD-induced kidney damage in
obesity plausibly by reducing
nicotinamide adenine dinucleotide phosphate oxidase activity and rescuing
nitrites.