title: Angiotensin II Type 2-Receptor Agonist C21 Reduces Proteinuria and Oxidative Stress in Kidney of High-Salt-Fed Obese Zucker Rats.
abstract: 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.
authors.affiliation: From the Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, TX.
authors.forename: Sanket N
authors.initials: SN
authors.lastname: Patel
authors.affiliation: From the Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, TX.
authors.forename: Quaisar
authors.initials: Q
authors.lastname: Ali
authors.affiliation: From the Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, TX. thussain@central.uh.edu.
authors.forename: Tahir
authors.initials: T
authors.lastname: Hussain
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000473:pathology*; D000704:Analysis of Variance; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001707:Biopsy, Needle; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D006973:Hypertension / Q000503:physiopathology / Q000517:prevention & control; D007150:Immunohistochemistry; D008297:Male; D015999:Multivariate Analysis; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011507:Proteinuria / Q000188:drug therapy / Q000517:prevention & control*; D011897:Random Allocation; D051381:Rats; D011924:Rats, Zucker; D012016:Reference Values; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D017673:Sodium Chloride, Dietary; D052250:Nitric Oxide Synthase Type III
keywords: AT2 receptor; NADPH oxidase; oxidative stress; rats, Zucker