Abstract P085: Angiotensin II Type 2-receptor Agonist C21 Reduces Proteinuria and Oxidative Stress in Kidney of High-salt Fed Obese Zucker Rats
Oxidative and nitrosative stress have been implicated in hypertension and kidney diseases. Recently we reported blood pressure reducing effect of AT2-receptor agonist C21 in high sodium-diet (HSD)-fed obese Zucker rats. In the present study we investigated C21-mediated reno-protection against HSD-related oxidative and nitrosative stress in obese Zucker rats. Obese rats (13 week) were fed normal sodium-diet (NSD) or HSD 4%, for 14 days, with/without C21, delivered subcutaneously via osmotic pump, 1 mg/kg/day. Compared with NSD controls, HSD-fed rats exhibited reduced eGFR (15.2±2.3 vs. 43.5±9.9 μL/min) and increased proteinuria (0.18±0.02 vs. 0.12±0.02 μg/min) and albuminuria (0.19±0.03 vs. 0.12±0.02 μg/min), which were associated with decreased cortical expression of the protein recycling receptors, megalin (0.25±0.02 vs. 0.47±0.07) and cubilin (0.77±0.16 vs. 1.27±0.14). C21 improved eGFR (27.4±4.9 μL/min) and reduced proteinuria (0.11±0.02 μg/min) and albuminuria (0.08±0.01 μg/min) without any effects on megalin or cubilin. Cortical NADPH oxidase (NOX) activity in HSD-fed rats was increased by 3-fold (0.37±0.07 vs. 0.13±0.04 ΔRLU/μg protein/min), while enzymatic defense (catalase/superoxide dismutase activity ratio) was unchanged. Urinary excretion of H2O2 (41.7±4.7 vs. 23.0±2.1 μM/mg creatinine) and 8-isoprostanes (7.9±1.6 vs. 1.4±0.2 pg/μg creatinine), indices of oxidative stress, were elevated in HSD-fed rats. C21 reduced NOX activity (0.11±0.04 ΔRLU/μg protein/min) as well as the excretion of H2O2 (30.5±3.0 μM/mg creatinine) and 8-Isoprostanes (4.1±1.0 pg/μg creatinine) in HSD-fed rats. Similarly, C21 also reduced carbonyls (5.5±1.4 vs. 10.5±0.9 μM/mg protein), an indicator of protein modification caused by oxidative stress. 3-nitrotyrosine, an indicator of nitrosative stress, remained unaltered in HSD and/or C21 groups. C21-treatment of HSD-fed rats improved plasma nitrites (22.1±2.2 vs. 15.3±0.5 μM/L), which could have been due to reduced oxidative stress in this group. Together results indicate that AT2R agonist exerts antioxidant effects, possibly by reducing NOX activity and by rescuing NO levels, which potentially contributes to the reduction in salt-induced proteinuria/nephropathy in obesity.
Author Disclosures: S.N. Patel: None. T. Hussain: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Significant; NIH R01 DK61578.
- © 2015 by American Heart Association, Inc.