Abstract 365: Differential Regulation of NOX2, NOX4 and SOD Expression in the Heart and Kidneys by PPAR-α During Angiotensin II Hypertension

Abstract

Previous reports suggest peroxisome proliferator-activated receptor-α (PPAR-α) agonist attenuates hypertension by suppressing oxidative stress and increasing superoxide dismutase (SOD) activity. We tested the hypothesis that the absence of PPAR-α would increase NADPH oxidase (NOX)2, NOX4 and decrease SOD expression in mice heart and kidneys during Ang II hypertension. Male (10 - 12 weeks old) PPAR-α knockout (KO) mice and their wild-type (WT) controls were implanted with biotelemetry devices and infused with a slow pressor dose of Ang II (400 ng/kg/min) for 12 days. Separate groups of KO + Ang II and WT + Ang II mice were given the NOX inhibitor, apocynin (1 g/L) or PPAR-α agonist, fenofibrate (145 mg/kg/day). Mean arterial pressure (MAP) was similar between KO (119 ± 2 mmHg) and WT (122 ± 2 mmHg) during the control period. On day 12 of Ang II, MAP was significantly higher in KO than WT, 161 ± 5 and 145 ± 4 mmHg, respectively. Fenofibrate significantly reduced MAP in WT + Ang II mice (134 ± 5 mmHg) and apocynin reduced MAP in KO + Ang II and WT + Ang II mice. Heart and kidney NOX2 expression were significantly increased (61 ± 5% and 33 ± 5 %, respectively) in KO + Ang II when compared to WT + Ang II mice. Apocynin treatment significantly reduced heart and kidney NOX2 expression in KO + Ang II mice. Heart NOX4 expression was significantly decreased (28 ± 3%) in WT + Ang II mice when compared to WT controls. No significant changes were observed in KO + Ang II heart NOX4 expression. Kidney NOX4 expression was significantly decreased in both Ang II-treated KO (77 ± 5%) and WT (50 ± 5%) mice when compared to their respective controls. WT + Ang II SOD expression in the heart was significantly lower than WT controls. Ang II did not lower heart SOD expression in KO mice. SOD expression in the kidneys was significantly decreased in KO + Ang II and WT + Ang II when compared to their respective controls. Fenofibrate significantly increased kidney SOD expression in WT + Ang II mice above WT controls. Fenofibrate did not significantly increase kidney SOD expression in KO + Ang II mice above KO controls. Our results suggest that increased heart and kidney NOX2 expression, along with decreased SOD expression in PPAR-α KO mice contributes to significant increases in MAP during Ang II hypertension.