Noxa1-Dependent Regulation of Nox1 NADPH Oxidase Activity in the Development of Angiotensin II-Induced Hypertension and an Early Phase of Renal Na+ Retention

Abnormal renal function, a major contributor to hypertension (HTN), in conjunction with oxidative stress, enhances the risk for renal failure and the development of cardiovascular disease. Increased reactive oxygen species (ROS) levels, resulting from the activation of NADPH oxidases, in the renal vascular and tubular cells have been implicated in pathophysiology of angiotensin II (Ang II)- and high salt (HS)- induced HTN. We previously reported that the deletion of NoxA1 subunit of Nox1 NADPH oxidase decreased ROS levels in the aortic smooth muscle cells and vasculature under pathophysiologic conditions. In this study, we investigated the importance of NoxA1-dependent Nox1 activity in the regulation of renal Na + excretion and blood pressure (BP). Chronic Ang II infusion (500ng/kg/min) for 2 weeks increased systolic BP (DSI telemetry) by 33 mmHg in the wild-type (WT) (p -/- mice. BP was unchanged in mice infused with saline. After 4 weeks of L-NAME-induced hypertension and recovery for 1 week, HTN induction by HS for 2 weeks increased BP by 17 mmHg in WT (p -/- mice. Na + excretion was measured in metabolic cages for 8 hr in response to an acute salt load (10% body weight of isotonic saline injected ip) before and during HTN. The rate of Na + excretion was similar in WT and systemic NoxA1 -/- mice before and 14 days after Ang II infusion. However, WT excreted Na + at a slower rate than NoxA1 -/- mice, with a smaller fraction (P + excretion was noted in WT vs. systemic NoxA1 -/- mice during the development of HTN 2-4 days after initiation of HS diet. This is consistent with the notion that relative positive renal Na + balance related to ROS generation is a causative factor of HTN. Supporting this, Ang II infusion increased NoxA1 protein levels in the cortex and medulla and ENaC protein levels in the medulla. These findings indicate that Ang II activation of NoxA1/Nox1 signaling in the kidney increases ROS levels, causing reduced Na + excretion, presumably due to renal vasoconstriction and/or enhanced tubular Na + reabsorption, which leads to increased BP.