Renal NOXA1/NOX1 Signaling Regulates Epithelial Sodium Channel and Sodium Retention in Angiotensin II-induced Hypertension.

NADPH oxidase (NOX)-derived reactive oxygen species (ROS) are implicated in the pathophysiology of hypertension in chronic kidney disease patients. Genetic deletion of NOX activator 1 () subunit of NOX1 decreases ROS under pathophysiological conditions. Here, we investigated the role of NOXA1-dependent NOX1 activity in the pathogenesis of angiotensin II (Ang II)-induced hypertension (AIH) and possible involvement of abnormal renal function. NOXA1 is present in epithelial cells of Henle's thick ascending limb and distal nephron. Telemetry showed lower basal systolic blood pressure (BP) in wild-type mice. Ang II infusion for 1 and 14 days increased NOXA1/NOX1 expression and ROS in kidney of male but not female wild-type mice. Mean BP increased 30 mmHg in wild-type males, with smaller increases in -deficient males and wild-type or females. In response to an acute salt load, Na excretion was similar in wild-type and mice before and 14 days after Ang II infusion. However, Na excretion was delayed after 1-2 days of Ang II in male wild-type mice. Ang II increased epithelial Na channel (ENaC) levels and activation in the collecting duct principal epithelial cells of wild-type but not mice. Aldosterone induced ROS levels and and expression and ENaC activity in a mouse renal epithelial cell line, responses abolished by small-interfering RNA. Ang II activation of renal NOXA1/NOX1-dependent ROS enhances tubular ENaC expression and Na reabsorption, leading to increased BP. Attenuation of AIH in females is attributed to weaker NOXA1/NOX1-dependent ROS signaling and efficient natriuresis. . 36, 550-566.