Antioxid Redox Signal. 2021 Oct 29.
Aleksandr Vendrov,
Mark D Stevenson,
Andrey Lozhkin,
Takayuki Hayami,
Nathan A Holland,
Xi Yang,
Nicolas Mass,
Hua Pan,
Samuel A Wickline,
James D Stockand,
Marschall S Runge,
Nageswara Rao Madamanchi,
William J Arendshorst.
AIMS: NADPH oxidase (NOX)-derived reactive oxygen species (ROS) are implicated in pathophysiology of hypertension (HTN) in chronic kidney disease. Genetic deletion of NOX activator 1 (Noxa1) subunit of NOX1 decreases ROS under pathophysiologic conditions. Here we investigated the role of NOXA1-dependent NOX1 activity in angiotensin II (Ang II)-induced hypertension (AIH) and possible involvement of dysregulated renal sodium excretion.
RESULTS: NOXA1 is present in epithelial cells of Henle's thick ascending limb and distal nephron. Telemetry showed lower basal systolic blood pressure (BP) in Noxa1-/- versus wild-type mice. Ang II infusion for 1 and 14 days increased NOXA1/NOX1 expression and ROS levels in kidneys of male but not female wild-type mice. Mean BP increased 30 mmHg in wild-type males, with smaller increases in Noxa1-deficient males and wild-type or Noxa1-/- females. In response to acute salt load, Na+ excretion was similar in wild-type and Noxa1-/- 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 versus Noxa1-/- mice. Ang II increased epithelial Na+ channel (ENaC) levels and activation in the collecting duct principal epithelial cells of wild-type but not Noxa1-/- mice. Aldosterone induced ROS levels and Noxa1 and Scnn1a expression and ENaC activity in a mouse renal epithelial cell line, responses abolished by Noxa1 siRNA. Innovation and Conclusion: Ang II activation of renal NOXA1/NOX1-dependent ROS enhances tubular ENaC expression and Na+ reabsorption, increasing BP. Attenuation of AIH in females is attributed to weaker NOXA1/NOX1-dependent ROS signaling and efficient natriuresis.