Angiotensin II acts through Rac1 to upregulate pendrin: role of NADPH oxidase

Am J Physiol Renal Physiol. 2024 Feb 1;326(2):F202-F218. doi: 10.1152/ajprenal.00139.2023. Epub 2023 Dec 7.


Angiotensin II increases apical plasma membrane pendrin abundance and function. This study explored the role of the small GTPase Rac1 in the regulation of pendrin by angiotensin II. To do this, we generated intercalated cell (IC) Rac1 knockout mice and observed that IC Rac1 gene ablation reduced the relative abundance of pendrin in the apical region of intercalated cells in angiotensin II-treated mice but not vehicle-treated mice. Similarly, the Rac1 inhibitor EHT 1864 reduced apical pendrin abundance in angiotensin II-treated mice, through a mechanism that does not require aldosterone. This IC angiotensin II-Rac1 signaling cascade modulates pendrin subcellular distribution without significantly changing actin organization. However, NADPH oxidase inhibition with APX 115 reduced apical pendrin abundance in vivo in angiotensin II-treated mice. Moreover, superoxide dismutase mimetics reduced Cl- absorption in angiotensin II-treated cortical collecting ducts perfused in vitro. Since Rac1 is an NADPH subunit, Rac1 may modulate pendrin through NADPH oxidase-mediated reactive oxygen species production. Because pendrin gene ablation blunts the pressor response to angiotensin II, we asked if pendrin blunts the angiotensin II-induced increase in kidney superoxide. Although kidney superoxide was similar in vehicle-treated wild-type and pendrin knockout mice, it was lower in angiotensin II-treated pendrin-null kidneys than in wild-type kidneys. We conclude that angiotensin II acts through Rac1, independently of aldosterone, to increase apical pendrin abundance. Rac1 may stimulate pendrin, at least partly, through NADPH oxidase. This increase in pendrin abundance contributes to the increment in blood pressure and kidney superoxide content seen in angiotensin II-treated mice.NEW & NOTEWORTHY This study defines a new signaling mechanism by which angiotensin II modulates oxidative stress and blood pressure.

Keywords: NADPH oxidase; Rac1; chloride; hypertension; pendrin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aldosterone / metabolism
  • Aldosterone / pharmacology
  • Angiotensin II* / metabolism
  • Angiotensin II* / pharmacology
  • Animals
  • Mice
  • Mice, Knockout
  • NADPH Oxidases / metabolism
  • Sulfate Transporters* / genetics
  • Superoxides / metabolism
  • rac1 GTP-Binding Protein* / metabolism


  • Aldosterone
  • Angiotensin II
  • NADPH Oxidases
  • Sulfate Transporters
  • Superoxides
  • Rac1 protein, mouse
  • rac1 GTP-Binding Protein
  • Slc26a4 protein, mouse