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Angiotensin II acts through Rac1 to upregulate pendrin: role of NADPH oxidase
Truyen D Pham1, Jill W Verlander2, Chao Chen2
1Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States.
American Journal of Physiology. Renal Physiology
|December 7, 2023
Summary
Angiotensin II increases pendrin abundance via Rac1 signaling, independently of aldosterone. This pathway elevates blood pressure and kidney superoxide levels, revealing a novel mechanism for angiotensin II regulation.
Area of Science:
- Nephrology
- Molecular Biology
- Cardiovascular Physiology
Background:
- Angiotensin II is known to increase pendrin abundance and function.
- The specific signaling pathways regulating this process remain incompletely understood.
Purpose of the Study:
- To investigate the role of the small GTPase Rac1 in angiotensin II-mediated regulation of pendrin.
- To elucidate the signaling cascade linking angiotensin II, Rac1, and pendrin in intercalated cells.
Main Methods:
- Generation of intercalated cell (IC) Rac1 knockout mice.
- Treatment with angiotensin II and Rac1 inhibitor (EHT 1864).
- Assessment of apical pendrin abundance, actin organization, NADPH oxidase activity, and reactive oxygen species production.
Main Results:
- IC Rac1 gene ablation and Rac1 inhibition reduced apical pendrin abundance in angiotensin II-treated mice.
- The angiotensin II-Rac1 pathway modulates pendrin distribution independently of aldosterone and actin organization.
- NADPH oxidase inhibition and superoxide dismutase mimetics affected apical pendrin abundance and chloride absorption.
- Pendrin knockout mice exhibited lower kidney superoxide levels in response to angiotensin II.
Conclusions:
- Angiotensin II stimulates apical pendrin abundance through Rac1, independent of aldosterone.
- Rac1 likely modulates pendrin via NADPH oxidase-mediated reactive oxygen species production.
- Increased pendrin abundance contributes to angiotensin II-induced hypertension and kidney oxidative stress.
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