Stimulation of Renin Secretion by Angiotensin II Blockade is Gsα-Dependent

• Published in: Journal of the American Society of Nephrology Vol. 21; no. 6; pp. 986 - 992
• Main Authors: LIMENG CHEN, SOO MI KIM, GOMEZ, Roberto A, SCHNERMANN, Jurgen, BRIGGS, Josephine P, EISNER, Christoph, OPPERMANN, Mona, YUNING HUANG, MIZEL, Diane, LINGLI LI, MIN CHEN, SEQUEIRA LOPEZ, Maria Luisa, WEINSTEIN, Lee S
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society of Nephrology 01.06.2010
• Subjects: Basic Research; Biological and medical sciences; Medical sciences; Nephrology. Urinary tract diseases; Nephrology; Enzyme; Secretion; Peptide hormone; Stimulation; Urology; Peptidases; Octapeptide; Renin angiotensin system; Renin; Hydrolases; Aspartic endopeptidases; Angiotensin II
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2009030307

Angiotensin II converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) presumably stimulate renin secretion by interrupting angiotensin II feedback inhibition. The increase in cytosolic calcium caused by activation of Gq-coupled AT1 receptors may mediate the renin-inhibitory effect of angiotensin II at the cellular level, implying that ACEI and ARB may work by reducing intracellular calcium. Here, we investigated whether angiotensin II blockade acts predominantly through Gs-mediated stimulation of adenylyl cyclase (AC) by testing the effect of ACEI and ARB in mice with juxtaglomerular cell-specific deficiency of the AC-stimulatory Gsα. The ACEI captopril and quinaprilate and the ARB candesartan significantly increased plasma renin concentration (PRC) to 20 to 40 times basal PRC in wild-type mice but did not significantly alter PRC in Gsα-deficient mice. Captopril also completely abrogated renin stimulation in wild-type mice after co-administration of propranolol, indomethacin, and L-NAME. Treatment with enalapril and a low-NaCl diet for 7 days led to a 35-fold increase in PRC among wild-type mice but no significant change in PRC among Gsα-deficient mice. Three different pharmacologic inhibitors of AC reduced the stimulatory effect of captopril by 70% to 80%. In conclusion, blockade of angiotensin II stimulates renin synthesis and release indirectly through the action of ligands that activate the cAMP/PKA pathway in a Gsα-dependent fashion, including catecholamines, prostaglandins, and nitric oxide.