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

Abstract

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 Gs␣. 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 Gs␣-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 Gs␣-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 Gs␣-dependent fashion, including catecholamines, prostaglandins, and nitric oxide. 21: 986 -992, 201021: 986 -992, . doi: 10.1681 Angiotensin II regulates renin secretion through a homeostatic mechanism that has been called the "short feedback loop," with renin synthesis and secretion inhibited by increases and stimulated by reductions of angiotensin II concentration. 1 The cellular mechanisms underlying the feedback effects of angiotensin II are not entirely clear. There is good experimental support for the notion that the acute inhibition is mediated, at least in part, by a direct type 1 angiotensin II receptor (AT 1A )-dependent effect of the peptide on cell calcium. 1,2 Angiotensin II inhibits renin release in kidney slices 3 and in isolated juxtaglomerular granular (JG) cells, where the effect is blocked by losartan. 4,5 In the isolated JG cell, angiotensin II increases intracellular calcium levels, with increases correlating with the reduction of renin release. 5 On the other hand, it is unclear whether the stimulatory arm of the short feedback loop (i.e., the increase of renin in response to a reduction of angiotensin II) can be explained by the reverse of the J Am Soc Nephrol

cAMP target sequences enhCRE and CNRE sense low-salt intake to increase human renin gene expression in vivo

“…We used pharmacological and genetic approaches to block the ang II effects and found that enhCRE and CNRE are not involved in the transactivation of human renin gene under these conditions. The partial discrepancy of our results with the earlier data [4] implies that the cAMP/PKA cascade (and particularly the human renin cAMP target sequences) may be critical for the regulation of renin expression by low-salt diet rather than by ang II (see also below). Alternatively, a range of in vitro and in vivo studies strongly suggest that mouse and human renin genes are not controlled through completely identical molecular mechanisms [11,19,34,40].…”

“…Ang II influences renin expression by a dual mechanism, including a direct action on the JG cells through Agt1r receptors and a modulation of the vascular tone that increases peripheral resistance and thus arterial pressure [2]. In addition, cAMP signaling was recently found to be crucial for the stimulation of mouse renin release by ang II blockade combined with low-salt diet [4]. We used pharmacological and genetic approaches to block the ang II effects and found that enhCRE and CNRE are not involved in the transactivation of human renin gene under these conditions.…”

Local Renal Circadian Clocks Control Fluid–Electrolyte Homeostasis and BP

“…The latter model has been widely used for the conditional inactivation of different genes expressed in the renin-secreting granular cells of the juxtaglomerular apparatus in the kidney. [21][22][23][24][25][26][27][28][29] These studies showed that, at the whole-organ level, the Ren1 d Cre is strongly expressed in the kidney, whereas in other tested tissues, the Cre expression was at or near background levels. 24 Nota bene, clearly, however, these results did not exclude that there might be minor populations of Cre-expressing cells in other tissues as well.…”

Angiotensin II as a Morphogenic Cytokine Stimulating Renal Fibrogenesis

“…Although the cause of its progression is multifactorial, [1][2][3] activation of the renin-angiotensin-aldosterone system (RAAS) is a key effector and RAAS inhibitors are among the beststudied renoprotective agents. 4 -7 Although the RAAS is complex, with new peptides such as angiotensin 1-7 and angiotensin IV exhibiting profibrotic effects by binding to specific receptors as well as observations that aldosterone and even renin itself can stimulate fibrogenesis in the kidney, 8 -12 and angiotensin II (Ang II) blockade can stimulate renin release, 13 the review presented here focuses exclusively on Ang II as the major component of the RAAS effect on morphogenesis. There are several excellent reviews covering the other components of the RAAS and their profibrotic actions in the kidney.…”