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Review
. 2023 Aug 22:14:1239492.
doi: 10.3389/fendo.2023.1239492. eCollection 2023.

Regulation of the renin-angiotensin-aldosterone system by cyclic nucleotides and phosphodiesterases

Stepan Gambaryan  1 , Sanika Mohagaonkar  2   3 , Viacheslav O Nikolaev  2   3
Affiliations
Review

Regulation of the renin-angiotensin-aldosterone system by cyclic nucleotides and phosphodiesterases

Stepan Gambaryan et al. Front Endocrinol (Lausanne). .

Abstract

The renin-angiotensin-aldosterone system (RAAS) is one of the key players in the regulation of blood volume and blood pressure. Dysfunction of this system is connected with cardiovascular and renal diseases. Regulation of RAAS is under the control of multiple intracellular mechanisms. Cyclic nucleotides and phosphodiesterases are the major regulators of this system since they control expression and activity of renin and aldosterone. In this review, we summarize known mechanisms by which cyclic nucleotides and phosphodiesterases regulate renin gene expression, secretion of renin granules from juxtaglomerular cells and aldosterone production from zona glomerulosa cells of adrenal gland. We also discuss several open questions which deserve future attention.

Keywords: aldosterone; cAMP; cGMP; phosphodiesterase; renin.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Overview on the renin-angiotensin-aldosterone System. ACTH secreted by the anterior pituitary gland stimulates aldosterone production from adrenal gland zona glomerulosa (ZG) cells. Renin secreted by JG cells of the kidney and its activity is a rate-limiting step controlling Angiotensin II concentrations which also activate aldosterone production. Aldosterone initiates sodium reabsorption from the kidney. This and all other figures were made using BioRender.
Figure 2
Figure 2
Crosstalk of cyclic nucleotide signaling pathways in cells. cGMP is synthesized by two independent pathways including transmembrane guanylate cyclases (GC-A) stimulated by ANP and sGC stimulated by NO. Adenylate cyclase (AC), which is activated by Gs coupled seven transmembrane receptors, is the main source of cAMP in the cells. cGMP by binding to PDE2 accelerates cAMP hydrolysis and by binding to PDE3 inhibits cAMP hydrolysis. Binding of cGMP to PKG and cAMP to PKA activates the kinases which phosphorylate multiple substrates regulating various intracellular processes. In addition, cAMP can directly bind to exchange protein activated by cAMP (Epac) that also has multiple targets in the cells. Cyclic nucleotides gated (CNG) channels are important mediators of cGMP/cAMP signaling in the cells.
Figure 3
Figure 3
Renin synthesis and secretion in JG cells. Translation of renin mRNA at the rough endoplasmic reticulum (RER) gives rise a 48 kDa protein (preprorenin) from which the pre-(signal)-peptide is enzymatically cleaved in the Golgi-apparatus, and enzymatically inactive prorenin is then glycosylated and stored in the renin granules. Within the granules, prorenin (43 kDa) is proteolytically cleaved to yield enzymatically active renin (41 kDa). cAMP stimulated both renin gene expression and release of renin granules.
Figure 4
Figure 4
Regulation of renin release from JG cells by cyclic nucleotides. Stimulation of adenylate cyclase (AC) by Gs coupled receptors, such as β1-adrenergic receptor (β1-AR) and prostaglandin receptors, increases cAMP levels that activate PKA which enhances renin release from the granules. NO and ANP by stimulation of sGC and GC-A, respectively, increase cGMP which has dual effect on renin release. PKG II and PDE2 are involved in the inhibition of renin secretion, whereas cGMP mediated inhibition of PDE3 prevents cAMP degradation and stimulates renin secretion.
Figure 5
Figure 5
Regulation of aldosterone production in ZG cells by cyclic nucleotides. ACTH binding to the Gs coupled MC2R increases cAMP and activates PKA. Phosphorylation of cholesterol ester hydrolase (CEH), StAR, and several transcription factors stimulates aldosterone production. Ang II binds to Gq/11 and Gi/o coupled AT1R that activates phospholipase C and increases cytosolic Ca2+ concentrations, thereby triggering aldosterone production. ANP by binding to GC-A increases cGMP that can inhibit aldosterone production by binding to PDE2 and reducing cAMP. Alternatively, cGMP can stimulate aldosterone production by activating PKG II. ANP inhibits not only ACTH/cAMP stimulated but also Ang II stimulated aldosterone production by a still unknown mechanism. The two question marks indicate that the exact pathways inhibiting aldosterone directly via cGMP and via ANP stimulated GC-A are still unknown.
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SG was supported by the IEPhB Research Program 075-00967-23-00; V.O.N and SM were supported by the Deutsche Forschungsgemeinschaft (grant NI 1301/7-1 to V.O.N.).

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