Aldosterone, Inflammation, Immune System, and Hypertension.

BACKGROUND An angiotensin-converting enzyme (ACE) gene polymorphism occurs in dogs; however, functional importance is not well studied. HYPOTHESIS We hypothesized that dogs with the polymorphism would show alternative renin-angiotensin aldosterone system (RAAS) pathway activation and classical RAAS pathway suppression before and after ACE-inhibitor administration, as compared to dogs without the polymorphism that would show this pattern only after ACE-inhibitor administration. ANIMALS Twenty-one dogs with mitral valve disease that were genotyped for the ACE gene polymorphism. METHODS This retrospective study utilized stored samples from 8 ACE gene polymorphism-negative (PN) dogs and 13 ACE gene polymorphism-positive (PP) dogs before and after enalapril administration. Equilibrium analysis was performed to evaluate serum RAAS metabolites and enzyme activities. Results were compared before and after enalapril, and between groups. RESULTS The classical RAAS pathway was suppressed and the alternative RAAS pathway was enhanced for both genotypes after administration of enalapril, with no differences before enalapril administration. Aldosterone breakthrough occurred in both PN (38%) and PP (54%) dogs despite angiotensin II suppression. Aldosterone was significantly higher (P = .02) in ACE gene PP dogs (median, 92.17 pM; IQR, 21.85-184.70) compared to ACE gene PN dogs (median, 15.91 pM; IQR, <15.00-33.92) after enalapril. CONCLUSIONS AND CLINICAL IMPORTANCE The ACE gene polymorphism did not alter baseline RAAS activity. Aldosterone breatkthrough in some dogs suggests nonangiotensin mediated aldosterone production that might be negatively influenced by genotype. These results support the use of aldosterone receptor antagonists with ACE-inhibitors when RAAS inhibition is indicated for dogs, especially those positive for the ACE gene polymorphism.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/jvim.15746

Renin-angiotensin aldosterone profile before and after angiotensin-converting enzyme-inhibitor administration in dogs with angiotensin-converting enzyme gene polymorphism.

Genetic and Genomic Mechanisms of Primary Aldosteronism.

Primary Aldosteronism: State-of-the-Art Review.

Old and new genes in primary aldosteronism

Aldosterone secretion by the zona glomerulosa of the adrenal cortex is controlled by circulating factors including the renin angiotensin system (RAS) and potassium. Mineralocorticoid production is also regulated through an autocrine/paracrine mechanism by a wide variety of bioactive signals released in the vicinity of adrenocortical cells by chromaffin cells, nerve endings, cells of the immune system, endothelial cells and adipocytes. These regulatory factors include conventional neurotransmitters and neuropeptides. Their physiological role in the control of aldosterone secretion is not fully understood, but it is likely that they participate in the RAS-independent regulation of zona glomerulosa cells. Interestingly, recent observations indicate that autocrine/paracrine processes are involved in the pathophysiology of primary aldosteronism. The intraadrenal regulatory systems observed in aldosterone-producing adenomas (APA), although globally similar to those occurring in the normal adrenal gland, harbor alterations at different levels, which tend to strengthen the potency of paracrine signals to activate aldosterone secretion. Enhancement of paracrine stimulatory tone may participate to APA expansion and aldosterone hypersecretion together with somatic mutations of driver genes which activate the calcium signaling pathway and subsequently aldosterone synthase expression. Intraadrenal regulatory mechanisms represent thus promising pharmacological targets for the treatment of primary aldosteronism.

Paracrine Regulation of Aldosterone Secretion in Physiological and Pathophysiological Conditions.

Mast cells are immune cells present in adrenals from various species.
 Proliferation and activation of adrenal mast cells seem to be influenced by
 environment, since they increase during summer and in response to sodium
 restriction in frogs and mouse, respectively. Although the physiological factors
 regulating adrenal mast cell activity have not been identified, they might
 involve neurotransmitters and the renin-angiotensin system. Some data indicate
 that adrenal mast cells stimulate proliferation of steroidogenic cells in the
 zona glomerulosa and activate the mineralocorticoid production. In human, mast
 cell degranulation stimulates aldosterone synthesis through the release of
 serotonin (5-HT) and activation of 5-HT4 receptors. Increase in mast cell
 population and upregulation of the 5-HT signaling pathway occur in
 aldosterone-producing adenomas. In particular, aldosterone-producing adenoma
 cells overexpress 5-HT4 receptors and are hyper-responsive to 5-HT4 receptor
 agonists. These data suggest that the intra-adrenal serotonergic regulatory
 system represents a potential target for development of both adrenal imaging
 methods to evaluate the lateralization of aldosterone production, and
 pharmacological treatments of primary aldosteronism.

/pdf/role-of-mast-cells-in-the-control-of-aldosterone-secretion-3rb7vibtkq.pdf

Role of Mast Cells in the Control of Aldosterone Secretion

Steroidogenic cell microenvironment and adrenal function in physiological and pathophysiological conditions

Chez l’homme, les mastocytes surrenaliens activent la secretion d’aldosterone via un mecanisme paracrine. Les mastocytes sont egalement detectes dans la surrenale fœtale ou leur presence est correlee a l’expression des enzymes necessaires a la production d’aldosterone, suggerant un role de ces cellules immunocompetentes dans la mise en place antenatale de la voie de synthese des mineralocorticoides. Afin d’explorer cette hypothese, nous avons etudie par RT-QPCR l’impact de l’absence de mastocytes sur l’expression des genes impliques dans la synthese et la regulation d’aldosterone en comparant, a differents stades de developpement perinatal (E18, E20, P0, P1, P7 et P14), un modele de souris deficientes en mastocytes (Kit W-sh/W-sh ) a la souche sauvage C57BL/6. Nous avons observe une expression surrenalienne significativement plus faible de Cyp11b2 chez les souris Kit W-sh/W-sh aux stades E18, E20, P0, P14 comparee aux souris sauvages. En revanche, il n’a pas ete note de difference d’expression pour les genes Cyp21a1 et Hsd3b1. De maniere surprenante, a P7, on constate une expression surrenalienne de Cyp11b2 plus elevee chez les souris Kit W-sh/W-sh . De plus, on note a ce stade une expression renale plus elevee du gene codant la renine sans difference d’expression surrenalienne du gene codant le recepteur de type 1 de l’angiotensine. Au total, ces resultats montrent que les mastocytes controlent l’expression du gene codant l’aldosterone synthase durant le developpement perinatal murin. Les mecanismes sous-jacents de l’interaction mastocytes/synthese des mineralocorticoides et le retentissement fonctionnel de l’absence de mastocytes en periode perinatale restent a determiner.

Alexandre Naccache

Papers

Paracrine Regulation of Aldosterone Secretion in Physiological and Pathophysiological Conditions.

Role of Mast Cells in the Control of Aldosterone Secretion

Steroidogenic cell microenvironment and adrenal function in physiological and pathophysiological conditions

Rôle des mastocytes dans la voie de synthèse des minéralocorticoïdes en période périnatale chez la souris