EJE Prize 2013: Regulation of aldosterone secretion: from physiology to disease

Abstract

Arterial hypertension is a major cardiovascular risk factor that affects between 10 and 40% of the population in industrialized countries. Primary aldosteronism (PA) is the most common form of secondary hypertension with an estimated prevalence of around 10% in referral centers and 4% in a primary care setting. Despite its high prevalence until recently, the underlying genetic and molecular basis of this common disease had remained largely obscure. Over the past decade, a number of insights have been achieved that have relied on in vitro cellular systems, wild-type and genetically modified in vivo models, as well as clinical studies in well-characterized patient populations. This progress has been made possible by a number of independent technical developments including that of specific hormone assays that allow measurement in small sample volumes as well as genetic techniques that enable high-throughput sequencing of a large number of samples. Furthermore, animal models have provided important insights into the physiology of aldosterone regulation that have served as a starting point for investigation of mechanisms involved in autonomous aldosterone secretion. Finally, national and international networks that have built up registries and biobanks have been instrumental in fostering translational research endeavors in PA. Therefore, it is to be expected that in the near future, further pathophysiological mechanisms that result in autonomous aldosterone secretion will be unraveled. European Journal of Endocrinology 168 R85-R93

PROGRESS IN ALDOSTERONISM: A review of the prevalence of primary aldosteronism in pre-hypertension and hypertension

“…In addition, in some studies higher aldosterone and lower potassium levels at diagnosis have been described and larger tumours were found compared with non-mutated cases (37,38,39,40,41). Conversely, in some but not all studies, it has been shown that patients harbouring ATPase mutations are more commonly men and are associated with the most severe forms of PA and rather smaller size tumours (30,39). These findings are particularly relevant in the familial form of PA (FH type 3) where specific mutations in the KJNC5 gene, as those altering the G151E amino acid, are associated with mild aldosteronism compared with those with G151R mutation that have a more severe clinical phenotype (28,32).…”

“…This form of PA results from an unequal crossing over between the highly homologous CYP11B2 and CYP11B1 genes that code for aldosterone synthase and steroid 11b-hydroxylase, producing a chimeric gene that is under adrenocorticotrophin (ACTH) rather than RAS control (28,29,30).…”

“…This has been designated as FH type 2, being autosomal dominantly transmitted, is considered heterogenous and although no precise molecular basis has been found, there is a suggestion for a link with chromosomal region 7p22 (31). An important breakthrough in the molecular pathogenesis of PA was made by Choi et al (32) by performing wholegenomic sequence identified mutations in the gene encoding the inwardly rectifying potassium channel Kir3.4 (KCNJ5) in patients with APAs (30). Subsequently, mutations in three further genes encoding for membrane proteins (the Na/K-ATPase (ATP1A1), the Ca ATPase (ATP2B3), and Ca1.3 (CACNAID)) have been described (33,34,35).…”

Association of polymorphisms in AGTR1 and AGTR2 genes with primary aldosteronism in the Chinese Han population

“…Based on several basic investigations the intra-adrenal RAS, which is a major regulator of aldosterone generation, was extensively focused on in investigating the mechanism of excessive aldosterone secretion. 9,10 To date, the pathophysiological role of the RAS in PA has been elucidated and components of the RAS such as AGTR1, AGTR2, CYP11B1, CYP11B2 and mineralocorticoid receptor have been reported to be widely involved in the regulation of autonomous aldosterone. It is known that the activation of AGTR1 can trigger the synthesis and secretion of aldosterone.…”

Mineralocorticoid regulation of cell function: the role of rapid signalling and gene transcription pathways

“…Aldosterone is synthesised in the zona glomerulosa of the adrenal gland under the regulation of the renin-angiotensin system (RAS), extracellular potassium levels and adrenocorticotropic hormone (ACTH). Its function in regulating salt and fluid balance is achieved by altering the sodium transport machinery of renal tubular epithelial cells (Loffing & Korbmacher 2009) and is critical for protection against hypovolaemia (Fine et al 1958, Beuschlein 2013.…”