SAT-552 Epigenetic Regulation of 11beta-Hydroxysteroid Dehydrogenase 1 and 2 Gene in Salt-Sensitive Hypertensive Rats

ENDO 2020 Epigenetic regulation of 11beta-hydroxysteroid dehydrogenase 1 and 2 gene in salt-sensitive hypertensive rats [Objective]11Beta-hydroxysteroid dehydrogenase type1 (11-HSD1) is the modulator of glucocorticoid hormone and type2 (11-HSD2) is the modulator of mineralocorticoid hormone. We investigated the effect of high salt diet on the methylation of both enzyme gene in salt-sensitive hypertensive (SSH) rats [Methods]SSH rats were fed a high (7% NaCl) or normal (0.45%) salt chow for 4 weeks. Body weight, blood pressure, plasma and urinary aldosterone concentration and PRA were measured. DNA was extracted from kidneys and visceral fats. Bisulfite sequencing and Pyrosequencing were done for the analysis of methylation status of 11-HSD1 and 2 gene. [Results] High salt diet significantly decreased methylation ratio of 11-HSD1 gene in the visceral fats of SSH rats compared with controls (p<0.05). The methylation ratio of 11-HSD2 gene in the kidney of SSH rats was not influenced by high salt diet. [Discussion and Conclusion]11-HSD1 overexpression in visceral fats in mice was reported to show SSH. We reported decreased 11-HSD2 activity in the artery in SSH rats. In this study high salt diet affected methylation status of 11-HSD1 in the adipose tissue but not 11-HSD2 gene in the kidney in SSH. Food intake such as salt may influence the epigenesis of 11-HSD and induce hypertension.

Aldosterone and Mineralocorticoid Receptor System in Cardiovascular Physiology and Pathophysiology

The mineralocorticoid hormone aldosterone (Aldo) has been intensively studied for its ability to influence both the physiology and pathophysiology of the cardiovascular system. Indeed, although research on Aldo actions for decades has mainly focused on its effects in the kidney, several lines of evidence have now demonstrated that this hormone exerts disparate extrarenal adverse effects, especially in the circulatory system. Accordingly, in the last lusters, a number of studies in preclinical models (in vitro and in vivo) and in humans have established that Aldo, following the interaction with its receptor—the mineralocorticoid receptor (MR)—is able to activate specific intracellular genomic and nongenomic pathways, thus regulating the homeostasis of the cardiovascular system. Importantly, through this mechanism of action, this hormone becomes a crucial regulator of the function and growth of different types of cells, including fibroblasts, cardiomyocytes, and vascular cells. For this main reason, it is plausible that when Aldo is present at high levels in the blood, it profoundly modifies the physiology of these cells, therefore being at the foundation of several cardiovascular disorders, such as heart failure (HF). On these grounds, in this review, we will provide an updated account on the current knowledge concerning Aldo activity in the cardiovascular system and the most recent preclinical studies and clinical trials designed to test better approaches able to counter the hyperactivity of the Aldo/MR signaling pathway in the setting of cardiovascular diseases.

James Francis Tait. 1 December 1925—2 February 2014

James F. Tait FRS, with his wife Sylvia A. S. Tait FRS, made an indelible contribution to life science and medicine with the isolation and characterization of aldosterone, the most potent mineralocorticoid hormone produced by the mammalian adrenal cortex. Trained as a physicist, Tait turned to endocrinology during his first academic appointment at the Medical School of the Middlesex Hospital in London, where he met Sylvia. Their collaboration resulted in this major achievement within five years of his appointment, and they were both elected to fellowships of the Royal Society in 1959, when James was just 34. Shortly afterwards the Taits moved to the Worcester Foundation for Experimental Biology in Massachusetts, where he virtually created the study of hormone dynamics, using sophisticated techniques involving isotopically labelled hormone infusions. Many of his most highly cited papers stem from this period. In 1970 the Taits returned to the Middlesex Hospital, when he was appointed to the Joel Chair of Physics as Applied to Medicine. Here they continued studies on aldosterone and other adrenal steroids, using animal cell models. He continued to be active after retiring in 1982, and published a history of aldosterone in 2009. As a hobby he made a magnificent photographic record of the churches and abbeys of Yorkshire. Although, initially, recognition of aldosterone's clinical significance was slow, today it is thought that 10% of the incidence of essential hypertension is attributable to excess aldosterone. Aldactone, the earliest aldosterone antagonist, as well as more recently developed blockers, have proved effective in congestive heart failure. Sixty years after its discovery, aldosterone remains a rich and dynamic research field.

GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism

Aldosterone is the main mineralocorticoid hormone in humans and plays a key role in maintaining water and electrolyte homeostasis. Primary aldosteronism (PA), characterized by autonomous aldosterone overproduction by the adrenal glands, affects 6% of the general hypertensive population and can be either sporadic or familial. Aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) are the two most frequent subtypes of sporadic PA and 4 forms of familial hyperaldosteronism (FH-I to FH-IV) have been identified. Over the last six years, the introduction of next-generation sequencing has significantly improved our understanding of the molecular mechanisms responsible for autonomous aldosterone overproduction in both sporadic and familial PA. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D), differently implicated in intracellular ion homeostasis, have been identified in nearly 60% of the sporadic APAs. Germline mutations in KCNJ5 and CACNA1H cause FH-III and FH-IV, respectively, while germline mutations in CACNA1D cause the rare PASNA syndrome, featuring primary aldosteronism seizures and neurological abnormalities. Further studies are warranted to identify the molecular mechanisms underlying BAH and FH-II, the most common forms of sporadic and familial PA whose molecular basis is yet to be uncovered.

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

The mineralocorticoid receptor (MR) and mineralocorticoids regulate epithelial handling of electrolytes, and induces diverse effects on other tissues. Traditionally, the effects of MR were ascribed to ligand–receptor binding and activation of gene transcription. However, the MR also utilises a number of intracellular signalling cascades, often by transactivating unrelated receptors, to change cell function more rapidly. Although aldosterone is the physiological mineralocorticoid, it is not the sole ligand for MR. Tissue-selective and mineralocorticoid-specific effects are conferred through the enzyme 11β-hydroxysteroid dehydrogenase 2, cellular redox status and properties of the MR itself. Furthermore, not all aldosterone effects are mediated via MR, with implication of the involvement of other membrane-bound receptors such as GPER. This review will describe the ligands, receptors and intracellular mechanisms available for mineralocorticoid hormone and receptor signalling and illustrate their complex interactions in physiology and disease.

Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney

In the 60 years that have passed since the discovery of the mineralocorticoid hormone aldosterone, much has been learned about its synthesis (both adrenal and extra-adrenal), regulation (by renin-angiotensin II, potassium, adrenocorticotrophin, and other factors), and effects (on both epithelial and nonepithelial tissues). Once thought to be rare, primary aldosteronism (PA, in which aldosterone secretion by the adrenal is excessive and autonomous of its principal regulator, angiotensin II) is now known to be the most common specifically treatable and potentially curable form of hypertension, with most patients lacking the clinical feature of hypokalemia, the presence of which was previously considered to be necessary to warrant further efforts towards confirming a diagnosis of PA. This, and the appreciation that aldosterone excess leads to adverse cardiovascular, renal, central nervous, and psychological effects, that are at least partly independent of its effects on blood pressure, have had a profound influence on raising clinical and research interest in PA. Such research on patients with PA has, in turn, furthered knowledge regarding aldosterone synthesis, regulation, and effects. This review summarizes current progress in our understanding of the physiology of aldosterone, and towards defining the causes (including genetic bases), epidemiology, outcomes, and clinical approaches to diagnostic workup (including screening, diagnostic confirmation, and subtype differentiation) and treatment of PA.

MicroRNAs and the regulation of aldosterone signaling in the kidney

The role of small noncoding RNAs, termed microRNAs (miRs), in development and disease has been recognized for many years. The number of miRs and regulated targets that reinforce a role for miRs in human disease and disease progression is ever-increasing. However, less is known about the involvement of miRs in steady-state, nondisease homeostatic pathways. In the kidney, much of the regulated ion transport is under the control of hormonal signaling. Evidence is emerging that miRs are involved in the hormonal regulation of kidney function and, particularly, in ion transport. In this short review, the production and intra- and extracellular signaling of miRs and the involvement of miRs in kidney disease are discussed. The discussion also focuses on the role of these small biological molecules in the homeostatic control of ion transport in the kidney. MiR regulation of and by corticosteroid hormones, in particular the mineralocorticoid hormone aldosterone, is considered. While information about the role of aldosterone-regulated miRs in the kidney is limited, an increase in the research in this area will undoubtedly highlight the involvement of miRs as central mediators of hormonal signaling in normal physiology.

Evidence for a mineralocorticoid-like receptor linked to branchial chloride cell proliferation in freshwater rainbow trout

SUMMARY Fish acclimated to ion-deficient water exhibit proliferation of branchial chloride cells. The objective of the present study was to investigate the role of cortisol in this response using the corticosteroid receptor antagonists RU486 and spironolactone. RU486 is a potent antagonist of the glucocorticoid actions of cortisol, whereas spironolactone exhibits high-affinity binding to mineralocorticoid receptors, with a resulting blockade of mineralocorticoid properties in mammals. Untreated rainbow trout, as well as rainbow trout given a single intraperitoneal implant of coconut oil alone, coconut oil containing RU486 (0.5 mg g–1) or coconut oil containing spironolactone (0.1 mg g–1), were exposed to either dechlorinated city-of-Ottawa tapwater or artificial softwater for 7 days. Neither corticosteroid antagonist nor acclimation condition affected circulating plasma cortisol levels, plasma ion concentrations or gill Na+-K+-ATPase activity. Kidney Na+-K+-ATPase activity was significantly higher in softwater-acclimated fish than in fish held in dechlorinated tapwater. In addition, whereas RU486 treatment was found to be without effect on gill morphometrics, treatment with spironolactone inhibited the proliferation of chloride cells normally associated with acclimation to ion-deficient water. The results of the present study provide further evidence for the mineralocorticoid actions of cortisol in freshwater fish, specifically in eliciting chloride cell proliferation. Furthermore, these results support the hypothesis that distinct glucocorticoid and mineralocorticoid receptor populations are present in teleost fish, despite the apparent absence of the classic mineralocorticoid hormone, aldosterone.