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Aldosterone, Inflammation, Immune System, and Hypertension.
Ferreira, NS, Tostes, RC, Paradis, P, Schiffrin, EL
American journal of hypertension. 2021;(1):15-27
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Abstract
Aldosterone is a mineralocorticoid hormone that controls body fluid and electrolyte balance. Excess aldosterone is associated with cardiovascular and metabolic diseases. Inflammation plays a critical role on vascular damage promoted by aldosterone and aggravates vascular abnormalities, including endothelial dysfunction, vascular remodeling, fibrosis and oxidative stress, and other manifestations of end-organ damage that are associated with hypertension, other forms of cardiovascular disease, and diabetes mellitus and the metabolic syndrome. Over the past few years, many studies have consistently shown that aldosterone activates cells of the innate and adaptive immune systems. Macrophages and T cells accumulate in the kidneys, heart, and vasculature in response to aldosterone, and infiltration of immune cells contributes to end-organ damage in cardiovascular and metabolic diseases. Aldosterone activates various subsets of innate immune cells such as dendritic cells and monocytes/macrophages, as well as adaptive immune cells such as T lymphocytes, and, by activation of mineralocorticoid receptors stimulates proinflammatory transcription factors and the production of adhesion molecules and inflammatory cytokines and chemokines. This review will briefly highlight some of the studies on the involvement of aldosterone in activation of innate and adaptive immune cells and its impact on the cardiovascular system. Since aldosterone plays a key role in many cardiovascular and metabolic diseases, these data will open up promising perspectives for the identification of novel biomarkers and therapeutic targets for prevention and treatment of diseases associated with increased levels of aldosterone, such as arterial hypertension, obesity, the metabolic syndrome, and heart failure.
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Unravelling the Genetic Basis of Primary Aldosteronism.
Mourtzi, N, Sertedaki, A, Markou, A, Piaditis, GP, Charmandari, E
Nutrients. 2021;(3)
Abstract
Primary aldosteronism (PA), a condition characterized by autonomous aldosterone hypersecretion, constitutes the most common cause of secondary hypertension. Over the last decade, major breakthroughs have been made in the field of genetics underpinning PA. The advent and wide application of Next Generation Sequencing (NGS) technology led to the identification of several somatic and germline mutations associated with sporadic and familial forms of PA. Somatic mutations in ion-channel genes that participate in aldosterone biosynthesis, including KCNJ5, CACNA1D, ATP1A1, and ATP2B3, have been implicated in the development of aldosterone-producing adenomas (APAs). On the other hand, germline variants in CLCN2, KCNJ5, CACNA1H, and CACNA1D genes have been implicated in the pathogenesis of the familial forms of PA, FH-II, FH-III, and F-IV, as well as PA associated with seizures and neurological abnormalities. However, recent studies have shown that the prevalence of PA is higher than previously thought, indicating the need for an improvement of our diagnostic tools. Further research is required to recognize mild forms of PA and to investigate the underlying molecular mechanisms.
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The Mineralocorticoid Receptor in Salt-Sensitive Hypertension and Renal Injury.
Ayuzawa, N, Fujita, T
Journal of the American Society of Nephrology : JASN. 2021;(2):279-289
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Abstract
Hypertension and its comorbidities pose a major public health problem associated with disease-associated factors related to a modern lifestyle, such high salt intake or obesity. Accumulating evidence has demonstrated that aldosterone and its receptor, the mineralocorticoid receptor (MR), have crucial roles in the development of salt-sensitive hypertension and coexisting cardiovascular and renal injuries. Accordingly, clinical trials have repetitively shown the promising effects of MR blockers in these diseases. We and other researchers have identified novel mechanisms of MR activation involved in salt-sensitive hypertension and renal injury, including the obesity-derived overproduction of aldosterone and ligand-independent signaling. Moreover, recent advances in the analysis of cell-specific and context-dependent mechanisms of MR activation in various tissues-including a classic target of aldosterone, aldosterone-sensitive distal nephrons-are now providing new insights. In this review, we summarize recent updates to our understanding of aldosterone-MR signaling, focusing on its role in salt-sensitive hypertension and renal injury.
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The landscape of molecular mechanism for aldosterone production in aldosterone-producing adenoma.
Oki, K, Gomez-Sanchez, CE
Endocrine journal. 2020;(10):989-995
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Abstract
Primary aldosteronism is the most common form of secondary hypertension with a prevalence of 5-10% in hypertensive patients. Aldosterone-producing adenoma (APA) is a subtype of primary aldosteronism, and somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CLCN2, or CTNNB1 were identified and recognized to drive aldosterone production and/or contribute to tumorigenesis in APA. Mutations of KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CLCN2 are known to activate calcium signaling, and its activation potentiate CYP11B2 (aldosterone synthesis) transcription in adrenal cells. Transcriptome analyses combined with bioinformatics using APA samples were conductive for each gene mutation mediated pivotal pathway, gene ontology, and clustering. Several important intracellular molecules in increase aldosterone production were detected by transcriptome analysis, and additional functional analyses demonstrated intracellular molecular mechanisms of aldosterone production which focused on calcium signal, CYP11B2 transcription and translation. Furthermore, DNA methylation analysis revealed that promoter region of CYP11B2 was entirely hypomethylated, but that of other steroidogenic enzymes were not in APA. Integration of transcriptome and DNA methylome analysis clarified some DNA methylation associated gene expression, and the transcripts have a role for aldosterone production. In this article, we reviewed the intracellular molecular mechanisms of aldosterone production in APA, and discussed future challenges for basic studies leading to clinical practice.
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The Potential Role of Aldosterone-Producing Cell Clusters in Adrenal Disease.
Lim, JS, Rainey, WE
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2020;(6):427-434
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Abstract
Primary aldosteronism (PA) is the most common cause of secondary hypertension. The hallmark of PA is adrenal production of aldosterone under suppressed renin conditions. PA subtypes include adrenal unilateral and bilateral hyperaldosteronism. Considerable progress has been made in defining the role for somatic gene mutations in aldosterone-producing adenomas (APA) as the primary cause of unilateral PA. This includes the use of next-generation sequencing (NGS) to define recurrent somatic mutations in APA that disrupt calcium signaling, increase aldosterone synthase (CYP11B2) expression, and aldosterone production. The use of CYP11B2 immunohistochemistry on adrenal glands from normal subjects, patients with unilateral and bilateral PA has allowed the identification of CYP11B2-positive cell foci, termed aldosterone-producing cell clusters (APCC). APCC lie beneath the adrenal capsule and like APA, many APCC harbor somatic gene mutations known to increase aldosterone production. These findings suggest that APCC may play a role in pathologic progression of PA. Herein, we provide an update on recent research directed at characterizing APCC and also discuss the unanswered questions related to the role of APCC in PA.
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Mitigating risk of aldosterone in diabetic kidney disease.
Frimodt-Møller, M, Persson, F, Rossing, P
Current opinion in nephrology and hypertension. 2020;(1):145-151
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PURPOSE OF REVIEW Diabetic kidney disease is a growing problem leading to end-stage kidney disease but also atherosclerotic cardiovascular disease and heart failure. Aldosterone is a key risk factor promoting inflammation and fibrosis causing cardio-renal failure. Current options and challenges with mitigating the risk of aldosterone are reviewed. RECENT FINDINGS More aggressive renin-angiotensin-aldosterone system (RAAS) blockade can be maintained in individuals with hyperkalemia if new potassium binders are added. Aldosterone synthase inhibitors may lower aldosterone without causing hyperkalemia. Novel nonsteroidal mineralocorticoid receptor antagonists (MRA) are able to lower proteinuria and markers of heart failure, with limited potassium problems and without renal impairment. Ongoing clinical trials are evaluating the safety and potential benefits of nonsteroidal MRAs on progression of renal disease and development of cardiovascular outcomes in type 2 diabetes and kidney disease. SUMMARY Aldosterone is an important driver of inflammation and fibrosis leading to renal and cardiovascular complications. MRA lower albuminuria but data showing prevention of end-stage kidney disease are lacking. Side effects including hyperkalemia have previously prevented long-term studies in diabetic kidney disease but new treatment strategies with potassium binders, aldosterone synthase inhibitors and nonsteroidal MRA have been developed for clinical testing.
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The Effect of Extracellular Calcium Metabolism on Aldosterone Biosynthesis in Physiological and Pathological Status.
Gao, X, Yamazaki, Y, Tezuka, Y, Omata, K, Ono, Y, Morimoto, R, Nakamura, Y, Satoh, F, Sasano, H
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2020;(6):448-453
Abstract
Primary aldosteronism (PA) was reported to frequently harbor not only cardiovascular diseases but also some metabolic disorders including secondary calcium metabolic diseases. Recently, the potential association between aldosterone producing cells and systemic calcium metabolism has been proposed. For instance, PA is frequently associated with hypercalciuria or hypocalcemia, which subsequently stimulates parathyroid hormone (PTH) secretion. This altered calcium metabolism in PA patients could frequently result in secondary osteoporosis and fracture in some patients. On the other hand, extracellular calcium itself directly acts on adrenal cortex and has been also proposed as an independent regulator of aldosterone biosynthesis in human adrenals. However, it is also true that both PTH and vitamin D pathways stimulate endocrine functions of adrenal cortical adenomas to co-secret both aldosterone and cortisol. Therefore, it has become pivotal to explore the potential crosstalk between aldosterone and systemic calcium metabolism. We herein reviewed recent advances in these fields.
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Five Reasons for the Failure to Diagnose Aldosterone Excess in Hypertension.
Piaditis, GP, Kaltsas, G, Markou, A, Chrousos, GP
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2020;(12):827-833
Abstract
Primary hyperaldosteronism (PA) is a well-known cause of hypertension although its exact prevalence amongst patients with apparent essential hypertension has been a matter of debate. A number of recent studies have suggested that mild forms of PA may be relatively common taking into consideration factors that were previously either overestimated or ignored when developing diagnostic tests of PA and when applying these tests into normotensive individuals. The performance characteristics and diagnostic accuracy of such tests are substantially increased when the adrenocorticotrophin effect, inappropriate potassium levels and their application in carefully selected normotensive individuals are considered. In the present review, we critically analyze these issues and provide evidence that several, particularly mild, forms of PA can be effectively identified exhibiting potentially important clinical implications.
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Paracrine Regulation of Aldosterone Secretion in Physiological and Pathophysiological Conditions.
Lefebvre, H, Duparc, C, Naccache, A, Lopez, AG, Castanet, M, Louiset, E
Vitamins and hormones. 2019;:303-339
Abstract
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.
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Aldosterone as a mediator of severity in retinal vascular disease: Evidence and potential mechanisms.
Allingham, MJ, Mettu, PS, Cousins, SW
Experimental eye research. 2019;:107788
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Abstract
Diabetic retinopathy (DR) and retinal vein occlusion (RVO) are the two most common retinal vascular diseases and are major causes of vision loss and blindness worldwide. Recent and ongoing development of medical therapies including anti-vascular endothelial growth factor and corticosteroid drugs for treatment of these diseases have greatly improved the care of afflicted patients. However, severe manifestations of retinal vascular disease result in persistent macular edema, progressive retinal ischemia and incomplete visual recovery. Additionally, choroidal vascular diseases including neovascular age-related macular degeneration (NVAMD) and central serous chorioretinopathy (CSCR) cause vision loss for which current treatments are incompletely effective in some cases and highly burdensome in others. In recent years, aldosterone has gained attention as a contributor to the various deleterious effects of retinal and choroidal vascular diseases via a variety of mechanisms in several retinal cell types. The following is a review of the role of aldosterone in retinal and choroidal vascular diseases as well as our current understanding of the mechanisms by which aldosterone mediates these effects.