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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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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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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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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 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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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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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.
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Expression of CYP11B2 in Aldosterone-Producing Adrenocortical Adenoma: Regulatory Mechanisms and Clinical Significance.
Nakamura, Y, Yamazaki, Y, Tezuka, Y, Satoh, F, Sasano, H
The Tohoku journal of experimental medicine. 2016;(3):183-190
Abstract
Aldosterone-producing adrenocortical adenoma (APA) is responsible for the majority of cases clinically diagnosed as primary aldosteronism. Aldosterone synthase (CYP11B2) is one of the enzymes that play essential roles in aldosterone synthesis and is involved in the pathogenesis of APA. Recent studies have demonstrated that various factors and regulators influence the expression and function of CYP11B2 in APA. In particular, somatic mutations, such as gain-of-function and loss-of-function mutations, have been identified in several genes, each of which encodes a pivotal protein that affects the calcium signaling pathway, the expression of CYP11B2, and aldosterone production. The gain-of-function mutations were reported in KCNJ5 that encodes G-protein activated inward rectifier K+ channel 4 (Kir3.4) and in CACNA1D, encoding calcium channel, voltage-dependent, L type, alpha subunit Cav1.3. The loss-of-function mutations were found in ATP1A1 that encodes Na+/K+ ATPase α subunit and in ATP2B3, encoding Ca2+ ATPase. Furthermore, the aberrant expression of gonadotropin-releasing hormone receptor is associated with the overexpression of CYP11B2 and overproduction of aldosterone in APA with activating mutations in CTNNB1 encoding β-catenin. On the other hand, CYP11B2 also catalyzes the conversion of cortisol to 18-hydroxycortisol and subsequently converts 18-hydroxycortisol to 18-oxocortisol. The recent studies have identified 18-oxocortisol as an important and distinct biomarker to diagnose primary aldosteronism. In this review, we summarize the recent findings on CYP11B2 and discuss the molecular pathogenesis of APA and the clinical significance of CYP11B2.
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Interactions between adrenal-regulatory and calcium-regulatory hormones in human health.
Brown, JM, Vaidya, A
Current opinion in endocrinology, diabetes, and obesity. 2014;(3):193-201
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Abstract
PURPOSE OF REVIEW To summarize the evidence characterizing the interactions between adrenal-regulating and calcium-regulating hormones, and the relevance of these interactions to human cardiovascular and skeletal health. RECENT FINDINGS Human studies support the regulation of parathyroid hormone (PTH) by the renin-angiotensin-aldosterone system (RAAS): angiotensin II may stimulate PTH secretion via an acute and direct mechanism, whereas aldosterone may exert a chronic stimulation of PTH secretion. Studies in primary aldosteronism, congestive heart failure, and chronic kidney disease have identified associations between hyperaldosteronism, hyperparathyroidism, and bone loss, which appear to improve when inhibiting the RAAS. Conversely, elevated PTH and insufficient vitamin D status have been associated with adverse cardiovascular outcomes, which may be mediated by the RAAS. Studies of primary hyperparathyroidism implicate PTH-mediated stimulation of the RAAS, and recent evidence shows that the vitamin D-vitamin D receptor complex may negatively regulate renin expression and RAAS activity. Ongoing human interventional studies are evaluating the influence of RAAS inhibition on PTH and the influence of vitamin D receptor agonists on RAAS activity. SUMMARY Although previously considered independent endocrine systems, emerging evidence supports a complex web of interactions between adrenal-regulating and calcium-regulating hormones, with implications for human cardiovascular and skeletal health.
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Roles of the circulating renin-angiotensin-aldosterone system in human pregnancy.
Lumbers, ER, Pringle, KG
American journal of physiology. Regulatory, integrative and comparative physiology. 2014;(2):R91-101
Abstract
This review describes the changes that occur in circulating renin-angiotensin-aldosterone system (RAAS) components in human pregnancy. These changes depend on endocrine secretions from the ovary and possibly the placenta and decidua. Not only do these hormonal secretions directly contribute to the increase in RAAS levels, they also cause physiological changes within the cardiovascular system and the kidney, which, in turn, induce reflex release of renal renin. High levels of ANG II play a critical role in maintaining circulating blood volume, blood pressure, and uteroplacental blood flow through interactions with the ANG II type I receptor and through increased production of downstream peptides acting on a changing ANG receptor phenotype. The increase in ANG II early in gestation is driven by estrogen-induced increments in angiotensinogen (AGT) levels, so there cannot be negative feedback leading to reduced ANG II production. AGT can exist in various forms in terms of redox state or complexed with other proteins as polymers; these affect the ability of renin to cleave ANG I from AGT. Thus, during pregnancy the rate of ANG I production varies not only because levels of renin change in response to homeostatic demand but also because AGT changes not only in concentration but in form. Activation of the circulating and intrarenal RAASs is essential for normal pregnancy outcome subserving the increased demand for salt and, hence, water during pregnancy. Thus, the complex integration of the secretions and actions of the circulating maternal renin-angiotensin system in pregnancy plays a key role in pregnancy outcome.