Role of aldosterone and mineralocorticoid receptor (MR) in addiction: A scoping review.

Preclinical and human studies suggest a role of aldosterone and mineralocorticoid receptor (MR) in addiction. This scoping review aimed to summarize (1) the relationship between alcohol and other substance use disorders (ASUDs) and dysfunctions of the aldosterone and MR, and (2) how pharmacological manipulations of MR may affect ASUD-related outcomes. Our search in four databases (MEDLINE, Embase, Web of Science, and Cochrane Library) indicated that most studies focused on the relationship between aldosterone, MR, and alcohol (n = 30), with the rest focused on opioids (n = 5), nicotine (n = 9), and other addictive substances (n = 9). Despite some inconsistencies, the overall results suggest peripheral and central dysregulations of aldosterone and MR in several species and that these dysregulations depended on the pattern of drug exposure and genetic factors. We conclude that MR antagonism may be a promising target in ASUD, yet future studies are warranted.

Pathophysiology and clinical management of hyperkalemia in chronic kidney disease.

Adaptive increases in kidney and gastrointestinal excretion of K+ help to prevent hyperkalemia in patients with chronic kidney disease (CKD) as long as the glomerular filtration rate (GFR) remains >15-20 mL/min. K+ balance is maintained by increased secretion per functioning nephron, which is mediated by elevated plasma K+ concentration, aldosterone, increased flow rate, and enhanced Na+-K+-ATPase activity. Fecal losses of potassium also increase in CKD. These mechanisms are effective in preventing hyperkalemia if urine output is in excess of 600 mL/day and the GFR exceeds 15 mL/min. Development of hyperkalemia with only mild to moderate reductions in GFR should prompt a search for intrinsic disease of the collecting duct, disturbances in mineralocorticoid activity, and/or decreased delivery of sodium to the distal nephron. The initial approach to treatment is to review the patient's medication profile and whenever possible discontinue drugs that impair kidney K+ excretion. Patients should be educated on sources of K+ in the diet and should be strongly encouraged to avoid the use of K+ containing salt substitutes as well as herbal remedies since herbs may be a hidden source of dietary K+. Effective diuretic therapy and correction of metabolic acidosis are effective strategies to minimize the potential for hyperkalemia. Discontinuation or use of submaximal doses of renin-angiotensin blockers should be discouraged given the cardiovascular protective effect these drugs provide. Potassium binding drugs can be useful to enable use of these drugs and potentially allow liberalization of the diet in CKD patients.

[Three ages of spironolactone. Evolution of views on spironolactone capabilities in the treatment of patients with heart failure.]

The article describes the history of the discovery of aldosterone and the creation of its antagonist, spironolactone. The effects of aldosterone associated with the stimulation of two types of receptors.  Long-term effect (nuclear or genomic) and fast - term (membrane). They are manifested not only by the influence on the water-salt metabolism and the volume of extracellular fluid, but also in the regulation of vascular tone and elasticity of the vascular wall and, most interestingly, the effect on cardiac remodeling. Early after its development  Spironolactone was considered as a medicine for water-salt metabolism regulation, diuresis and normalization of blood pressure. In the following period,  Spironolactone embraced a new area - systolic heart failure. The drug was considered not only to enhance safe diuresis, but also to eliminate the phenomenon of escape of the antialdosterone effect angiotensin-converting enzyme inhibitors. The change in the paradigm of heart failure towards the prevailing changes in her diastolic phenotype, which is based on excessive diffuse myocardial fibrosis, changed role of spironolactone in the treatment of heart failure. Currently, it is considered as an independent drug, due to its powerful antifibrotic effect, blocking which controls the whole complex of endo- and paracrine effects of aldosterone.

Pathophysiology of Hypertension: The Mosaic Theory and Beyond.

Dr Irvine Page proposed the Mosaic Theory of Hypertension in the 1940s advocating that hypertension is the result of many factors that interact to raise blood pressure and cause end-organ damage. Over the years, Dr Page modified his paradigm, and new concepts regarding oxidative stress, inflammation, genetics, sodium homeostasis, and the microbiome have arisen that allow further refinements of the Mosaic Theory. A constant feature of this approach to understanding hypertension is that the various nodes are interdependent and that these almost certainly vary between experimental models and between individuals with hypertension. This review discusses these new concepts and provides an introduction to other reviews in this compendium of Circulation Research.

Aldosterone and Mineralocorticoid Receptor Signaling as Determinants of Cardiovascular and Renal Injury: From Hans Selye to the Present.

BACKGROUND: A full understanding of the mechanisms of action of aldosterone and its interaction with the mineralocorticoid receptor (MR) allows a theoretical framework to predict the therapeutic potential of MR antagonists (MRAs) in CKD, and heart failure with reduced ejection fraction. SUMMARY: The initial focus on the mechanisms of action of aldosterone was directed primarily on its role in modulating renal excretory function. In contrast, many recent studies have demonstrated a wider and expanded role for aldosterone in modulating inflammation, collagen formation, fibrosis, and necrosis. Increasing evidence has accrued that implicates the pathophysiological overactivation of the MR as a major determinant of progression of CKD. By promoting inflammation and fibrosis, MR overactivation constitutes a pivotal determinant of CKD progression and its associated morbidity and mortality. In accord with this mechanism of action, blockade of the MR is currently being investigated as a novel treatment regimen to slow the progression of CKD. The recently reported FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) study demonstrated that patients with CKD and type 2 diabetes who were treated with finerenone (a novel nonsteroidal MRA) manifested a lower risk of a composite primary outcome event compared with patients in the placebo arm (defined as kidney failure, or a sustained decrease of ≥40% in the estimated glomerular filtration rate from baseline, or death from renal causes). In addition, patients in the finerenone group also manifested a lower risk of a key secondary outcome event (defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). Key Messages: Based on the success of the FIDELIO-DKD study, future studies should be implemented testing the hypothesis that a wide array of nondiabetic CKD is modulated by overactivation of the MR, and consequently may be amenable to treatment with novel nonsteroidal MRAs. Future studies are encouraged to elucidate the clinical implications of the interplay of nonsteroidal MRAs and the components of the renin-angiotensin cascade. The unique and recently reported interrelationship of fibroblast growth factor (FGF23) and aldosterone may also constitute a propitious subject for future investigation.

Kidney and epigenetic mechanisms of salt-sensitive hypertension.

Dietary salt intake increases blood pressure (BP) but the salt sensitivity of BP differs between individuals. The interplay of ageing, genetics and environmental factors, including malnutrition and stress, contributes to BP salt sensitivity. In adults, obesity is often associated with salt-sensitive hypertension. The children of women who experience malnutrition during pregnancy are at increased risk of developing obesity, diabetes and salt-sensitive hypertension as adults. Similarly, the offspring of mice that are fed a low-protein diet during pregnancy develop salt-sensitive hypertension in association with aberrant DNA methylation of the gene encoding type 1A angiotensin II receptor (AT1AR) in the hypothalamus, leading to upregulation of hypothalamic AT1AR and renal sympathetic overactivity. Ageing is also associated with salt-sensitive hypertension. In aged mice, promoter methylation leads to reduced kidney production of the anti-ageing factor Klotho and a decrease in circulating soluble Klotho. In the setting of Klotho deficiency, salt-induced activation of the vascular Wnt5a-RhoA pathway leads to ageing-associated salt-sensitive hypertension, potentially as a result of reduced renal blood flow and increased peripheral resistance. Thus, kidney mechanisms and aberrant DNA methylation of certain genes are involved in the development of salt-sensitive hypertension during fetal development and old age. Three distinct paradigms of epigenetic memory operate on different timescales in prenatal malnutrition, obesity and ageing.

The Mineralocorticoid Receptor in Salt-Sensitive Hypertension and Renal Injury.

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.

Renin-angiotensin-aldosterone system and COVID-19 infection.

With the multiplication of COVID-19 severe acute respiratory syndrome cases due to SARS-COV2, some concerns about angiotensin-converting enzyme 1 (ACE1) inhibitors (ACEi) and angiotensin II type 1 receptor blockers (ARB) have emerged. Since the ACE2 (angiotensin-converting enzyme 2) enzyme is the receptor that allows SARS COV2 entry into cells, the fear was that pre-existing treatment with ACEi or ARB might increase the risk of developing severe or fatal severe acute respiratory syndrome in case of COVID-19 infection. The present article discusses these concerns. ACE2 is a membrane-bound enzyme (carboxypeptidase) that contributes to the inactivation of angiotensin II and therefore physiologically counters angiotensin II effects. ACEis do not inhibit ACE2. Although ARBs have been shown to up-regulate ACE2 tissue expression in experimental animals, evidence was not always consistent in human studies. Moreover, to date there is no evidence that ACEi or ARB administration facilitates SARS-COV2 cell entry by increasing ACE2 tissue expression in either animal or human studies. Finally, some studies support the hypothesis that elevated ACE2 membrane expression and tissue activity by administration of ARB and/or infusion of soluble ACE2 could confer protective properties against inflammatory tissue damage in COVID-19 infection. In summary, based on the currently available evidence and as advocated by many medical societies, ACEi or ARB should not be discontinued because of concerns with COVID-19 infection, except when the hemodynamic situation is precarious and case-by-case adjustment is required.

Salt Appetite and its Effects on Cardiovascular Risk in Primary Aldosteronism.

First described in 1955 by Jerome W. Conn, primary aldosteronism (PA) today is well established as a relevant cause of secondary hypertension and accounts for about 5-10 % of hypertensives. The importance of considering PA is based on its deleterious target organ damage far beyond the effect of elevated blood pressure and on PA being a potentially curable form of hypertension. Aside the established contributory role of high dietary salt intake to arterial hypertension and cardiovascular disease, high salt intake is mandatory for aldosterone-mediated deleterious effects on target-organ damage in patients with primary aldosteronism. Consequently, counselling patients on the need to reduce salt intake represents a major component in the treatment of PA to minimize cardiovascular damage. Unfortunately, in PA patients salt intake is high and far beyond the target values of 5 g per day, recommended by the World Health Organization. Insufficient patient motivation for lifestyle interventions can be further complicated by enhancing effects of aldosterone on salt appetite, via central and gustatory pathways. In this context, treatment for PA by adrenalectomy results in a spontaneous decrease in dietary salt intake and might therefore provide further reduction of cardiovascular risk in PA than specific medical treatment alone. Furthermore, there is evidence from clinical studies that even after sufficient treatment of PA dietary salt intake remains a relevant prognostic factor for cardiovascular risk. This review will focus on the synergistic benefits derived from both blockade of aldosterone-mediated effects and reduction in dietary salt intake on cardiovascular risk.

Aldosterone Contributed to Pulmonary Arterial Hypertension Development via Stimulating Aquaporin Expression and Pulmonary Arterial Smooth Muscle Cells Proliferation.

INTRODUCTION AND OBJECTIVE: The regulatory network of aquaporin (AQP) 1 and renin-angiotensin-aldosterone (ALDO) system are not quite clear in pulmonary arterial hypertension (PAH). Thus, we explored the role of AQP1, ALDO and spirolactone (SP) in the PAH animal model and pulmonary arterial smooth muscle cells (PASMCs). METHOD: PAH rat model was established by monocrotaline (MCT) via intraperitoneal in SD rat. Hemodynamic measurement was conducted via the external jugular vein cannula. PASMCs were extracted from normal SD rat and cultured in SmGM medium. α-Actin expression was identified by immunocytochemistry. Protein levels were assessed by Western blot. Cell viability was assayed using the MTT method. Apoptosis rate was evaluated by flow cytometry. ALDO level was measured by ELISA. RESULT: SP decreased AQP1 and ß-catenin expressions in PAH rat model induced successfully by MCT. Moreover, ALDO increased AQP1 expression and cell viability in PASMCs, which were extracted from rat and identified by α-actin expression. AQP1 downregulation decreased ß-catenin expression, and SP lowered AQP1 and ß-catenin expressions elevated by ALDO in PASMCs. SP offset ALDO's effect on the upregulation of cell viability as well as AQP1 and ß-catenin expressions in PASMCs. In addition, AQP1 downregulation and SP have a negative effect on Ki-67 and proliferating cell nuclear antigen expressions as well as cell viability after ALDO treatment in PASMCs. CONCLUSION: ALDO might contribute to PAH development via stimulating AQP1 expression and PASMCs proliferation. However, SP could be considered an effective drug regulating PASMCs proliferation through modulating AQP1 and ß-catenin expressions in PAH.

Mitigating risk of aldosterone in diabetic kidney disease.

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.

Links between aldosterone excess and metabolic complications: A comprehensive review.

Shortly after the first description of primary aldosteronism (PA) appeared in the 1950s by Jerome Conn, an association of the condition with diabetes mellitus was documented. However, a clear pathophysiological interrelationship linking the two entities has yet to be established. Nevertheless, so far, many mechanisms contributing to insulin resistance and dysregulation of glucose uptake have been described. At the same time, many observational studies have reported an increased prevalence of the metabolic syndrome (MetS) among patients with PA. Regarding the relationship between aldosterone levels and obesity, a vicious cycle of adipokine-induced aldosterone production and aldosterone adipogenic action may be further contributing to MetS manifestations in PA patients. However, whether aldosterone excess affects lipid metabolism is still under investigation. Also, recent findings of the coexistence of glucocorticoid excess in many cases of PA highlight the need for further studies to examine the presumed link between high aldosterone levels and various metabolic parameters. In the present review, our focus is to comprehensively present the spectrum of available research findings concerning the possible associations between aldosterone excess and metabolic alterations, including impaired glucose metabolism, insulin resistance and, consequently, diabetes, altered lipid metabolism and the development of fatty liver. In addition, the complex relationship between obesity and aldosterone is discussed in detail.

Role of aldosterone in the activation of primary mice hepatic stellate cell and liver fibrosis via NLRP3 inflammasome.

BACKGROUND AND AIMS: Emerging evidence suggests aldosterone (aldo) and NLRP3 inflammasome are important factors for HSC activation and liver fibrosis. However, the interaction between aldo and NLRP3 inflammasome in HSC activation and liver fibrosis remains largely unknown. The aim of this study is to investigate the relationship between aldo and NLRP3 inflammasome in liver fibrosis. METHODS: Serum and liver specimens collected from 40 patients with or without liver fibrosis were used to test the level of aldo and NLRP3. Primary HSC isolated from C57BL/6 mice were treated with aldo, and the effects of aldo on NLRP3 inflammasome and HSC activation were detected in vitro. Two animal models were used to verify the effect of aldo on liver fibrosis in vivo: hyperaldosteronism model was established in wild-type and NLRP3 knockout (NLRP3-/- ) mice by micro-pump, and liver fibrosis mouse model was built by tetrachloromethane (CCl4 ). RESULTS: Patients with liver fibrosis showed higher aldo levels and increased NLRP3 expression in liver. In vitro, aldo induced the activation of primary mouse HSCs by promoting the expression and assembly of NLRP3 inflammasome. In vivo, NLRP3 knockout could alleviate the liver fibrosis induced by aldo in mice. In addition, treatment with spironolactone (spi) could inhibit the NLRP3 expression, HSC activation, and liver fibrosis induced by CCl4 . CONCLUSIONS: Aldo promotes the activation of HSCs and liver fibrosis through NLRP3 inflammasome relative pathways. Intervention of aldo and NLRP3 inflammasome-related pathways may provide a promising strategy for treatment of liver fibrosis.

Arterial Hypertension, Aldosterone, and Atrial Fibrillation.

PURPOSE: Atrial fibrillation is the most common sustained arrhythmia, with a prevalence of 1-2% in the general population and over 15% in people older than 80 years. Due to aging of the population it imposes an increasing burden on the healthcare system because of the need for life-long pharmacological treatment and the associated increased risk of heart failure and hospitalization. Hence, identification of the factors that predispose to atrial fibrillation it is of utmost relevance. RECENT FINDINGS: Several conditions exist that are characterized by inappropriately high levels of aldosterone, mostly primary aldosteronism and the severe or drug-resistant forms of arterial hypertension. In these forms, aldosterone can cause prominent target organ damage, mostly in the heart, vasculature, and kidney. This review examines the experimental data and clinical evidences that support a link between hyperaldosteronism and atrial fibrillation, and how this knowledge should lead to a change in our management of the hypertensive patients presenting with atrial fibrillation.

Aldosterone as a mediator of severity in retinal vascular disease: Evidence and potential mechanisms.

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.

Role of Aldosterone in Renal Fibrosis.

Aldosterone is a mineralocorticoid hormone, as its main renal effect has been considered as electrolyte and water homeostasis in the distal tubule, thus maintaining blood pressure and extracellular fluid homeostasis through the activation of mineralocorticoid receptor (MR) in epithelial cells. However, over the past decade, numerous studies have documented the significant role of aldosterone in the progression of chronic kidney disease (CKD) which has become a subject of interest. It is being studied that aldosterone can affect cardiovascular and renal system, thereby contributing to tissue inflammation, injury, glomerulosclerosis, and interstitial fibrosis. Aldosterone acts on renal vessels, renal cells (glomerular mesangial cells, podocytes, vascular smooth muscle cells, tubular epithelial cells, and interstitial fibroblasts), and infiltrating inflammatory cells, inducing reactive oxygen species (ROS) production, upregulated epithelial growth factor receptor (EGFR), and type 1 angiotensin (AT1) receptor expressions, and activating nuclear factor kappa B (NF-κB), activator protein-1 (AP-1), and EGFR to further promote cell proliferation, apoptosis, and proliferation. Phenotypic transformation of epithelial cells stimulates the expression of transforming growth factor-ß (TGF-ß), connective tissue growth factor (CTGF), osteopontin (OPN), and plasminogen activator inhibitor-1 (PAI-1), eventually leading to renal fibrosis. MR antagonisms are related to inhibition of aldosterone-mediated pro-inflammatory and pro-fibrotic effect. In this review, we will summarize the important role of aldosterone in the pathogenesis of renal injury and fibrosis, emphasizing on its multiple underlying mechanisms and advances in aldosterone research along with the potential therapeutics for targeting MR in a renal fibrosis.

[Antifibrotic renal role of mineralcorticoid receptor antagonists].

Cardiovascular and renal diseases are one of the main health problems in all industrialized countries. Their incidence is constantly increasing due to the aging of the population and the greater prevalence of obesity and type 2 diabetes. Clinical evidence suggests that aldosterone and the activation of mineralocorticoid receptors (MR) have a role in the pathophysiology of cardiovascular and renal diseases. Moreover, clinical studies demonstrate the benefits of mineralocorticoid receptor antagonists (MRAs) on mortality and progression of heart and kidney disease. In addition to renal effects on body fluid homeostasis, aldosterone has multiple extrarenal effects including the induction of inflammation, vascular rigidity, collagen formation and stimulation of fibrosis. Given the fundamental role of MR activation in renal and cardiac fibrosis, effective and selective blocking of the signal with MRAs can be used in the clinical practice to prevent or slow down the progression of heart and kidney diseases. The aim of the present work is to review the role of MRAs in light of the new evidence as well as its potential use as an antifibrotic in chronic kidney disease (CKD). The initial clinical results suggest that MRAs are potentially useful in treating patients with chronic kidney disease, particularly in cases of diabetic nephropathy. We don't yet have efficacy and safety data on the progression of kidney disease up to the end stage (ESRD) and filling this gap represents an important target for future trials.

Angiotensin II and aldosterone in retinal vasculopathy and inflammation.

Angiotensin II and aldosterone are the main effectors of the renin-angiotensin aldosterone system (RAAS) and have a central role in hypertension as well as cardiovascular and renal disease. The localization of RAAS components within the retina has led to studies investigating the roles of angiotensin II, aldosterone and the counter regulatory arm of the pathway in vision-threatening retinopathies. This review will provide a brief overview of RAAS components as well as the vascular pathology that develops in the retinal diseases, retinopathy of prematurity, diabetic retinopathy and neovascular age-related macular degeneration. The review will discuss pre-clinical and clinical evidence that modulation of the RAAS alters the development of vasculopathy and inflammation in the aforementioned retinopathies, as well as the emerging role of aldosterone and the mineralocorticoid receptor in central serous chorioretinopathy.