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Frontiers in Endocrinology 2023Aldosterone, as a mineralocorticoid of adrenal origin, has effects that are not limited to the urinary tract. As an important regulator in Vasoactive hormone pathways,... (Review)
Review
Aldosterone, as a mineralocorticoid of adrenal origin, has effects that are not limited to the urinary tract. As an important regulator in Vasoactive hormone pathways, aldosterone may play an effect in the pathogenesis of diabetic retinopathy (DR) through the regulation of oxidative stress, vascular regulation, and inflammatory mechanisms. This implies that mineralocorticoids, including aldosterone, have great potential and value for the diagnosis and treatment of DR. Because early studies did not focus on the intrinsic association between mineralocorticoids and DR, targeted research is still in its infancy and there are still many obstacles to its application in the clinical setting. Recent studies have improved the understanding of the effects of aldosterone on DR, and we review them with the aim of exploring possible mechanisms for the treatment and prevention of DR.
Topics: Humans; Aldosterone; Mineralocorticoids; Diabetic Retinopathy; Mineralocorticoid Receptor Antagonists; Diabetes Mellitus
PubMed: 37113483
DOI: 10.3389/fendo.2023.1163787 -
Diabetologia Feb 2024The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart,... (Review)
Review
The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart, vasculature, adipose tissue and kidneys. The inhibition of the MR with classical MR antagonists (MRA) has successfully improved outcomes most evidently in heart failure. However, real and perceived risk of side effects and limited tolerability associated with classical MRA have represented barriers to implementing MRA in settings where they have been already proven efficacious (heart failure with reduced ejection fraction) and studying their potential role in settings where they might be beneficial but where risk of safety events is perceived to be higher (renal disease). Novel non-steroidal MRA have distinct properties that might translate into favourable clinical effects and better safety profiles as compared with MRA currently used in clinical practice. Randomised trials have shown benefits of non-steroidal MRA in a range of clinical contexts, including diabetic kidney disease, hypertension and heart failure. This review provides an overview of the literature on the systemic impact of MR overactivation across organ systems. Moreover, we summarise the evidence from preclinical studies and clinical trials that have set the stage for a potential new paradigm of MR antagonism.
Topics: Humans; Diabetic Nephropathies; Heart Failure; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Naphthyridines; Receptors, Mineralocorticoid
PubMed: 38127122
DOI: 10.1007/s00125-023-06031-1 -
Hormone Research in Paediatrics 2018Disorders of adrenal steroidogenesis comprise autosomal recessive conditions affecting steroidogenic enzymes of the adrenal cortex. Those are located within the 3 major... (Review)
Review
Disorders of adrenal steroidogenesis comprise autosomal recessive conditions affecting steroidogenic enzymes of the adrenal cortex. Those are located within the 3 major branches of the steroidogenic machinery involved in the production of mineralocorticoids, glucocorticoids, and androgens. This mini review describes the principles of adrenal steroidogenesis, including the newly appreciated 11-oxygenated androgen pathway. This is followed by a description of pathophysiology, biochemistry, and clinical implications of steroidogenic disorders, including mutations affecting cholesterol import and steroid synthesis, the latter comprising both mutations affecting steroidogenic enzymes and co-factors required for efficient catalysis. A good understanding of adrenal steroidogenic pathways and their regulation is crucial as the basis for sound management of these disorders, which in the majority present in early childhood.
Topics: Adrenal Gland Diseases; Androgens; Cholesterol; Genetic Diseases, Inborn; Glucocorticoids; Humans; Mineralocorticoids; Mutation
PubMed: 29874650
DOI: 10.1159/000488034 -
Journal of Veterinary Internal Medicine Jul 2021Desoxycorticosterone pivalate (DOCP) is a commonly used mineralocorticoid replacement for dogs with primary hypoadrenocorticism (HA), but manufacturer-recommended dosing...
BACKGROUND
Desoxycorticosterone pivalate (DOCP) is a commonly used mineralocorticoid replacement for dogs with primary hypoadrenocorticism (HA), but manufacturer-recommended dosing protocols can be cost-prohibitive. Recent reports also have raised concerns that label dose protocols could be excessive.
OBJECTIVE
To investigate the relative efficacy and adverse effects of 2 DOCP dosages in dogs with primary glucocorticoid and mineralocorticoid deficient HA.
ANIMALS
Thirty-seven dogs, including 19 test population dogs and 18 controls.
METHODS
Randomized controlled double-blinded clinical trial. Dogs with newly diagnosed primary HA were assigned to standard (2.2 mg/kg q30d, control population) or low-dose (1.1 mg/kg q30d, test population) DOCP treatment. Clinical and laboratory variables were assessed 10 to 14 days and approximately 30 days after each DOCP treatment for 90 days.
RESULTS
Mean serum sodium to potassium ratios at reevaluations were ≥32 in both populations throughout the study. No dog developed electrolyte abnormalities warranting medical treatment, although hypokalemia occurred on at least 1 occasion in 9 controls and 6 test population dogs. Urine specific gravities (median, interquartile range) were lower in control dogs (1.022, 1.016-1.029) as compared to test population dogs (1.033, 1.023-1.039; P = .006). Plasma renin activity was overly suppressed on 84 of 104 (80.8%) assessments in control dogs whereas increased renin activity occurred on 23 of 112 (20.5%) assessments in test population dogs.
CONCLUSIONS AND CLINICAL IMPORTANCE
Low-dose DOCP protocols appear to be safe and effective for treatment of HA in most dogs. Standard-dose protocols are more likely to result in biochemical evidence of overtreatment.
Topics: Adrenal Insufficiency; Animals; Desoxycorticosterone; Dog Diseases; Dogs; Mineralocorticoids
PubMed: 34114259
DOI: 10.1111/jvim.16195 -
American Journal of Physiology.... Feb 202021-Hydroxylase deficiency (21OHD) is a rare genetic disorder in which salt-wasting syndrome occurs in 75% of cases, due to inability to synthesize cortisol and...
21-Hydroxylase deficiency (21OHD) is a rare genetic disorder in which salt-wasting syndrome occurs in 75% of cases, due to inability to synthesize cortisol and aldosterone. Recent mass spectrometry progress allowed identification of 21-deoxysteroids, i.e., 17-hydroxyprogesterone (17OHP), 21-deoxycortisol (21DF), and 21-deoxycorticosterone (21DB). We hypothesized that they may interfere with mineralocorticoid signaling and fludrocortisone therapy in patients with congenital adrenal hyperplasia (CAH) without effective glucocorticoid replacement and ACTH suppression. Our goal was to quantify circulating 21-deoxysteroids in a pediatric cohort with CAH related to 21OHD and to examine their impact on mineralocorticoid receptor (MR) activation. Twenty-nine patients with salt-wasting phenotype were classified in two groups according to their therapeutic control. During routine follow-up, 17OHP, 21DF, 21DB, and cortisol levels were quantified by liquid chromatography with tandem mass spectrometry before hydrocortisone intake and 1 and 2.5 h following treatment administration. Luciferase reporter gene assays were performed on transfected HEK293T cells while in silico modeling examined structural interactions between these steroids within ligand-binding domain of MR. Plasma 17OHP, 21DF, and 21DB accumulate in uncontrolled patients reaching micromolar concentrations even after hydrocortisone intake. 21DF and 21DB act as partial MR agonists with antagonist features similar to 17OHP, consistent with altered anchoring to Asn and unfavorable contact with Ala in ligand-binding pocket of MR. Our results demonstrate a complex interaction between all accumulating 21-deoxysteroids in uncontrolled 21OHD patients and mineralocorticoid signaling and suggest that appropriate steroid profiling should optimize management and follow-up of such patients, as keeping those steroids to low plasma levels should attest therapeutic efficacy and prevent interference with MR signaling.
Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adrenal Hyperplasia, Congenital; Child; Child, Preschool; Cohort Studies; Cortodoxone; Female; HEK293 Cells; Humans; Hydrocortisone; Infant; Male; Mineralocorticoids; Molecular Docking Simulation; Receptors, Mineralocorticoid; Signal Transduction; Steroids; Young Adult
PubMed: 31821037
DOI: 10.1152/ajpendo.00368.2019 -
Journal of Molecular Endocrinology Jan 2017Corticosteroids influence the development and function of the heart and its response to injury and pressure overload via actions on glucocorticoid (GR) and... (Review)
Review
Corticosteroids influence the development and function of the heart and its response to injury and pressure overload via actions on glucocorticoid (GR) and mineralocorticoid (MR) receptors. Systemic corticosteroid concentration depends largely on the activity of the hypothalamic-pituitary-adrenal (HPA) axis, but glucocorticoid can also be regenerated from intrinsically inert metabolites by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), selectively increasing glucocorticoid levels within cells and tissues. Extensive studies have revealed the roles for glucocorticoid regeneration by 11β-HSD1 in liver, adipose, brain and other tissues, but until recently, there has been little focus on the heart. This article reviews the evidence for glucocorticoid metabolism by 11β-HSD1 in the heart and for a role of 11β-HSD1 activity in determining the myocardial growth and physiological function. We also consider the potential of 11β-HSD1 as a therapeutic target to enhance repair after myocardial infarction and to prevent the development of cardiac remodelling and heart failure.
Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Disease Susceptibility; Glucocorticoids; Heart; Heart Diseases; Humans; Intracellular Space; Isoenzymes; Mineralocorticoids; Myocardium
PubMed: 27553202
DOI: 10.1530/JME-16-0128 -
Annals of Translational Medicine Jun 2022Critical illness-related corticosteroid insufficiency (CIRCI) describes hypothalamic-pituitary-axis impairment during critical illness associated with three major... (Review)
Review
BACKGROUND AND OBJECTIVE
Critical illness-related corticosteroid insufficiency (CIRCI) describes hypothalamic-pituitary-axis impairment during critical illness associated with three major pathophysiological events; dysregulation of the hypothalamic-pituitary-axis, altered cortisol metabolism, and tissue corticosteroid resistance. Similar changes are evident with regard to mineralocorticoid dysfunction in critical illness. Hyperreninemic hypoaldosteronism describes a sub-population of critically ill patients with an impaired adrenal aldosterone response to increased levels of renin. In the light of the recent demonstration of significant mortality improvements associated with adjunctive glucocorticoid treatment in combination with fludrocortisone in septic shock, and the suggestion that angiotensin II is effective in treating vasodilatory shock, the clinical relevance of mineralocorticoid dysfunction in critical illness requires further exploration. This interpretative review considers hyperreninemic hypoaldosteronism, a concept worth re-examining in the light of the potential mortality benefit of mineralocorticoid supplementation in critical illness. We compare the pathophysiological and clinical characteristics of CIRCI and hyperreninemic hypoaldosteronism, two syndromes that represent corticosteroid and mineralocorticoid dysfunction in critical illness. We highlight gaps in the literature and give novel insights into the limitations of assessment, diagnosis and treatment.
METHODS
English language abstracts and articles published before June 2021 were identified through PubMed and Google Scholar. Randomized trials, observational studies, basic sciences studies, systematic and narrative reviews were considered. Reference lists of articles were searched for further relevant material.
KEY CONTENT AND FINDINGS
Difficulties are encountered in interpreting measures of gluco- and mineralo-corticoid activity in critical illness. Aldosterone levels, like cortisol, have been shown to be increased in sepsis and hemorrhagic shock. The finding of hyperreninemia and hyperaldosteronism with an aldosterone/plasma renin activity ratio below 2 should prompt consideration of hyperreninemic hypoaldosteronism, a finding, which likely signifies the loss of negative feedback control of the renin-angiotensin-aldosterone system.
CONCLUSIONS
As there is evidence to suggest that in acute critical illness, hyperreninemic hypoaldosteronism, is associated with poor outcomes, co-administration of hydrocortisone with fludrocortisone in patients with septic shock should be considered. In keeping with the concept of CIRCI, we suggest the term critical illness-related mineralocorticoid insufficiency as a more appropriate description of the impaired aldosterone response to increased levels of renin seen in this group of patients.
PubMed: 35813323
DOI: 10.21037/atm-21-5572 -
Anesthesiology Aug 2020The recent demonstration of the significant reduction in mortality in patients with septic shock treated with adjunctive glucocorticoids combined with fludrocortisone... (Review)
Review
The recent demonstration of the significant reduction in mortality in patients with septic shock treated with adjunctive glucocorticoids combined with fludrocortisone and the effectiveness of angiotensin II in treating vasodilatory shock have renewed interest in the role of the mineralocorticoid axis in critical illness. Glucocorticoids have variable interactions at the mineralocorticoid receptor. Similarly, mineralocorticoid receptor-aldosterone interactions differ from mineralocorticoid receptor-glucocorticoid interactions and predicate receptor-ligand interactions that differ with respect to cellular effects. Hyperreninemic hypoaldosteronism or selective hypoaldosteronism, an impaired adrenal response to increasing renin levels, occurs in a subgroup of hemodynamically unstable critically ill patients. The suggestion is that there is a defect at the level of the adrenal zona glomerulosa associated with a high mortality rate that may represent an adaptive response aimed at increasing cortisol levels. Furthermore, cross-talk exists between angiotensin II and aldosterone, which needs to be considered when employing therapeutic strategies.
Topics: Aldosterone; Clinical Trials as Topic; Critical Illness; Glucocorticoids; Humans; Hypoaldosteronism; Mineralocorticoids
PubMed: 32501957
DOI: 10.1097/ALN.0000000000003365 -
Kidney International Dec 1992(1) Decreased 11 beta-OHSD activity permits binding of cortisol to the Type I (mineralocorticoid) receptor in humans, thereby producing spironolactone-inhibitable Na+...
(1) Decreased 11 beta-OHSD activity permits binding of cortisol to the Type I (mineralocorticoid) receptor in humans, thereby producing spironolactone-inhibitable Na+ retention, hypokalemia and hypertension, the syndrome of apparent mineralocorticoid excess (AME). (2) Blockade of either the Type I receptor with spironolactone or the Type II (glucocorticoid) receptor with RU-486 does not consistently abolish the effects of stress level cortisol on Na+ retention and hypertension in acute studies in normal humans, suggesting the existence of an additional glucocorticoid receptor. (3) Enhanced glucocorticoid 6 beta-hydroxylation could play an etiologic role in certain hypertensive syndromes. (4) Both decreased 11 beta-OHSD and increased 6 beta-OHase are candidates as intermediate phenotypes for the remote phenotype essential hypertension.
Topics: 11-beta-Hydroxysteroid Dehydrogenases; Animals; Glucocorticoids; Humans; Hydrocortisone; Hydroxysteroid Dehydrogenases; Hypertension; Mineralocorticoids; Receptors, Glucocorticoid
PubMed: 1474763
DOI: 10.1038/ki.1992.421 -
International Journal of Molecular... Jan 2024Diabetic Kidney Disease (DKD) is a significant complication of diabetes and primary cause of end-stage renal disease globally. The exact mechanisms underlying DKD remain... (Review)
Review
Diabetic Kidney Disease (DKD) is a significant complication of diabetes and primary cause of end-stage renal disease globally. The exact mechanisms underlying DKD remain poorly understood, but multiple factors, including the renin-angiotensin-aldosterone system (RAAS), play a key role in its progression. Aldosterone, a mineralocorticoid steroid hormone, is one of the key components of RAAS and a potential mediator of renal damage and inflammation in DKD. miRNAs, small noncoding RNA molecules, have attracted interest due to their regulatory roles in numerous biological processes. These processes include aldosterone signaling and mineralocorticoid receptor (MR) expression. Numerous miRNAs have been recognized as crucial regulators of aldosterone signaling and MR expression. These miRNAs affect different aspects of the RAAS pathway and subsequent molecular processes, which impact sodium balance, ion transport, and fibrosis regulation. This review investigates the regulatory roles of particular miRNAs in modulating aldosterone signaling and MR activation, focusing on their impact on kidney injury, inflammation, and fibrosis. Understanding the complex interaction between miRNAs and the RAAS could lead to a new strategy to target aldosterone signaling and MR activation using miRNAs. This highlights the potential of miRNA-based interventions for DKD, with the aim of enhancing kidney outcomes in individuals with diabetes.
Topics: Humans; Aldosterone; Diabetic Nephropathies; Fibrosis; Inflammation; MicroRNAs; Mineralocorticoids; Receptors, Mineralocorticoid
PubMed: 38255942
DOI: 10.3390/ijms25020869