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The Journal of Steroid Biochemistry and... Jun 2023The search for mineralocorticoids to explain some cases of low renin hypertension with suppressed aldosterone levels led to the isolation of the abundant steroid...
The search for mineralocorticoids to explain some cases of low renin hypertension with suppressed aldosterone levels led to the isolation of the abundant steroid 18-hydroxycortisol in human urine. 18-Hydroxycortisol proved to be inactive, but because of its similarity to precursors for the synthesis of aldosterone, bullfrog adrenals were incubated with cortisol, resulting in the discovery of 18-oxocortisol which is structurally similar to aldosterone, but with a 17α-hydroxy group like cortisol. 18-Oxocortisol is a weak mineralocorticoid. Its synthesis occurs primarily in the zona glomerulosa where co-expression of the CYP11B2 (aldosterone synthase) and the CYP17A1 (17α-hydroxylase) occurs in a variable number of cells. The clinical value of the measurement of 18-oxocortisol is that it serves to distinguish subtypes of primary aldosteronism. It is significantly elevated in patients with aldosterone-producing adenomas in comparison to those with idiopathic bilateral hyperaldosteronism and helps predict the type of somatic mutation in the aldosterone-producing adenomas, as it is higher in those with KCNJ5 mutations compared to other gene mutations.
Topics: Humans; Hydrocortisone; Aldosterone; Hyperaldosteronism; Mineralocorticoids; Cytochrome P-450 CYP11B2; Adenoma; G Protein-Coupled Inwardly-Rectifying Potassium Channels
PubMed: 36921907
DOI: 10.1016/j.jsbmb.2023.106291 -
American Journal of Physiology.... Jun 2023Approximately 30%-40% of patients with type 1 or type 2 diabetes (T1D/T2D) develop diabetic kidney disease (DKD), which can lead to end-stage kidney disease (ESKD).... (Review)
Review
Approximately 30%-40% of patients with type 1 or type 2 diabetes (T1D/T2D) develop diabetic kidney disease (DKD), which can lead to end-stage kidney disease (ESKD). Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been investigated as treatments for DKD. However, these drugs do not prevent overactivation of the mineralocorticoid receptor (MR). Studies have shown a correlation between MR hyperactivation, renal injury, and DKD. Finerenone, a novel and selective nonsteroidal mineralocorticoid receptor antagonist (NS-MRA), was approved for the treatment of patients with DKD, and is associated with lower rates of hyperkalemia. Other NS-MRAs (such as KBP-5074, BR-4628, esaxerenone, and apararenone) may also be effective drugs for the treatment of DKD. This review summarizes the effects of pharmacological MR blockade on diabetes and diabetes-associated CKD, with a particular focus on the therapeutic mechanisms of NS-MRAs in preclinical studies and ongoing clinical studies. Further investigation of combined treatment with renoprotective drugs and NS-MRAs to improve the treatment of DKD is needed.
Topics: Humans; Mineralocorticoid Receptor Antagonists; Diabetic Nephropathies; Diabetes Mellitus, Type 2; Kidney; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic
PubMed: 37166263
DOI: 10.1152/ajpendo.00022.2023 -
Annual Review of Medicine Jan 2023Primary aldosteronism (PA) is the most common cause of secondary hypertension but is frequently underrecognized and undertreated. Patients with PA are at a markedly... (Review)
Review
Primary aldosteronism (PA) is the most common cause of secondary hypertension but is frequently underrecognized and undertreated. Patients with PA are at a markedly increased risk for target organ damage to the heart and kidneys. While patients with unilateral PA can be treated surgically, many patients with PA are not eligible or willing to undergo surgery. Steroidal mineralocorticoid receptor antagonists (MRAs) are highly effective for treating PA and reducing the risk of target organ damage. However, steroidal MRAs are often underprescribed and can be poorly tolerated by some patients due to side effects. Nonsteroidal MRAs reduce adverse renal and cardiovascular outcomes among patients with diabetic kidney disease and are bettertolerated than steroidal MRAs. While their blood pressure-lowering effects remain unclear, these agents may have a potential role in reducing target organ damage in patients with PA.
Topics: Humans; Mineralocorticoid Receptor Antagonists; Hyperaldosteronism; Kidney; Hypertension; Blood Pressure
PubMed: 36375469
DOI: 10.1146/annurev-med-042921-100438 -
Journal of the American Heart... Apr 2024Aldosterone is a steroid hormone that primarily acts through activation of the mineralocorticoid receptor (MR), a nuclear receptor responsible for downstream genomic... (Review)
Review
Aldosterone is a steroid hormone that primarily acts through activation of the mineralocorticoid receptor (MR), a nuclear receptor responsible for downstream genomic regulation. Classically, activation of the MR in the renal tubular epithelium is responsible for sodium retention and volume expansion, raising systemic blood pressure. However, activation of the MR across a wide distribution of tissue types has been implicated in multiple adverse consequences for cardiovascular, cerebrovascular, renal, and metabolic disease, independent of blood pressure alone. Primary aldosteronism, heart failure, and chronic kidney disease are states of excessive aldosterone production and MR activity where targeting MR activation has had clinical benefits out of proportion to blood pressure lowering. The growing list of established and emerging therapies that target aldosterone and MR activation may provide new opportunities to improve clinical outcomes and enhance cardiovascular and renal health.
Topics: Humans; Aldosterone; Blood Pressure; Hyperaldosteronism; Receptors, Mineralocorticoid; Heart; Kidney; Mineralocorticoid Receptor Antagonists; Drug-Related Side Effects and Adverse Reactions; Hypertension
PubMed: 38497438
DOI: 10.1161/JAHA.123.030142 -
Biomolecules Jun 2023The renin angiotensin aldosterone system is a key regulator of blood pressure. Aldosterone is the final effector of this pathway, acting predominantly via... (Review)
Review
The renin angiotensin aldosterone system is a key regulator of blood pressure. Aldosterone is the final effector of this pathway, acting predominantly via mineralocorticoid receptors. Aldosterone facilitates the conservation of sodium and, with it, water and acts as a powerful stimulus for potassium excretion. However, evidence for the pathological impact of excess mineralocorticoid receptor stimulation is increasing. Here, we discussed how in the heart, hyperaldosteronism is associated with fibrosis, cardiac dysfunction, and maladaptive hypertrophy. In the kidney, aldosterone was shown to cause proteinuria and fibrosis and may contribute to the progression of kidney disease. More recently, studies suggested that aldosterone excess damaged endothelial cells. Here, we reviewed how damage to the endothelial glycocalyx may contribute to this process. The endothelial glycocalyx is a heterogenous, negatively charged layer on the luminal surface of cells. Aldosterone exposure alters this layer. The resulting structural changes reduced endothelial reactivity in response to protective shear stress, altered permeability, and increased immune cell trafficking. Finally, we reviewed current therapeutic strategies for limiting endothelial damage and suggested that preventing glycocalyx remodelling in response to aldosterone exposure may provide a novel strategy, free from the serious adverse effect of hyperkalaemia seen in response to mineralocorticoid blockade.
Topics: Humans; Aldosterone; Endothelium, Vascular; Endothelial Cells; Mineralocorticoid Receptor Antagonists; Fibrosis
PubMed: 37371584
DOI: 10.3390/biom13061004 -
International Journal of Molecular... May 2021Sexual dimorphism involves differences between biological sexes that go beyond sexual characteristics. In mammals, differences between sexes have been demonstrated... (Review)
Review
Sexual dimorphism involves differences between biological sexes that go beyond sexual characteristics. In mammals, differences between sexes have been demonstrated regarding various biological processes, including blood pressure and predisposition to develop hypertension early in adulthood, which may rely on early events during development and in the neonatal period. Recent studies suggest that corticosteroid signaling pathways (comprising glucocorticoid and mineralocorticoid signaling pathways) have distinct tissue-specific expression and regulation during this specific temporal window in a sex-dependent manner, most notably in the kidney. This review outlines the evidence for a gender differential expression and activation of renal corticosteroid signaling pathways in the mammalian fetus and neonate, from mouse to human, that may favor mineralocorticoid signaling in females and glucocorticoid signaling in males. Determining the effects of such differences may shed light on short term and long term pathophysiological consequences, markedly for males.
Topics: Adrenal Cortex Hormones; Aldosterone; Animals; Blood Pressure; Gene Expression Regulation, Developmental; Glucocorticoids; Humans; Hypertension; Kidney; Mineralocorticoids; Organogenesis; Receptors, Glucocorticoid; Receptors, Mineralocorticoid; Sex Characteristics; Signal Transduction
PubMed: 34069759
DOI: 10.3390/ijms22105275 -
Journal of Lipid Research Nov 2023Activation of brown adipose tissue (BAT) contributes to energy dissipation and metabolic health. Although mineralocorticoid receptor (MR) antagonists have been...
Activation of brown adipose tissue (BAT) contributes to energy dissipation and metabolic health. Although mineralocorticoid receptor (MR) antagonists have been demonstrated to improve metabolism under obesity, the underlying mechanisms remain incompletely understood. We aimed to evaluate the role of BAT MR in metabolic regulation. After 8 weeks of high-fat diet (HFD) feeding, BAT MR KO (BMRKO) mice manifested significantly increased bodyweight, fat mass, serum fasting glucose, and impaired glucose homeostasis compared with littermate control (LC) mice, although insulin resistance and fasting serum insulin were not significantly changed. Metabolic cage experiments showed no change in O consumption, CO production, or energy expenditure in obese BMRKO mice. RNA sequencing analysis revealed downregulation of genes related to fatty acid metabolism in BAT of BMRKO-HFD mice compared with LC-HFD mice. Moreover, H&E and immunohistochemical staining demonstrated that BMRKO exacerbated HFD-induced macrophage infiltration and proinflammatory genes in epididymal white adipose tissue (eWAT). BMRKO-HFD mice also manifested significantly increased liver weights and hepatic lipid accumulation, an increasing trend of genes related to lipogenesis and lipid uptake, and significantly decreased genes related to lipolytic and fatty acid oxidation in the liver. Finally, the level of insulin-induced AKT phosphorylation was substantially blunted in eWAT but not liver or skeletal muscle of BMRKO-HFD mice compared with LC-HFD mice. These data suggest that BAT MR is required to maintain metabolic homeostasis, likely through its regulation of fatty acid metabolism in BAT and impacts on eWAT and liver.
Topics: Animals; Mice; Adipocytes, Brown; Adipose Tissue, Brown; Diet, High-Fat; Fatty Acids; Glucose; Insulin; Insulin Resistance; Lipids; Mice, Inbred C57BL; Mice, Obese; Receptors, Mineralocorticoid; Energy Metabolism
PubMed: 37734559
DOI: 10.1016/j.jlr.2023.100449 -
Clinical Journal of the American... Jun 2021
Topics: Glomerular Filtration Rate; Humans; Mineralocorticoid Receptor Antagonists; Renal Insufficiency; Stroke Volume
PubMed: 34117077
DOI: 10.2215/CJN.04460421 -
Endocrinology and Metabolism (Seoul,... Dec 2019Primary aldosteronism (PA) results from excess production of mineralocorticoid hormone aldosterone by the adrenal cortex. It is normally caused either by unilateral... (Review)
Review
Primary aldosteronism (PA) results from excess production of mineralocorticoid hormone aldosterone by the adrenal cortex. It is normally caused either by unilateral aldosterone-producing adenoma (APA) or by bilateral aldosterone excess as a result of bilateral adrenal hyperplasia. PA is the most common cause of secondary hypertension and associated morbidity and mortality. While most cases of PA are sporadic, an important insight into this debilitating disease has been derived through investigating the familial forms of the disease that affect only a minor fraction of PA patients. The advent of gene expression profiling has shed light on the genes and intracellular signaling pathways that may play a role in the pathogenesis of these tumors. The genetic basis for several forms of familial PA has been uncovered in recent years although the list is likely to expand. Recently, the work from several laboratories provided evidence for the involvement of mammalian target of rapamycin pathway and inflammatory cytokines in APAs; however, their mechanism of action in tumor development and pathophysiology remains to be understood.
Topics: Aldosterone; Animals; Humans; Hyperaldosteronism; Inflammation Mediators; TOR Serine-Threonine Kinases
PubMed: 31884735
DOI: 10.3803/EnM.2019.34.4.355 -
Cardiovascular Endocrinology &... Sep 2023This review examines the role of mineralocorticoid receptor antagonists (MRAs) in cardiovascular biology and the molecular mechanisms involved in mineralocorticoid... (Review)
Review
This review examines the role of mineralocorticoid receptor antagonists (MRAs) in cardiovascular biology and the molecular mechanisms involved in mineralocorticoid receptor antagonism. The data discussed suggest that MRAs can play an important role in decreasing the impact of inflammation and fibrosis on cardiorenal outcomes. Evidence derived from major randomized clinical trials demonstrates that steroidal MRAs reduce mortality in patients with heart failure and reduced ejection fraction. Initial positive findings observed in patients with chronic kidney disease and type 2 diabetes (T2D) indicate the possible mechanisms of action of nonsteroidal MRAs, and the clinical benefits for patients with cardiorenal disease and T2D. This article supports the application of basic science concepts to expand our understanding of the molecular mechanisms of action involved in pathophysiology. This approach encourages the development of treatment options before diseases clinically manifest. Video Abstract: http://links.lww.com/CAEN/A42.
PubMed: 37614245
DOI: 10.1097/XCE.0000000000000289