-
Acta Pharmacologica Sinica Jun 2023Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, and lacks effective treatment. The aberration of WNT pathway underlies many pathological...
Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, and lacks effective treatment. The aberration of WNT pathway underlies many pathological processes including cardiac fibrosis and hypertrophy, while porcupine is an acyltransferase essential for the secretion of WNT ligands. In this study we investigated the role of WNT signaling pathway in HFpEF as well as whether blocking WNT signaling by a novel porcupine inhibitor CGX1321 alleviated HFpEF. We established two experimental HFpEF mouse models, namely the UNX/DOCA model and high fat diet/L-NAME ("two-hit") model. The UNX/DOCA and "two-hit" mice were treated with CGX1321 (3 mg·kg·d) for 4 and 10 weeks, respectively. We showed that CGX1321 treatment significantly alleviated cardiac hypertrophy and fibrosis, thereby improving cardiac diastolic function and exercise performance in both models. Furthermore, both canonical and non-canonical WNT signaling pathways were activated, and most WNT proteins, especially WNT3a and WNT5a, were upregulated during the development of HEpEF in mice. CGX1321 treatment inhibited the secretion of WNT ligands and repressed both canonical and non-canonical WNT pathways, evidenced by the reduced phosphorylation of c-Jun and the nuclear translocation of β-catenin and NFATc3. In an in vitro HFpEF model, MCM and ISO-treated cardiomyocytes, knockdown of porcupine by siRNA leads to a similar inhibitory effect on WNT pathways, cardiomyocyte hypertrophy and cardiac fibroblast activation as CGX1321 did, whereas supplementation of WNT3a and WNT5a reversed the anti-hypertrophy and anti-fibrosis effect of CGX1321. We conclude that WNT signaling activation plays an essential role in the pathogenesis of HFpEF, and porcupine inhibitor CGX1321 exerts a therapeutic effect on HFpEF in mice by attenuating cardiac hypertrophy, alleviating cardiac fibrosis and improving cardiac diastolic function.
Topics: Animals; Mice; Cardiomegaly; Cardiomyopathies; Desoxycorticosterone Acetate; Fibrosis; Heart Failure; Myocytes, Cardiac; Stroke Volume; Wnt Signaling Pathway
PubMed: 36473990
DOI: 10.1038/s41401-022-01025-y -
Hypertension Research : Official... Feb 2023
Topics: Mineralocorticoid Receptor Antagonists; Antihypertensive Agents; Pyrroles; Sulfones; Receptors, Mineralocorticoid
PubMed: 36289363
DOI: 10.1038/s41440-022-01056-2 -
British Journal of Pharmacology Jul 2022Mineralocorticoid receptor antagonists (MRAs) are highly effective therapies for cardiovascular and renal disease. However, the widespread clinical use of currently... (Review)
Review
Mineralocorticoid receptor antagonists (MRAs) are highly effective therapies for cardiovascular and renal disease. However, the widespread clinical use of currently available MRAs in cardiorenal medicine is hampered by an increased risk of hyperkalaemia. The mineralocorticoid receptor (MR) is a nuclear receptor responsible for fluid and electrolyte homeostasis in epithelial tissues, whereas pathophysiological MR activation in nonepithelial tissues leads to undesirable pro-inflammatory and profibrotic effects. Therefore, new strategies that selectively target the deleterious effects of the MR but spare its physiological function are needed. In this review, we discuss recent pharmacological developments starting from novel non-steroidal MRAs, such as finerenone or esaxerenone, that are now entering clinical use, to concepts arising from the current knowledge of the MR signalling pathway, aiming at receptor-coregulator interaction, epigenetics or downstream effectors of the MR. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.
Topics: Aldosterone; Humans; Kidney Diseases; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid
PubMed: 34698367
DOI: 10.1111/bph.15719 -
JACC. Heart Failure Apr 2021
Topics: Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume
PubMed: 33714742
DOI: 10.1016/j.jchf.2020.12.009 -
American Journal of Physiology. Renal... Apr 2021Serum and glucocorticoid-regulated kinase 1 (SGK1) stimulates aldosterone-dependent renal Na reabsorption and modulates blood pressure. In addition, genetic ablation or...
Serum and glucocorticoid-regulated kinase 1 (SGK1) stimulates aldosterone-dependent renal Na reabsorption and modulates blood pressure. In addition, genetic ablation or pharmacological inhibition of SGK1 limits the development of kidney inflammation and fibrosis in response to excess mineralocorticoid signaling. In this work, we tested the hypothesis that a systemic increase in SGK1 activity would potentiate mineralocorticoid/salt-induced hypertension and kidney injury. To that end, we used a transgenic mouse model with increased SGK1 activity. Mineralocorticoid/salt-induced hypertension and kidney damage was induced by unilateral nephrectomy and treatment with deoxycorticosterone acetate and NaCl in the drinking water for 6 wk. Our results show that although SGK1 activation did not induce significantly higher blood pressure, it produced a mild increase in glomerular filtration rate, increased albuminuria, and exacerbated glomerular hypertrophy and fibrosis. Transcriptomic analysis showed that extracellular matrix- and immune response-related terms were enriched in the downregulated and upregulated genes, respectively, in transgenic mice. In conclusion, we propose that systemically increased SGK1 activity is a risk factor for the development of mineralocorticoid-dependent kidney injury in the context of low renal mass and independently of blood pressure. Increased activity of the protein kinase serum and glucocorticoid-regulated kinase 1 may be a risk factor for accelerated renal damage. Serum and glucocorticoid-regulated kinase 1 expression could be a marker for the rapid progression toward chronic kidney disease and a potential therapeutic target to slow down the process.
Topics: Acute Kidney Injury; Animals; Blood Pressure; Fibrosis; Immediate-Early Proteins; Mice; Mineralocorticoids; Protein Serine-Threonine Kinases; Signal Transduction; Sodium Chloride; Sodium Chloride, Dietary
PubMed: 33586495
DOI: 10.1152/ajprenal.00505.2020 -
Kidney International Mar 2023Hypertension (HT) is a major cardiovascular risk factor that affects 10% to 40% of the general population in an age-dependent manner. Detection of secondary forms of HT... (Review)
Review
Hypertension (HT) is a major cardiovascular risk factor that affects 10% to 40% of the general population in an age-dependent manner. Detection of secondary forms of HT is particularly important because it allows the targeted management of the underlying disease. Among hypertensive patients, the prevalence of endocrine HT reaches up to 10%. Adrenal diseases are the most frequent cause of endocrine HT and are associated with excess production of mineralocorticoids (mainly primary aldosteronism), glucocorticoids (Cushing syndrome), and catecholamines (pheochromocytoma). In addition, a few rare diseases directly affecting the action of mineralocorticoids and glucocorticoids in the kidney also lead to endocrine HT. Over the past years, genomic and genetic studies have allowed improving our knowledge on the molecular mechanisms of endocrine HT. Those discoveries have opened new opportunities to transfer knowledge to clinical practice for better diagnosis and specific treatment of affected subjects. In this review, we describe the physiology of adrenal hormone biosynthesis and action, the clinical and biochemical characteristics of different forms of endocrine HT, and their underlying genetic defects. We discuss the impact of these discoveries on diagnosis and management of patients, as well as new perspectives related to the use of new biomarkers for improved patient care.
Topics: Humans; Glucocorticoids; Mineralocorticoids; Hyperaldosteronism; Hypertension; Adrenal Gland Neoplasms; Biomarkers
PubMed: 36646167
DOI: 10.1016/j.kint.2022.12.021 -
Endocrinology Nov 2021Mineralocorticoid receptor (MR) antagonists (MRA), also referred to as aldosterone blockers, are now well-recognized for their clinical benefit in patients who have... (Review)
Review
Mineralocorticoid receptor (MR) antagonists (MRA), also referred to as aldosterone blockers, are now well-recognized for their clinical benefit in patients who have heart failure (HF) with reduced ejection fraction (HFrEF). Recent studies have also shown MRA can improve outcomes in patients with HFpEF, where the ejection fraction is preserved but left ventricular filling is reduced. While the MR is a steroid hormone receptor best known for antinatriuretic actions on electrolyte homeostasis in the distal nephron, it is now established that the MR has many physiological and pathophysiological roles in the heart, vasculature, and other nonepithelial tissue types. It is the impact of MR activation on these tissues that underpins the use of MRA in cardiovascular disease, in particular HF. This mini-review will discuss the origins and the development of MRA and highlight how their use has evolved from the "potassium-sparing diuretics" spironolactone and canrenone over 60 years ago, to the more receptor-selective eplerenone and most recently the emergence of new nonsteroidal receptor antagonists esaxerenone and finerenone.
Topics: Animals; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Molecular Targeted Therapy; Receptors, Mineralocorticoid; Spironolactone; Stroke Volume
PubMed: 34050730
DOI: 10.1210/endocr/bqab105 -
Essays in Biochemistry Dec 2021Mineralocorticoid receptors (MRs) are transcriptional regulators that mediate the diverse physiological and pathophysiological actions of corticosteroid hormones across... (Review)
Review
Mineralocorticoid receptors (MRs) are transcriptional regulators that mediate the diverse physiological and pathophysiological actions of corticosteroid hormones across many tissues. In the kidney aldosterone control of sodium/water resorption via DNA-binding actions of the MR is established. MRs also regulate tissues not involved in electrolyte homeostasis such as the heart, adipose tissue, brain, and inflammatory cells where the MRs can respond to both aldosterone and cortisol. The pathology of inappropriate MR activation in non-epithelial tissues are well-described, and steroidal antagonists of the MR have been clinically beneficial in the management of heart failure and blood pressure for decades. However, the role of cortisol-dependent MR activation in the physiological setting is less well defined. Like other steroid hormone receptors, the MR also regulates non-DNA-binding pathways including MAPK pathways and G protein coupled receptors to provide diversity to MR signaling. Whether nonDNA binding pathways are more relevant for MR activation in non-epithelial, versus epithelial, tissues remain unclear. This review will focus on molecular regulation of ligand-dependent MR activation and the physiology and pathophysiology of MR actions in the heart with a focus on the cardiomyocyte and provide a discussion of relevant genomic and non-genomic MR pathways and potential new transcriptional partners for the MR and their relevance for health and disease. Understanding MR actions in the heart will provide new insights into cell-selective mechanisms that underpin the therapeutic benefits of MRAs, and are a critical step towards developing next-generation tissue selective MR modulators with improved safety profiles.
Topics: Aldosterone; Myocytes, Cardiac; Receptors, G-Protein-Coupled; Receptors, Mineralocorticoid; Signal Transduction
PubMed: 34414409
DOI: 10.1042/EBC20210006 -
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 -
Molecular and Cellular Endocrinology Mar 2021The syndromes of mineralocorticoid excess describe a heterogeneous group of clinical manifestations leading to endocrine hypertension, typically either through direct... (Review)
Review
The syndromes of mineralocorticoid excess describe a heterogeneous group of clinical manifestations leading to endocrine hypertension, typically either through direct activation of mineralocorticoid receptors or indirectly by impaired pre-receptor enzymatic regulation or through disturbed renal sodium homeostasis. The phenotypes of these disorders can be caused by inherited gene variants and somatic mutations or may be acquired upon exposures to exogenous substances. Regarding the latter, the symptoms of an acquired mineralocorticoid excess have been reported during treatment with azole antifungal drugs. The current review describes the occurrence of mineralocorticoid excess particularly during the therapy with posaconazole and itraconazole, addresses the underlying mechanisms as well as inter- and intra-individual differences, and proposes a therapeutic drug monitoring strategy for these two azole antifungals. Moreover, other therapeutically used azole antifungals and ongoing efforts to avoid adverse mineralocorticoid effects of azole compounds are shortly discussed.
Topics: Animals; Antifungal Agents; Azoles; Drug Monitoring; Humans; Mineralocorticoids; Syndrome
PubMed: 33484741
DOI: 10.1016/j.mce.2021.111168