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mineralocorticoid receptor

Jonatan Barrera-Chimal, Gabriel R Estrela, Sebastian M Lechner, Sébastien Giraud, Soumaya El Moghrabi, Shiem Kaaki, Peter Kolkhof, Thierry Hauet, Frédéric Jaisser
Acute kidney injury induced by ischemia/reperfusion is an independent risk factor for chronic kidney disease. Macrophage recruitment plays an essential role during the injury and repair phases after an ischemic episode in the kidney. Here we show that the novel non-steroidal mineralocorticoid receptor antagonist finerenone or selective myeloid mineralocorticoid receptor ablation protects against subsequent chronic dysfunction and fibrosis induced by an episode of bilateral kidney ischemia/reperfusion in mice...
March 13, 2018: Kidney International
Frank Edelmann, Christoph Knosalla, Klaus Mörike, Christiane Muth, Peggy Prien, Stefan Störk
BACKGROUND: Chronic heart failure (CHF) is the most common reason for hospital admissions in Germany. For the National Disease Management Guideline (NDMG) on CHF, a multidisciplinary expert panel revised the chapters on drug therapy, invasive therapy, and care coordination, following the methods of evidence-based medicine. METHODS: Recommendations are based on international guideline adaptations or systematic literature search. They were developed by a multidisciplinary expert panel, approved in a formal consensus procedure, and tested in open consultation, as specified by the requirements for S3 guidelines...
February 23, 2018: Deutsches Ärzteblatt International
Milton Packer, Dalane W Kitzman
Obesity-related heart failure with a preserved ejection fraction (HFpEF) is an important phenotype prevalent in the community, especially in people with metabolic disorders (e.g., dyslipidemia, diabetes). These individuals exhibit a marked expansion of plasma volume, but ventricular distensibility is limited, most likely as a result of cardiac microvascular rarefaction acting in concert with myocardial and pericardial fibrosis. Consequently, the increase in plasma volume causes a disproportionate increase in cardiac filling pressures, leading to heart failure, even though systolic ejection is not impaired...
March 7, 2018: JACC. Heart Failure
Eric P Hoffman, Valerie Riddle, Maxime A Siegler, Daniel Dickerson, Miroslav Backonja, William G Kramer, Kanneboyina Nagaraju, Heather Gordish-Dressman, Jesse M Damsker, John M McCall
BACKGROUND: Glucocorticoid drugs are highly effective anti-inflammatory agents, but chronic use is associated with extensive pharmacodynamic safety concerns that have a considerable negative impact on patient quality of life. PURPOSE: Vamorolone (VBP15) is a first-in-class steroidal multi-functional drug that shows potent inhibition of pro-inflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor, high affinity antagonism for the mineralocorticoid receptor, and membrane stabilization properties...
March 7, 2018: Steroids
Anna Kurek, Katarzyna Głombik, Jan Detka, Agnieszka Basta-Kaim, Marta Kubera, Władysław Lasoń, Bogusława Budziszewska
Obesity is a disease that often co-occurs with depression, and some evidence indicates that chronic stress in the perinatal period, in association with overactive glucocorticoids, can cause permanent changes that increase the risk of the development of both depression and obesity later in life. However, the mechanism responsible for the overly potent action of glucocorticoids in both depression and obesity is not known. The aim of the present study was to determine the expression of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) and the factors that affect GR function (FKBP51, Bag-1 and HSP70) in a prenatal stress animal model of depression, a model of obesity and a model of both depression and obesity...
March 9, 2018: Journal of Neuroendocrinology
Søren Brandt Poulsen, Kavee Limbutara, Robert Andrew Fenton, Trairak Pisitkun, Birgitte M Christensen
The renal aldosterone-sensitive distal tubule (ASDT) is crucial for sodium reabsorption and blood pressure regulation. The ASDT consists of the late distal convoluted tubule (DCT2), connecting tubule (CNT) and collecting duct. Due to difficulties in isolating epithelial cells from the ASDT in large quantities, few transcriptome studies have been performed on this segment. Moreover, no studies exist on isolated DCT2 and CNT cells (excluding intercalated cells), and the role of aldosterone for regulating the transcriptome of these specific cell types is largely unknown...
March 9, 2018: Physiological Genomics
R De Vecchis, C Ariano, G Di Biase, M Noutsias
INTRODUCTION: In heart failure with reduced left ventricular ejection fraction (HFREF) patients, the dosage of sacubitril/valsartan is modulated according to a gradual increase regimen. Nevertheless, if patients exhibit tolerability problems, a provisional reduction of the dose of sacubitril/valsartan or even its interruption are recommended. MATERIAL AND METHODS: This study provides estimates of respective proportions of patients receiving minimum or intermediate doses of sacubitril/valsartan...
March 8, 2018: Herz
Chloe S Chaudhury, Julia B Purdy, Chia-Ying Liu, Caryn G Morse, Takara L Stanley, David Kleiner, Colleen Hadigan
BACKGROUND & AIMS: Nonalcoholic fatty liver disease is common in HIV, but there are no approved therapies. The aim of this open-label proof-of-concept study was to determine the effect of the mineralocorticoid receptor antagonist eplerenone on hepatic fat in HIV-infected patients with hepatic fat ≥ 5% by magnetic resonance spectroscopy. METHODS: Five subjects received eplerenone (25 mg daily x 1 week followed by 50 mg daily x 23 weeks). Laboratory tests were done at each visit, and the primary endpoint, change in hepatic fat content, was determined by MRI spectroscopy at baseline and week 24...
March 6, 2018: Liver International: Official Journal of the International Association for the Study of the Liver
Kuo-How Huang, Chih-Chin Yu, Ya-Hui Hu, Chin-Chen Chang, Chieh-Kai Chan, Shih-Cheng Liao, Yao-Chou Tsai, Shih-Chieh Jeff Chueh, Vin-Cent Wu, Yen-Hung Lin
BACKGROUND/PURPOSE: Even with the increasing recognition of primary aldosteronism (PA) as a cause of refractory hypertension and an issue of public health, the consensus of its optimal surgical or medical treatment in Taiwan has not been reached. Our objective was to develop a clinical practice guideline that is feasible for real-world management of PA patients in Taiwan. METHODS: The Taiwan Society of Aldosteronism (TSA) Task Force recognized the above-mentioned issues and reached this Taiwan PA consensus at its inaugural meeting, in order to provide updated information of internationally acceptable standards, and also to incorporate our local disease characteristics and constraints into PA management...
March 2, 2018: Journal of the Formosan Medical Association, Taiwan Yi Zhi
Mario Boehm, Nadine Arnold, Adam Braithwaite, Josephine Pickworth, Changwu Lu, Tatyana Novoyatleva, David G Kiely, Friedrich Grimminger, Hossein A Ghofrani, Norbert Weissmann, Werner Seeger, Allan Lawrie, Ralph T Schermuly, Baktybek Kojonazarov
BACKGROUND: Aldosterone is a mineralocorticoid hormone critically involved in arterial blood pressure regulation. Although pharmacological aldosterone antagonism reduces mortality and morbidity among patients with severe left-sided heart failure, the contribution of aldosterone to the pathobiology of pulmonary arterial hypertension (PAH) and right ventricular (RV) heart failure is not fully understood. METHODS: The effects of Eplerenone (0.1% Inspra® mixed in chow) on pulmonary vascular and RV remodeling were evaluated in mice with pulmonary hypertension (PH) caused by Sugen5416 injection with concomitant chronic hypoxia (SuHx) and in a second animal model with established RV dysfunction independent from lung remodeling through surgical pulmonary artery banding...
March 2, 2018: BMC Pulmonary Medicine
Adriana Mihaela Ilieșiu, Andreea Simona Hodorogea
Heart failure with preserved ejection fraction (HFpEF) is a growing epidemiologic problem affecting more than half of the patients with heart failure (HF). HFpEF has a significant morbidity and mortality and so far no treatment has been clearly demonstrated to improve the outcomes in HFpEF, in contrast to the efficacy of treatment in heart failure with reduced ejection fraction (HFrEF).The failure of proven beneficial drugs in HFrEF to influence the outcome of patients with HFpEF could be related to the heterogeneity of the disease, its various phenotypes and multifactorial pathophysiology, incompletely elucidated yet...
March 2, 2018: Advances in Experimental Medicine and Biology
Milton Packer
Among patients with heart failure and a preserved ejection (HFpEF), obesity is associated with a distinct phenotype that is characterized by adiposity-driven plasma volume expansion and cardiac overfilling, which is coupled with an impairment of ventricular distensibility. These pathophysiological abnormalities may be related to the increased actions of specific adipocyte-derived signalling molecules (aldosterone, neprilysin and leptin) that work in concert with increased renal sympathetic nerve traffic and activated beta2 -adrenergic receptors to promote sodium retention, microvascular rarefaction, cardiac fibrosis and systemic inflammation...
March 1, 2018: European Journal of Heart Failure
Harald Murck, Michael Ploch, Stuart Montgomery
A close association between vegetative regulation and affect is common knowledge. Recently, the role of aldosterone and the activity of its receptor [mineralocorticoid receptor (MR)] in the clinical outcome for treatment with standard antidepressants has been shown including low systolic blood pressure and a low concentration of plasma sodium (Na), both of which appear to be related to therapy resistance to standard antidepressants. We carried out a retrospective analysis of a double-blind placebo-controlled trial of St John's wort extract LI160 in 247 outpatients with major depression...
February 27, 2018: International Clinical Psychopharmacology
Keita Harada, Hidetada Matsuoka, Masumi Inoue
M-type K+ channels contribute to the resting membrane potential in the sympathetic ganglion neurons of various animals, whereas their expression in adrenal medullary (AM) cells has been controversial. The present experiment aims to explore the expression of M channels comprising the KCNQ2 subunit in the rat AM cell and its immortalized cell line PC12 cells at the protein level and how its expression in PC12 cells is regulated. The KCNQ2 isoform was recognized in homogenates of PC12 cells but not the rat adrenal medullae by immunoblotting and KCNQ2-like immunoreactivity (IR) was detected in PC12 cells but not in rat AM cells...
February 27, 2018: Cell and Tissue Research
Ganesh Pathare, Manuel Anderegg, Giuseppe Albano, Florian Lang, Daniel G Fuster
Fibroblast growth factor 23 (FGF23) participates in the orchestration of mineral metabolism by inducing phosphaturia and decreasing the production of 1,25(OH)2 D3 . It is known that FGF23 release is stimulated by aldosterone and extracellular volume depletion. To characterize this effect further in a model of mild hypovolemia, we studied mice lacking the thiazide sensitive NaCl cotransporter (NCC). Our data indicate that NCC knockout mice (KO) have significantly higher FGF23, PTH and aldosterone concentrations than corresponding wild type (WT) mice...
February 26, 2018: Scientific Reports
Tatsuya Sakamoto, Susumu Hyodo, Wataru Takagi
Corticosteroid receptors are critical for homeostasis maintenance, but understanding of the principal roles of the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) throughout vertebrates is limited. Lines of constitutive GR-knockout zebrafish and MR-knockout medaka have recently been generated as the first adult-viable corticosteroid receptor-knockout animals, in contrast to the lethality of these receptor knockouts in mice. Here, we describe behavioral and physiological modifications following disruption of corticosteroid receptor function in these animal models...
February 23, 2018: Journal of Steroid Biochemistry and Molecular Biology
Mario Fritsch Neves, Ana Rosa Cunha, Michelle Rabello Cunha, Ronaldo Altenburg Gismondi, Wille Oigman
Many cardiovascular diseases present renin-angiotensin-aldosterone system (RAAS) hyperactivity as an important pathophysiological mechanism to be target in the therapeutic approaches. Moreover, arterial stiffness is currently considered as a new independent risk factor for cardiovascular disease in different clinical conditions, including hypertension and chronic kidney disease. In fact, excessive stimulation of angiotensin type 1 (AT1) receptors, as well as mineralocorticoid receptors, results in cellular growth, oxidative stress and vascular inflammation, which may lead to arterial stiffness and accelerate the process of vascular aging...
February 23, 2018: High Blood Pressure & Cardiovascular Prevention: the Official Journal of the Italian Society of Hypertension
Krister Bamberg, Ulrika Johansson, Karl Edman, Lena William-Olsson, Susanna Myhre, Anders Gunnarsson, Stefan Geschwindner, Anna Aagaard, Anna Björnson Granqvist, Frédéric Jaisser, Yufeng Huang, Kenneth L Granberg, Rasmus Jansson-Löfmark, Judith Hartleib-Geschwindner
Excess mineralocorticoid receptor (MR) activation promotes target organ dysfunction, vascular injury and fibrosis. MR antagonists like eplerenone are used for treating heart failure, but their use is limited due to the compound class-inherent hyperkalemia risk. Here we present evidence that AZD9977, a first-in-class MR modulator shows cardio-renal protection despite a mechanism-based reduced liability to cause hyperkalemia. AZD9977 in vitro potency and binding mode to MR were characterized using reporter gene, binding, cofactor recruitment assays and X-ray crystallopgraphy...
2018: PloS One
Dany Jaffuel, Nicolas Molinari, Philippe Berdague, Atul Pathak, Michel Galinier, Marion Dupuis, Jean-Etienne Ricci, Jean-Pierre Mallet, Arnaud Bourdin, François Roubille
AIMS: Sleep-disordered breathing (SDB) is a highly prevalent co-morbidity in patients with chronic heart failure (CHF) and can play a detrimental role in the pathophysiology course of CHF. However, the best way to manage SDB in CHF remains a matter of debate. Sacubitril-valsartan has been included in the 2016 European Society of Cardiology guidelines as an alternative to angiotensin-converting enzyme inhibitors to further reduce the risk of progression of CHF, CHF hospitalization, and death in ambulatory patients...
February 22, 2018: ESC Heart Failure
Lei Lei, Yuanjie Mao
The common ultimate pathological feature for all cardiovascular diseases, congestive heart failure (CHF), is now considered as one of the main public health burdens that is associated with grave implications. Neurohormonal systems play a critical role in cardiovascular homeostasis, pathophysiology, and cardiovascular diseases. Hormone treatments such as the newly invented dual-acting drug valsartan/sacubitril are promising candidates for CHF, in addition to the conventional medications encompassing beta receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists...
January 1, 2018: Journal of International Medical Research
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