Publications by authors named "Celso E Gomez-Sanchez"

152 Publications

The Mineralocorticoid Receptor and the Heart.

Endocrinology 2021 Jun 27. Epub 2021 Jun 27.

Medical Service, G.V. (Sonny) Montgomery VA Medical Center and Department of Pharmacology and Toxicology, and Medicine, University of Mississippi Medical Center, Jackson, MS, USA.

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http://dx.doi.org/10.1210/endocr/bqab131DOI Listing
June 2021

Mineralocorticoid Receptor Antagonists Eplerenone and Spironolactone Modify Adrenal Cortex Morphology and Physiology.

Biomedicines 2021 Apr 20;9(4). Epub 2021 Apr 20.

Department of Experimental Biology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.

Mineralocorticoid receptor antagonists (MRAs) are a class of anti-hypertensive drugs that act by blocking aldosterone action. The aim of this study was to evaluate whether the MRAs spironolactone and eplerenone influence adrenal cortical physiology and morphology. Spontaneous hypertensive rats (SHR, = 18) and normotensive rats (WKY, = 18) were randomly exposed to a daily dose of spironolactone ( = 6), eplerenone ( = 6), or no drug ( = 6) over 28 days. After that, aldosterone, corticosterone, and 11-deoxycorticosterone plasma concentrations were quantified. Adrenal glands were subjected to morphological analysis to assess lipid droplets content, capsular width, cell proliferation, and steroidogenic proteins expression. The adrenal cortex in untreated SHR showed higher lipid droplet content as than in WKY. In SHR, MRA treatment was associated with higher circulating aldosterone levels and Ki-67 expression in aldosterone-secreting cells. In WKY, the only difference observed after MRA spironolactone treatment was a narrower capsule. There was no difference in abundance of steroidogenic enzyme between groups. In conclusion, MRAs modify adrenal gland function and morphology in SHR. The effects observed within the adrenal glomerulosa with aldosterone-secreting cell proliferation and higher circulating aldosterone levels suggests that MRA treatment provokes activation of the renin angiotensin system. The prognostic value of hyperaldosteronism secondary to MRAs blockade requires further investigation.
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http://dx.doi.org/10.3390/biomedicines9040441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074383PMC
April 2021

11β-hydroxysteroid dehydrogenases: A growing multi-tasking family.

Mol Cell Endocrinol 2021 04 17;526:111210. Epub 2021 Feb 17.

Department of Pharmacology and Toxicology, Jackson, MS, USA; Medicine (Endocrinology), Jackson, MS, USA; University of Mississippi Medical Center and G.V. (Sonny) Montgomery VA Medical Center(3), Jackson, MS, USA.

This review briefly addresses the history of the discovery and elucidation of the three cloned 11β-hydroxysteroid dehydrogenase (11βHSD) enzymes in the human, 11βHSD1, 11βHSD2 and 11βHSD3, an NADP-dependent dehydrogenase also called the 11βHSD1-like dehydrogenase (11βHSD1L), as well as evidence for yet identified 11βHSDs. Attention is devoted to more recently described aspects of this multi-functional family. The importance of 11βHSD substrates other than glucocorticoids including bile acids, 7-keto sterols, neurosteroids, and xenobiotics is discussed, along with examples of pathology when functions of these multi-tasking enzymes are disrupted. 11βHSDs modulate the intracellular concentration of glucocorticoids, thereby regulating the activation of the glucocorticoid and mineralocorticoid receptors, and 7β-27-hydroxycholesterol, an agonist of the retinoid-related orphan receptor gamma (RORγ). Key functions of this nuclear transcription factor include regulation of immune cell differentiation, cytokine production and inflammation at the cell level. 11βHSD1 expression and/or glucocorticoid reductase activity are inappropriately increased with age and in obesity and metabolic syndrome (MetS). Potential causes for disappointing results of the clinical trials of selective inhibitors of 11βHSD1 in the treatment of these disorders are discussed, as well as the potential for more targeted use of inhibitors of 11βHSD1 and 11βHSD2.
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http://dx.doi.org/10.1016/j.mce.2021.111210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108011PMC
April 2021

Corticotroph tumor progression after bilateral adrenalectomy (Nelson's syndrome): systematic review and expert consensus recommendations.

Eur J Endocrinol 2021 Mar;184(3):P1-P16

Section on Genetics & Endocrinology Eunice Kennedy Shriver National Insitute of Child Health & Human Development (NICHD) National Institute of Health (NIH), NIH Clinical Research Center, Bethesda, Maryland, USA.

Background: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing.

Methods: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018.

Results: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients).

Conclusions: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.
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http://dx.doi.org/10.1530/EJE-20-1088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060870PMC
March 2021

Effect of Dietary Sodium Modulation on Pig Adrenal Steroidogenesis and Transcriptome Profiles.

Hypertension 2020 12 19;76(6):1769-1777. Epub 2020 Oct 19.

From the Medizinische Klinik und Poliklinik IV, Klinikum der Universität München (T.V., I.-S.K., M.R., T.A.W.), Ludwig-Maximilians-Universität München, Munich, Germany.

Primary aldosteronism is a frequent form of endocrine hypertension caused by aldosterone overproduction from the adrenal cortex. Regulation of aldosterone biosynthesis has been studied in rodents despite differences in adrenal physiology with humans. We, therefore, investigated pig adrenal steroidogenesis, morphology, and transcriptome profiles of the zona glomerulosa (zG) and zona fasciculata in response to activation of the renin-angiotensin-aldosterone system by dietary sodium restriction. Six-week-old pigs were fed a low- or high-sodium diet for 14 days (3 pigs per group, 0.4 g sodium/kg feed versus 6.8 g sodium/kg). Plasma aldosterone concentrations displayed a 43-fold increase (=0.011) after 14 days of sodium restriction (day 14 versus day 0). Low dietary sodium caused a 2-fold increase in thickness of the zG (<0.001) and an almost 3-fold upregulation of (<0.05) compared with high dietary sodium. Strong immunostaining of the KCNJ5 (G protein-activated inward rectifier potassium channel 4), which is frequently mutated in primary aldosteronism, was demonstrated in the zG. mRNA sequencing transcriptome analysis identified significantly altered expression of genes modulated by the renin-angiotensin-aldosterone system in the zG (n=1172) and zona fasciculata (n=280). These genes included many with a known role in the regulation of aldosterone synthesis and adrenal function. The most highly enriched biological pathways in the zG were related to cholesterol biosynthesis, steroid metabolism, cell cycle, and potassium channels. This study provides mechanistic insights into the physiology and pathophysiology of aldosterone production in a species closely related to humans and shows the suitability of pigs as a translational animal model for human adrenal steroidogenesis.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011841PMC
December 2020

Functional imaging with 11C-metomidate PET for subtype diagnosis in primary aldosteronism.

Eur J Endocrinol 2020 Dec;183(6):539-550

Endocrinology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Objective: Endocrine Society guidelines recommend adrenal venous sampling (AVS) in primary aldosteronism (PA) if adrenalectomy is considered. We tested whether functional imaging of adrenal cortex with 11C-metomidate (11C-MTO) could offer a noninvasive alternative to AVS in the subtype classification of PA.

Design: We prospectively recruited 58 patients with confirmed PA who were eligible for adrenal surgery.

Methods: Subjects underwent AVS and 11C-MTO-PET without dexamethasone pretreatment in random order. The lateralization of 11C-MTO-PET and adrenal CT were compared with AVS in all subjects and in a prespecified adrenalectomy subgroup in which the diagnosis was confirmed with immunohistochemical staining for CYP11B2.

Results: In the whole study population, the concordance of AVS and 11C-MTO-PET was 51% and did not differ from that of AVS and adrenal CT (53%). The concordance of AVS and 11C-MTO-PET was 55% in unilateral and 44% in bilateral PA. In receiver operating characteristics analysis, the maximum standardized uptake value ratio of 1.16 in 11C-MTO-PET had an AUC of 0.507 (P = n.s.) to predict allocation to adrenalectomy or medical therapy with sensitivity of 55% and specificity of 44%. In the prespecified adrenalectomy subgroup, AVS and 11C-MTO-PET were concordant in 10 of 19 subjects with CYP11B2-positive adenoma and in 6 of 10 with CYP11B2-positivity without an adenoma.

Conclusions: The concordance of 11C-MTO-PET with AVS was clinically suboptimal, and did not outperform adrenal CT. In a subgroup with CYP11B2-positive adenoma, 11C-MTO-PET identified 53% of cases. 11C-MTO-PET appeared to be inferior to AVS for subtype classification of PA.
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http://dx.doi.org/10.1530/EJE-20-0532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045447PMC
December 2020

The landscape of molecular mechanism for aldosterone production in aldosterone-producing adenoma.

Endocr J 2020 Oct 24;67(10):989-995. Epub 2020 Sep 24.

Division of Endocrinology, G.V. (Sonny) Montgomery VA Medical Center and Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.

Primary aldosteronism is the most common form of secondary hypertension with a prevalence of 5-10% in hypertensive patients. Aldosterone-producing adenoma (APA) is a subtype of primary aldosteronism, and somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CLCN2, or CTNNB1 were identified and recognized to drive aldosterone production and/or contribute to tumorigenesis in APA. Mutations of KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CLCN2 are known to activate calcium signaling, and its activation potentiate CYP11B2 (aldosterone synthesis) transcription in adrenal cells. Transcriptome analyses combined with bioinformatics using APA samples were conductive for each gene mutation mediated pivotal pathway, gene ontology, and clustering. Several important intracellular molecules in increase aldosterone production were detected by transcriptome analysis, and additional functional analyses demonstrated intracellular molecular mechanisms of aldosterone production which focused on calcium signal, CYP11B2 transcription and translation. Furthermore, DNA methylation analysis revealed that promoter region of CYP11B2 was entirely hypomethylated, but that of other steroidogenic enzymes were not in APA. Integration of transcriptome and DNA methylome analysis clarified some DNA methylation associated gene expression, and the transcripts have a role for aldosterone production. In this article, we reviewed the intracellular molecular mechanisms of aldosterone production in APA, and discussed future challenges for basic studies leading to clinical practice.
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http://dx.doi.org/10.1507/endocrj.EJ20-0478DOI Listing
October 2020

Segmental Adrenal Vein Sampling in Patients With Primary Aldosteronism: Superlative or Superfluous?

Hypertension 2020 09 12;76(3):662-664. Epub 2020 Aug 12.

G.V. (Sonny) Montgomery VA Medical Center (C.E.G.-S.), University of Mississippi Medical Center, Jackson.

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427809PMC
September 2020

Incomplete Pattern of Steroidogenic Protein Expression in Functioning Adrenocortical Carcinomas.

Biomedicines 2020 Jul 30;8(8). Epub 2020 Jul 30.

Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal.

Autonomous steroid secretion is a common feature of adrenocortical carcinomas (ACC), although not always clinically evident owing to inefficient steroidogenesis with increased release of steroid precursors. Our study aim was to analyze the expression profile of four key proteins involved in the steroidogenesis cascade, in different adrenocortical tumors. Expression of proteins involved in steroidogenesis, namely steroidogenic acute regulatory protein (StAR), 11β-hydroxylase (CYP11B1), aldosterone synthase (CYP11B2) and 17α-hydroxylase (CYP17A1), were analyzed by immunohistochemistry in ACC ( = 14), adenomas presenting with Cushing's syndrome (ACAc) ( = 11) and clinically non-functioning adenomas (ACAn) ( = 15). A percentage of the stained area for each protein was analyzed using ImageJ software for computerized morphometric quantification. CYP11B1, StAR and CYP17A1 expression were significantly lower in ACC when compared to ACAc. In addition, ACC presented co-staining cells for CYP11B1 and CYP11B2. CYP11B1 was the steroidogenic enzyme with the most discriminative power to distinguish ACC from ACAc, with a sensitivity of 100%, specificity of 92%, and an expression higher than 4.44%, indicating the presence of a cortisol secreting adenoma. ACC depicts an incomplete pattern of steroidogenic protein expression, with decreased CYP11B1 and CYP17A1, which could explain the predominant secretion of steroid precursors.
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http://dx.doi.org/10.3390/biomedicines8080256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460193PMC
July 2020

International Histopathology Consensus for Unilateral Primary Aldosteronism.

J Clin Endocrinol Metab 2021 Jan;106(1):42-54

Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Germany.

Objective: Develop a consensus for the nomenclature and definition of adrenal histopathologic features in unilateral primary aldosteronism (PA).

Context: Unilateral PA is the most common surgically treated form of hypertension. Morphologic examination combined with CYP11B2 (aldosterone synthase) immunostaining reveals diverse histopathologic features of lesions in the resected adrenals.

Patients And Methods: Surgically removed adrenals (n = 37) from 90 patients operated from 2015 to 2018 in Munich, Germany, were selected to represent the broad histologic spectrum of unilateral PA. Five pathologists (Group 1 from Germany, Italy, and Japan) evaluated the histopathology of hematoxylin-eosin (HE) and CYP11B2 immunostained sections, and a consensus was established to define the identifiable features. The consensus was subsequently used by 6 additional pathologists (Group 2 from Australia, Brazil, Canada, Japan, United Kingdom, United States) for the assessment of all adrenals with disagreement for histopathologic diagnoses among group 1 pathologists.

Results: Consensus was achieved to define histopathologic features associated with PA. Use of CYP11B2 immunostaining resulted in a change of the original HE morphology-driven diagnosis in 5 (14%) of 37 cases. Using the consensus criteria, group 2 pathologists agreed for the evaluation of 11 of the 12 cases of disagreement among group 1 pathologists.

Conclusion: The HISTALDO (histopathology of primary aldosteronism) consensus is useful to standardize nomenclature and achieve consistency among pathologists for the histopathologic diagnosis of unilateral PA. CYP11B2 immunohistochemistry should be incorporated into the routine clinical diagnostic workup to localize the likely source of aldosterone production.
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http://dx.doi.org/10.1210/clinem/dgaa484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765663PMC
January 2021

Immunohistochemistry of the Human Adrenal CYP11B2 in Normal Individuals and in Patients with Primary Aldosteronism.

Horm Metab Res 2020 Jun 14;52(6):421-426. Epub 2020 Apr 14.

Department of Uro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan.

The CYP11B2 enzyme is the terminal enzyme in the biosynthesis of aldosterone. Immunohistochemistry using antibodies against CYP11B2 defines cells of the adrenal ZG that synthesize aldosterone. CYP11B2 expression is normally stimulated by angiotensin II, but becomes autonomous in primary hyperaldosteronism, in most cases driven by recently discovered somatic mutations of ion channels or pumps. Cells expressing CYP11B2 in young normal humans form a continuous band beneath the adrenal capsule; in older individuals they form discrete clusters, aldosterone-producing cell clusters (APCC), surrounded by non-aldosterone producing cells in the outer layer of the adrenal gland. Aldosterone-producing adenomas may exhibit a uniform or heterogeneous expression of CYP11B2. APCC frequently persist in the adrenal with an aldosterone-producing adenoma suggesting autonomous CYP11B2 expression in these cells as well. This was confirmed by finding known mutations that drive aldosterone production in adenomas in the APCC of clinically normal people. Unilateral aldosteronism may also be due to multiple CYP11B2-expressing nodules of various sizes or a continuous band of hyperplastic ZG cells expressing CYP11B2. Use of CYP11B2 antibodies to identify areas for sequencing has greatly facilitated the detection of aldosterone-driving mutations.
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http://dx.doi.org/10.1055/a-1139-2079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299743PMC
June 2020

Aldosterone-Producing Adenomas: More Than Meets the Eye.

Hypertension 2020 04 2;75(4):927-929. Epub 2020 Mar 2.

Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan (K.O.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7121874PMC
April 2020

Endoplasmic Reticulum Chaperone Calmegin Is Upregulated in Aldosterone-Producing Adenoma and Associates With Aldosterone Production.

Hypertension 2020 02 23;75(2):492-499. Epub 2019 Dec 23.

From the Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan (K.I., K.O., H.O., K.K., G.N., Y.Y., R.B., N.H., M.Y.).

The endoplasmic reticulum (ER) plays a pivotal role in syntheses of proteins and steroid hormones and regulation of intracellular Ca level. We aimed to investigate ER-associated genes in aldosterone-producing adenomas (APAs) and clarify their effect on aldosterone production. Microarray analysis targeting 288 ER-associated genes was conducted using nonfunctioning adrenocortical adenomas (n=5) and APAs (n=19). Immunohistochemistry and quantitative polymerase chain reaction analyses were performed with 13 nonfunctioning adrenocortical adenoma and 48 APA samples. Functional studies were performed with human adrenocortical carcinoma (HAC15) cells, some of which were genetically modified using lentiviruses. The ER chaperone calmegin () was the most highly expressed ER-associated gene in APAs relative to nonfunctioning adrenocortical adenomas. Analysis with quantitative polymerase chain reaction revealed to be 9.5-fold upregulated in APAs relative to nonfunctioning adrenocortical adenomas. There were no differences among different APA genotypes affecting aldosterone production. Immunohistochemistry analysis revealed that CLGN was strongly expressed in APAs and aldosterone-producing cell clusters. Angiotensin II stimulation or KCNJ5 T158A overexpression in HAC15 cells did not affect mRNA levels. overexpression in HAC15 cells increased aldosterone levels but did not stimulate mRNA levels. Pathway and gene ontology analyses using RNA sequencing results showed that tRNA aminoacyl metabolism was the most enriched pathway in -overexpressing cells. CYP11B2 (aldosterone synthase) and HSD3B2 (3 beta-hydroxysteroid dehydrogenase/delta 5->4-isomerase type 2) protein expression were more abundant in -overexpressing cells. knockdown using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) method in HAC15 cells that carry the mutation did not affect aldosterone production. To summarize, was upregulated and associated with aldosterone production via translational regulation of CYP11B2 in APAs.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004827PMC
February 2020

Chemogenetic activation of adrenocortical Gq signaling causes hyperaldosteronism and disrupts functional zonation.

J Clin Invest 2020 01;130(1):83-93

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.

The mineralocorticoid aldosterone is produced in the adrenal zona glomerulosa (ZG) under the control of the renin-angiotensin II (AngII) system. Primary aldosteronism (PA) results from renin-independent production of aldosterone and is a common cause of hypertension. PA is caused by dysregulated localization of the enzyme aldosterone synthase (Cyp11b2), which is normally restricted to the ZG. Cyp11b2 transcription and aldosterone production are predominantly regulated by AngII activation of the Gq signaling pathway. Here, we report the generation of transgenic mice with Gq-coupled designer receptors exclusively activated by designer drugs (DREADDs) specifically in the adrenal cortex. We show that adrenal-wide ligand activation of Gq DREADD receptors triggered disorganization of adrenal functional zonation, with induction of Cyp11b2 in glucocorticoid-producing zona fasciculata cells. This result was consistent with increased renin-independent aldosterone production and hypertension. All parameters were reversible following termination of DREADD-mediated Gq signaling. These findings demonstrate that Gq signaling is sufficient for adrenocortical aldosterone production and implicate this pathway in the determination of zone-specific steroid production within the adrenal cortex. This transgenic mouse also provides an inducible and reversible model of hyperaldosteronism to investigate PA therapeutics and the mechanisms leading to the damaging effects of aldosterone on the cardiovascular system.
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http://dx.doi.org/10.1172/JCI127429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934213PMC
January 2020

Mineralocorticoid Receptor Signaling Contributes to Normal Muscle Repair After Acute Injury.

Front Physiol 2019 25;10:1324. Epub 2019 Oct 25.

Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, United States.

Acute skeletal muscle injury is followed by a temporal response of immune cells, fibroblasts, and muscle progenitor cells within the muscle microenvironment to restore function. These same cell types are repeatedly activated in muscular dystrophy from chronic muscle injury, but eventually, the regenerative portion of the cycle is disrupted and fibrosis replaces degenerated muscle fibers. Mineralocorticoid receptor (MR) antagonist drugs have been demonstrated to increase skeletal muscle function, decrease fibrosis, and directly improve membrane integrity in muscular dystrophy mice, and therefore are being tested clinically. Conditional knockout of MR from muscle fibers in muscular dystrophy mice also improves skeletal muscle function and decreases fibrosis. The mechanism of efficacy likely results from blocking MR signaling by its endogenous agonist aldosterone, being produced at high local levels in regions of muscle damage by infiltrating myeloid cells. Since chronic and acute injuries share the same cellular processes to regenerate muscle, and MR antagonists are clinically used for a wide variety of conditions, it is crucial to define the role of MR signaling in normal muscle repair after injury. In this study, we performed acute injuries using barium chloride injections into muscles both in myofiber MR conditional knockout mice on a wild-type background (MRcko) and in MR antagonist-treated wild-type mice. Steps of the muscle regeneration response were analyzed at 1, 4, 7, or 14 days after injury. Presence of the aldosterone synthase enzyme was also assessed during the injury repair process. We show for the first time aldosterone synthase localization in infiltrating immune cells of normal skeletal muscle after acute injury. MRcko mice had an increased muscle area infiltrated by aldosterone synthase positive myeloid cells compared to control injured animals. Both MRcko and MR antagonist treatment stabilized damaged myofibers and increased collagen infiltration or compaction at 4 days post-injury. MR antagonist treatment also led to reduced myofiber size at 7 and 14 days post-injury. These data support that MR signaling contributes to the normal muscle repair process following acute injury. MR antagonist treatment delays muscle fiber growth, so temporary discontinuation of these drugs after a severe muscle injury could be considered.
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http://dx.doi.org/10.3389/fphys.2019.01324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830343PMC
October 2019

Retinoic acid receptor α as a novel contributor to adrenal cortex structure and function through interactions with Wnt and Vegfa signalling.

Sci Rep 2019 10 11;9(1):14677. Epub 2019 Oct 11.

INSERM, UMRS_970, Paris Cardiovascular Research Center, Paris, France.

Primary aldosteronism (PA) is the most frequent form of secondary arterial hypertension. Mutations in different genes increase aldosterone production in PA, but additional mechanisms may contribute to increased cell proliferation and aldosterone producing adenoma (APA) development. We performed transcriptome analysis in APA and identified retinoic acid receptor alpha (RARα) signaling as a central molecular network involved in nodule formation. To understand how RARα modulates adrenal structure and function, we explored the adrenal phenotype of male and female Rarα knockout mice. Inactivation of Rarα in mice led to significant structural disorganization of the adrenal cortex in both sexes, with increased adrenal cortex size in female mice and increased cell proliferation in males. Abnormalities of vessel architecture and extracellular matrix were due to decreased Vegfa expression and modifications in extracellular matrix components. On the molecular level, Rarα inactivation leads to inhibition of non-canonical Wnt signaling, without affecting the canonical Wnt pathway nor PKA signaling. Our study suggests that Rarα contributes to the maintenance of normal adrenal cortex structure and cell proliferation, by modulating Wnt signaling. Dysregulation of this interaction may contribute to abnormal cell proliferation, creating a propitious environment for the emergence of specific driver mutations in PA.
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http://dx.doi.org/10.1038/s41598-019-50988-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789122PMC
October 2019

Primary Aldosteronism: KCNJ5 Mutations and Adrenocortical Cell Growth.

Hypertension 2019 10 26;74(4):809-816. Epub 2019 Aug 26.

From the Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, Germany (Y.Y., D.J., E.T.A.P., L.S.M., H.S., F.B., M.R., T.A.W.).

Aldosterone-producing adenomas with somatic mutations in the KCNJ5 G-protein-coupled inwardly rectifying potassium channel are a cause of primary aldosteronism. These mutations drive aldosterone excess, but their role in cell growth is undefined. Our objective was to determine the role of KCNJ5 mutations in adrenal cell proliferation and apoptosis. The Ki67 proliferative index was positively correlated with adenoma diameter in aldosterone-producing adenomas with a KCNJ5 mutation (=0.435, =0.007), a negative correlation was noted in adenomas with no mutation detected (=-0.548, =0.023). Human adrenocortical cell lines were established with stable expression of cumate-inducible wild-type or mutated KCNJ5. Increased cell proliferation was induced by low-level induction of KCNJ5-T158A expression compared with control cells (=0.009), but increased induction ablated this difference. KCNJ5-G151R displayed no apparent proliferative effect, but KCNJ5-G151E and L168R mutations each resulted in decreased cell proliferation (difference <0.0001 from control cells, both comparisons). Under conditions tested, T158A had no effect on apoptosis, but apoptosis increased with expression of G151R (<0.0001), G151E (=0.008), and L168R (<0.0001). We generated a specific KCNJ5 monoclonal antibody which was used in immunohistochemistry to demonstrate strong KCNJ5 expression in adenomas without a mutation and in the zona glomerulosa adjacent to adenomas irrespective of genotype as well as in aldosterone-producing cell clusters. Double immunofluorescence staining for KCNJ5 and CYP11B2 (aldosterone synthase) showed markedly decreased KCNJ5 immunostaining in CYP11B2-positive cells compared with CYP11B2-negative cells in aldosterone-producing adenomas with a KCNJ5 mutation. Together, these findings support the concept that cell growth effects of KCNJ5 mutations are determined by the expression level of the mutated channel.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739168PMC
October 2019

DLK1/PREF1 marks a novel cell population in the human adrenal cortex.

J Steroid Biochem Mol Biol 2019 10 29;193:105422. Epub 2019 Jun 29.

Centre for Endocrinology, William Harvey Research Institute, Bart's and the London, School of Medicine and Dentistry, Queen Mary University of London, London, UK. Electronic address:

The adrenal cortex governs fundamental metabolic processes though synthesis of glucocorticoid, mineralocorticoids and androgens. Studies in rodents have demonstrated that the cortex undergoes a self-renewal process and that capsular/subcapsular stem/progenitor cell pools differentiate towards functional steroidogenic cells supporting the dynamic centripetal streaming of adrenocortical cells throughout life. We previously demonstrated that the Notch atypical ligand Delta-like homologue 1 (DLK1)/preadipocyte factor 1 (PREF1) is expressed in subcapsular Sf1 and Shh-positive, CYP11B1-negative and CYP11B2-partially positive cortical progenitor cells in rat adrenals, and that secreted DLK1 can modulate GLI1 expression in H295R cells. Here we show that the human adrenal cortex remodels with age to generate clusters of relatively undifferentiated cells expressing DLK1. These clusters (named DLK1-expressing cell clusters or DCCs) increased with age in size and were found to be different entities to aldosterone-producing cell clusters, another well-characterized and age-dependent cluster structure. DLK1 was markedly overexpressed in adrenocortical carcinomas but not in aldosterone-producing adenomas. Thus, this data identifies a novel cell population in the human adrenal cortex and might suggest a yet-to be identified role of DLK1 in the pathogenesis of adrenocortical carcinoma in humans.
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http://dx.doi.org/10.1016/j.jsbmb.2019.105422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736711PMC
October 2019

Measurement of 11-dehydrocorticosterone in mice, rats and songbirds: Effects of age, sex and stress.

Gen Comp Endocrinol 2019 09 27;281:173-182. Epub 2019 May 27.

Department of Zoology, University of British Columbia, Vancouver, BC, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada; Department of Psychology, University of British Columbia, Vancouver, BC, Canada; Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Glucocorticoids (GCs) are secreted into the blood by the adrenal glands and are also locally-produced by organs such as the lymphoid organs (bone marrow, thymus, and spleen). Corticosterone is the primary circulating GC in many species, including mice, rats and birds. Within lymphoid organs, corticosterone can be locally produced from the inactive metabolite, 11-dehydrocorticosterone (DHC). However, very little is known about endogenous DHC levels, and no immunoassays are currently available to measure DHC. Here, we developed an easy-to-use and inexpensive immunoassay to measure DHC that is accurate, precise, sensitive, and specific. The DHC immunoassay was validated in multiple ways, including comparison with a mass spectrometry assay. After assay validations, we demonstrated the usefulness of this immunoassay by measuring DHC (and corticosterone) in mice, rats and song sparrows. Overall, corticosterone levels were higher than DHC levels across species. In Study 1, using mice, we measured steroids in whole blood and lymphoid organs at postnatal day (PND) 5, PND23, and PND90. Corticosterone and DHC showed distinct tissue-specific patterns across development. In Studies 2 and 3, we measured circulating corticosterone and DHC in adult rats and song sparrows, before and after restraint stress. In rats and song sparrows, restraint stress rapidly increased circulating levels of both steroids. This novel DHC immunoassay revealed major changes in DHC concentrations during development and in response to stress, which have important implications for understanding GC physiology, effects of stress on immune function, and regulation of local GC levels.
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http://dx.doi.org/10.1016/j.ygcen.2019.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751571PMC
September 2019

18-Oxocortisol Synthesis in Aldosterone-Producing Adrenocortical Adenoma and Significance of KCNJ5 Mutation Status.

Hypertension 2019 06;73(6):1283-1290

From the Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine (Y.T., R.M., M.K., S.I., F.S.).

Peripheral 18-oxocortisol (18oxoF) level could contribute to the detection of aldosterone-producing adenoma (APA) in patients with primary aldosteronism. However, peripheral 18oxoF varies among such patients, which is a big drawback concerning its clinical application. We studied 48 cases of APA, 35 harboring KCNJ5 mutation, to clarify the significance of clinical and pathological parameters about peripheral 18oxoF. Peripheral 18oxoF concentration ranged widely from 0.50 to 183.13 ng/dL and correlated positively with intratumoral areas stained positively for steroidogenic enzymes ( P<0.0001). The peripheral 18oxoF level also correlated significantly with that of circulating aldosterone ( P<0.0001) but not with that of cortisol, a precursor of 18oxoF. However, a significant correlation was detected between peripheral 18oxoF and intratumoral glucocorticoids ( P<0.05). In addition, peripheral 18oxoF correlated positively with the number of hybrid cells double positive for 11β-hydroxylase and aldosterone synthase ( P<0.0001). Comparing between the cases with and those without KCNJ5 mutation, the KCNJ5-mutated group demonstrated a significantly higher concentration of peripheral 18oxoF (28.4±5.6 versus 3.0±0.9 ng/dL, P<0.0001) and a larger intratumoral environment including the hybrid cells ( P<0.001), possibly representing a deviation from normal aldosterone biosynthesis. After multivariate analysis, KCNJ5 mutation status turned out to be the most associated factor involved in 18oxoF synthesis in APA ( P<0.0001). Results of our present study first revealed that enhanced 18oxoF synthesis in APA could come from a functional deviation of aldosterone biosynthesis from the normal zona glomerulosa and the utility of peripheral 18oxoF measurement could be influenced by the prevalence of KCNJ5 mutation in an APA.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.12064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6758910PMC
June 2019

Cardiomyocyte glucocorticoid and mineralocorticoid receptors directly and antagonistically regulate heart disease in mice.

Sci Signal 2019 04 16;12(577). Epub 2019 Apr 16.

Signal Transduction Laboratory, NIEHS, NIH, DHHS, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.

Stress is increasingly associated with heart dysfunction and is linked to higher mortality rates in patients with cardiometabolic disease. Glucocorticoids are primary stress hormones that regulate homeostasis through two nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), both of which are present in cardiomyocytes. To examine the specific and coordinated roles that these receptors play in mediating the direct effects of stress on the heart, we generated mice with cardiomyocyte-specific deletion of GR (cardioGRKO), MR (cardioMRKO), or both GR and MR (cardioGRMRdKO). The cardioGRKO mice spontaneously developed cardiac hypertrophy and left ventricular systolic dysfunction and died prematurely from heart failure. In contrast, the cardioMRKO mice exhibited normal heart morphology and function. Despite the presence of myocardial stress, the cardioGRMRdKO mice were resistant to the cardiac remodeling, left ventricular dysfunction, and early death observed in the cardioGRKO mice. Gene expression analysis revealed the loss of gene changes associated with impaired Ca handling, increased oxidative stress, and enhanced cell death and the presence of gene changes that limited the hypertrophic response and promoted cardiomyocyte survival in the double knockout hearts. Reexpression of MR in cardioGRMRdKO hearts reversed many of the cardioprotective gene changes and resulted in cardiac failure. These findings reveal a critical role for balanced cardiomyocyte GR and MR stress signaling in cardiovascular health. Therapies that shift stress signaling in the heart to favor more GR and less MR activity may provide an improved approach for treating heart disease.
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http://dx.doi.org/10.1126/scisignal.aau9685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082727PMC
April 2019

Expression of aldosterone synthase CYP11B2 was inversely correlated with longevity.

J Steroid Biochem Mol Biol 2019 07 8;191:105361. Epub 2019 Apr 8.

Department of Uro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan; Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan. Electronic address:

Immunohistochemistry of human aldosterone synthase (CYP11B2) has revealed that most of aldosterone is autonomously produced in aldosterone-producing cell clusters (APCCs) beneath the capsule of adult adrenals rather than physiologically in the zona glomerulosa (ZG). APCCs have been occasionally found to harbor a somatic mutation of ion channel/pump genes, and number and size of APCCs increase with age until 50 years old. Herein, the objective of the study was to examine APCC development in 106 autopsied adrenals from 85 elderly individuals who died at ages from 50 to 103 years. We obtained the following results: (1) physiological CYP11B2 expression in ZG were attenuated in more elderly persons; (2) number and size of APCCs decreased with age; (3) detachment of APCC from the capsule appeared to occur occasionally over the wide range of the ages; and (4) incidental micro aldosterone-producing adenomas (APAs) and possible APCC-to-APA transitional lesions (pAATLs) were found primarily in samples from persons aged 50-60 years but not in samples from more elderly persons; pAATL was a putative designation based on our previous results indicating that it consisted of subcapsular APCC-like portion and inner APA-like portions. Thus, the formation of the CYP11B2-expressing lesions as well as thickening of the ZG in the adrenals were inversely correlated with age of death in the individuals aged over 50 years. Considering that autopsy samples were used in this study, inactive production of aldosterone regardless of autonomous or physiological manners may have survival advantages in individuals aged over 50 years.
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http://dx.doi.org/10.1016/j.jsbmb.2019.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786771PMC
July 2019

Genetic Characteristics of Aldosterone-Producing Adenomas in Blacks.

Hypertension 2019 04;73(4):885-892

From the Department of Molecular and Integrative Physiology (K.N., W.E.R.), University of Michigan, Ann Arbor.

Somatic mutations have been identified in aldosterone-producing adenomas (APAs) in genes that include KCNJ5, ATP1A1, ATP2B3, and CACNA1D. Based on independent studies, there appears to be racial differences in the prevalence of somatic KCNJ5 mutations, particularly between East Asians and Europeans. Despite the high cardiovascular disease mortality of blacks, there have been no studies focusing on somatic mutations in APAs in this population. In the present study, we investigated genetic characteristics of APAs in blacks using a CYP11B2 (aldosterone synthase) immunohistochemistry-guided next-generation sequencing approach. The adrenal glands with adrenocortical adenomas from 79 black patients with primary aldosteronism were studied. Seventy-three tumors from 69 adrenal glands were confirmed to be APAs by CYP11B2 immunohistochemistry. Sixty-five of 73 APAs (89%) had somatic mutations in aldosterone-driver genes. Somatic CACNA1D mutations were the most prevalent genetic alteration (42%), followed by KCNJ5 (34%), ATP1A1 (8%), and ATP2B3 mutations (4%). CACNA1D mutations were more often observed in APAs from males than those from females (55% versus 29%, P=0.033), whereas KCNJ5 mutations were more prevalent in APAs from females compared with those from males (57% versus 13%, P<0.001). No somatic mutations in aldosterone-driver genes were identified in tumors without CYP11B2 expression. In conclusion, 89% of APAs in blacks harbor aldosterone-driving mutations, and unlike Europeans and East Asians, the most frequently mutated aldosterone-driver gene was CACNA1D. Determination of racial differences in the prevalence of aldosterone-driver gene mutations may facilitate the development of personalized medicines for patients with primary aldosteronism.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.12070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416065PMC
April 2019

A ZNRF3-dependent Wnt/β-catenin signaling gradient is required for adrenal homeostasis.

Genes Dev 2019 02 28;33(3-4):209-220. Epub 2019 Jan 28.

Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, Michigan 48109, USA.

Spatiotemporal control of Wnt signaling is essential for the development and homeostasis of many tissues. The transmembrane E3 ubiquitin ligases ZNRF3 (zinc and ring finger 3) and RNF43 (ring finger protein 43) antagonize Wnt signaling by promoting degradation of frizzled receptors. ZNRF3 and RNF43 are frequently inactivated in human cancer, but the molecular and therapeutic implications remain unclear. Here, we demonstrate that adrenocortical-specific loss of ZNRF3, but not RNF43, results in adrenal hyperplasia that depends on Porcupine-mediated Wnt ligand secretion. Furthermore, we discovered a Wnt/β-catenin signaling gradient in the adrenal cortex that is disrupted upon loss of ZNRF3. Unlike β-catenin gain-of-function models, which induce high Wnt/β-catenin activation and expansion of the peripheral cortex, ZNRF3 loss triggers activation of moderate-level Wnt/β-catenin signaling that drives proliferative expansion of only the histologically and functionally distinct inner cortex. Genetically reducing β-catenin dosage significantly reverses the ZNRF3-deficient phenotype. Thus, homeostatic maintenance of the adrenal cortex is dependent on varying levels of Wnt/β-catenin activation, which is regulated by ZNRF3.
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http://dx.doi.org/10.1101/gad.317412.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362817PMC
February 2019

Visualizing Adrenal Steroids in Primary Aldosteronism.

Hypertension 2018 12;72(6):1269-1271

Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, Germany (T.A.W.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309413PMC
December 2018

Tumor Cell Subtypes Based on the Intracellular Hormonal Activity in KCNJ5-Mutated Aldosterone-Producing Adenoma.

Hypertension 2018 09;72(3):632-640

From the Department of Pathology (Y.Y., K.I., Y.N., H.S.).

Aldosterone-producing adenomas (APAs) harbor marked intratumoral heterogeneity in terms of morphology, steroidogenesis, and genetics. However, an association of biological significance of morphologically identified tumor cell subtypes and genotypes is virtually unknown. KCNJ5 mutation is most frequently detected and generally considered a curable phenotype by adrenalectomy. Therefore, to explore the biological significance of KCNJ5 mutation in APA based on intracellular hormonal activities, 35 consecutively selected APAs (n=18; KCNJ5 mutated, n=17; wild type) were quantitatively examined in the whole tumor areas by newly developed digital image analysis incorporating their histological and ultrastructural features (14 cells from 2 KCNJ5-mutated APAs and 15 cells from 1 wild type) and CYP11B2 immunoreactivity. Results demonstrated that KCNJ5-mutated APAs had significantly lower nuclear/cytoplasm ratio and more abundant clear cells than wild type. CYP11B2 immunoreactivity was not significantly different between these genotypes, but a significant correlation was detected between the proportion of clear cells and CYP11B2 immunoreactivity in all of the APAs examined. CYP11B2 was predominantly immunolocalized in clear cells in KCNJ5-mutated APAs. Quantitative ultrastructural analysis revealed that KCNJ5-mutated APAs had significantly more abundant and smaller-sized mitochondria with well-developed cristae than wild type, whereas wild type had more abundant lipid droplets per unit area despite the small number of the cases examined. Our results did provide the novel insights into the morphological features of APA based on their biological significance. KCNJ5-mutated APAs were characterized by predominance of enlarged lipid-rich clear cells possibly resulting in increased neoplastic aldosterone biosynthesis.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.10907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759988PMC
September 2018

Immunohistopathology and Steroid Profiles Associated With Biochemical Outcomes After Adrenalectomy for Unilateral Primary Aldosteronism.

Hypertension 2018 09;72(3):650-657

From the Medizinische Klinik und Poliklinik IV, Klinikum der Universität München (L.S.M., X.W., E.S., F.B., M.R., T.A.W.).

Unilateral primary aldosteronism (PA) is the most common surgically curable form of hypertension that must be accurately differentiated from bilateral PA for therapeutic management (surgical versus medical). Adrenalectomy results in biochemical cure (complete biochemical success) in almost all patients diagnosed with unilateral PA; the remaining patients with partial or absent biochemical success comprise those with persisting aldosteronism who were misdiagnosed as unilateral PA preoperatively. To identify determinants of postsurgical biochemical outcomes, we compared the adrenal histopathology and the peripheral venous steroid profiles of patients with partial and absent or complete biochemical success after adrenalectomy for unilateral PA. A large multicenter cohort of adrenals from patients with absent and partial biochemical success (n=43) displayed a higher prevalence of hyperplasia (49% versus 21%; P=0.004) and a lower prevalence of solitary functional adenoma (44% versus 79%; P<0.001) compared with adrenals from age- and sex-matched patients with PA with complete biochemical success (n=52). We measured the peripheral plasma steroid concentrations in a subgroup of these patients (n=43) and in a group of patients with bilateral PA (n=27). Steroid profiling was associated with histopathologic phenotypes (solitary functional adenoma, hyperplasia, and aldosterone-producing cell clusters) and classified patients according to biochemical outcome or diagnosis of bilateral PA. If validated, peripheral venous steroid profiling may be a useful tool to guide the decision to perform surgery based on expectations of biochemical outcome after the procedure.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202235PMC
September 2018

Mineralocorticoid Receptor Antagonists in Muscular Dystrophy Mice During Aging and Exercise.

J Neuromuscul Dis 2018;5(3):295-306

Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.

Background: Mineralocorticoid receptor antagonists added to angiotensin converting enzyme inhibitors have shown preclinical efficacy for both skeletal and cardiac muscle outcomes in young sedentary dystrophin-deficient mdx mice also haploinsufficient for utrophin, a Duchenne muscular dystrophy (DMD) model. The mdx genotypic DMD model has mild pathology, making non-curative therapeutic effects difficult to distinguish at baseline. Since the cardiac benefit of mineralocorticoid receptor antagonists has been translated to DMD patients, it is important to optimize potential advantages for skeletal muscle by further defining efficacy parameters.

Objective: We aimed to test whether therapeutic effects of mineralocorticoid receptor antagonists added to angiotensin converting enzyme inhibitors are detectable using three different reported methods of exacerbating the mdx phenotype.

Methods: We tested treatment with lisinopril and the mineralocorticoid receptor antagonist spironolactone in: 10 week-old exercised, 1 year-old sedentary, and 5 month-old isoproterenol treated mdx mice and performed comprehensive functional and histological measurements.

Results: None of the protocols to exacerbate mdx phenotypes resulted in dramatically enhanced pathology and no significant benefit was observed with treatment.

Conclusions: Since endogenous mineralocorticoid aldosterone production from immune cells in dystrophic muscle may explain antagonist efficacy, it is likely that these drugs work optimally during the narrow window of peak inflammation in mdx mice. Exercised and aged mdx mice do not display prolific damage and inflammation, likely explaining the absence of continued efficacy of these drugs. Since inflammation is more prevalent in DMD patients, the therapeutic window for mineralocorticoid receptor antagonists in patients may be longer.
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http://dx.doi.org/10.3233/JND-180323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732783PMC
November 2018
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