Publications by authors named "Kenji Oki"

77 Publications

Effect of Intraprocedural Cortisol Measurement on ACTH-stimulated Adrenal Vein Sampling in Primary Aldosteronism.

J Endocr Soc 2022 Sep 26;6(9):bvac104. Epub 2022 Jul 26.

Endocrine Center, Ijinkai Takeda General Hospital, Kyoto 601-1495, Japan.

Context: Adrenocorticotropin (ACTH) loading is used to increase the success rate of adrenal vein sampling (AVS).

Objective: We aimed to determine the effect of intraprocedural cortisol measurement (ICM) on ACTH-stimulated AVS (AS-AVS) owing to a lack of reliable data on this topic.

Methods: This multicenter, retrospective, observational study took place in 28 tertiary centers in Japan. Among 4057 patients enrolled, 2396 received both basal AVS (B-AVS) and AS-AVS and were divided into 2 groups according to whether ICM was used. The effect of ICM on AS-AVS was measured.

Results: In patients who underwent both AVS procedures, the ICM group had significantly higher success rates for both B-AVS and AS-AVS than the non-ICM group did. However, the probability of failure of AS-AVS after a successful B-AVS and the probability of success of AS-AVS after a failed B-AVS were not significantly different in the 2 groups. For subtype diagnosis, propensity-score matching revealed no significant difference between the 2 groups, and the discrepancy rate between B-AVS and AS-AVS for subtype diagnosis was also not significantly different.

Conclusion: ICM significantly increased the success rate of B-AVS and AS-AVS in protocols in which both AVS procedures were performed and had no effect on subtype diagnosis. However, in protocols in which both AVS procedures were performed, the results suggest ICM may not be necessary when performing AS-AVS if ICM is used only when B-AVS is performed. Our study suggests that ICM during AVS plays an important role and should be recommended.
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http://dx.doi.org/10.1210/jendso/bvac104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9342856PMC
September 2022

NFIA determines the -effect of genetic variation on Ucp1 expression in murinethermogenic adipocytes.

iScience 2022 Aug 7;25(8):104729. Epub 2022 Jul 7.

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan.

Thermogenic brown and beige adipocytes counteract obesity by enhancing energy dissipation via uncoupling protein-1 (Ucp1). However, the effect of genetic variation on these cells, a major source of disease susceptibility, has been less well studied. Here we examined beige adipocytes from obesity-prone C57BL/6J (B6) and obesity-resistant 129X1/SvJ (129) mouse strains and identified a -regulatory variant rs47238345 that is responsible for differential Ucp1 expression. The alternative T allele of rs47238345 at the -12kb enhancer in 129 facilitates the allele-specific binding of nuclear factor I-A (NFIA) to mediate allele-specific enhancer-promoter interaction and transcription. Furthermore, CRISPR-Cas9/Cpf1-mediated single nucleotide polymorphism (SNP) editing of rs47238345 resulted in increased Ucp1 expression. We also identified Lim homeobox protein 8 (Lhx8), whose expression is higher in 129 than in B6, as a acting regulator of Ucp1 in mice and humans. These results demonstrate the - and acting effects of genetic variation on Ucp1 expression that underlie phenotypic diversity.
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http://dx.doi.org/10.1016/j.isci.2022.104729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304612PMC
August 2022

Association of cardiovascular disease risk and changes in renin levels by mineralocorticoid receptor antagonists in patients with primary aldosteronism.

Hypertens Res 2022 Jun 28. Epub 2022 Jun 28.

Clinical Research Center, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.

A recent report stated that patients with primary aldosteronism who remain renin suppressed during mineralocorticoid receptor antagonist treatment might have a higher risk of developing cardiovascular disease than those with unsuppressed renin activity. We retrospectively investigated the incidence of composite cardiovascular disease and risk factors for cardiovascular disease in 1115 Japanese patients with primary aldosteronism treated with mineralocorticoid receptor antagonists. The median follow-up period was 3.0 years, and the incidence of cardiovascular events was very low (2.1%) throughout 5 years of follow-up. Changes in plasma renin activity from before to after mineralocorticoid receptor antagonist treatment were divided into three groups based on tertile, low, intermediate, and high plasma renin activity change groups, with incidences of cardiovascular disease events of 2.1%, 0.5%, and 3.7%, respectively. Multivariate Cox regression analysis revealed age (adjusted hazard ratio, 1.07; 95% confidence interval, [1.02-1.12]) and body mass index (adjusted hazard ratio, 1.13 [1.04-1.23]) as independent risk factors for cardiovascular disease. The high plasma renin activity change group had significantly higher cardiovascular disease risk with mineralocorticoid receptor antagonist treatment than the intermediate plasma renin activity change group (adjusted hazard ratio, 5.71 [1.28-25.5]). These data suggest that a high change in renin level after mineralocorticoid receptor antagonist treatment may not necessarily predict a better prognosis of cardiovascular disease in patients with primary aldosteronism.
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http://dx.doi.org/10.1038/s41440-022-00960-xDOI Listing
June 2022

Familial Hyperaldosteronism Type 3 with a Rapidly Growing Adrenal Tumor: An In Situ Aldosterone Imaging Study.

Curr Issues Mol Biol 2021 Dec 28;44(1):128-138. Epub 2021 Dec 28.

Department of Urology and Andrology, Kansai Medical University, Osaka 573-1191, Japan.

Primary aldosteronism is most often caused by aldosterone-producing adenoma (APA) and bi-lateral adrenal hyperplasia. Most APAs are caused by somatic mutations of various ion channels and pumps, the most common being the inward-rectifying potassium channel . Germ line mutations of cause familial hyperaldosteronism type 3 (FH3), which is associated with severe hyperaldosteronism and hypertension. We present an unusual case of FH3 in a young woman, first diagnosed with primary aldosteronism at the age of 6 years, with bilateral adrenal hyperplasia, who underwent unilateral adrenalectomy (left adrenal) to alleviate hyperaldosteronism. However, her hyperaldosteronism persisted. At the age of 26 years, tomography of the remaining adrenal revealed two different adrenal tumors, one of which grew substantially in 4 months; therefore, the adrenal gland was removed. A comprehensive histological, immunohistochemical, and molecular evaluation of various sections of the adrenal gland and in situ visualization of aldosterone, using matrix-assisted laser desorption/ionization imaging mass spectrometry, was performed. Aldosterone synthase (CYP11B2) immunoreactivity was observed in the tumors and adrenal gland. The larger tumor also harbored a somatic β-catenin activating mutation. Aldosterone visualized in situ was only found in the subcapsular regions of the adrenal and not in the tumors. Collectively, this case of FH3 presented unusual tumor development and histological/molecular findings.
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http://dx.doi.org/10.3390/cimb44010010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8929039PMC
December 2021

Association of DNA methylation with steroidogenic enzymes in Cushing's adenoma.

Endocr Relat Cancer 2022 Aug 29;29(8):495-502. Epub 2022 Jun 29.

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

DNA methylation and demethylation regulate the transcription of genes. DNA methylation-associated gene expression of adrenal steroidogenic enzymes may regulate cortisol production in cortisol-producing adenoma (CPA). We aimed to determine the DNA methylation levels of all genes encoding steroidogenic enzymes involved in CPA. Additionally, the aims were to clarify the DNA methylation-associated gene expression and evaluate the difference of CPA genotype from others using DNA methylation data. Twenty-five adrenal CPA and six nonfunctioning adrenocortical adenoma (NFA) samples were analyzed. RNA sequencing and DNA methylation array were performed. The methylation levels at 118 methylation sites of the genes were investigated, and their methylation and mRNA levels were subsequently integrated. Among all the steroidogenic enzyme genes studied, CYP17A1 gene was mainly found to be hypomethylated in CPA compared to that in NFA, and the Benjamini-Hochberg procedure demonstrated that methylation levels at two sites in the CYP17A1 gene body were statistically significant. PRKACA mutant CPAs predominantly exhibited hypomethylation of CYP17A1 gene compared with the GNAS mutant CPAs. Inverse associations between CYP17A1 methylation in three regions of the gene body and its mRNA levels were observed in the NFAs and CPAs. In applying clustering analysis using CYP17A1 methylation and mRNA levels, CPAs with PRKACA mutation were differentiated from NFAs and CPAs with a GNAS mutation. We demonstrated that CPAs exhibited hypomethylation of the CYP17A1 gene body in CPA, especially in the PRKACA mutant CPAs. Methylation of CYP17A1 gene may influence its transcription levels.
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http://dx.doi.org/10.1530/ERC-22-0115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339517PMC
August 2022

Hypomethylation associated vitamin D receptor expression in ATP1A1 mutant aldosterone-producing adenoma.

Mol Cell Endocrinol 2022 05 4;548:111613. Epub 2022 Mar 4.

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

DNA methylation alteration is tissue-specific and play a pivotal role in regulating gene transcription during cell proliferation and survival. We aimed to detect genes regulated by DNA methylation, and then investigated whether the gene influenced cell proliferation or survival in adrenal cells. DNA methylation and qPCR analyses were performed in nonfunctioning adrenocortical adenoma (NFA, n = 12) and aldosterone-producing adenoma (APA, n = 35) samples. The VDR gene promoter was markedly hypomethylated in APA with ATP1A1 mutation, and the promoter methylation levels showed a significant inverse association with the transcripts in APA. ATP1A1 mutation led to VDR transcription in HAC15 cells, and VDR suppression abrogated ATP1A1 mutation-mediated cell proliferation in HAC15 cells. We demonstrated that APA with ATP1A1 mutation showed entire hypomethylation in the VDR promoter and abundant VDR mRNA and protein expression. VDR suppression abrogated ATP1A1 mutation-mediated cell proliferation in HAC15 cells. Abundant VDR expression would be essential for ATP1A1 mutation-mediated cell proliferation.
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http://dx.doi.org/10.1016/j.mce.2022.111613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9082579PMC
May 2022

Mutant in Aldosterone-Producing Adenoma Leads to Cell Proliferation.

Int J Mol Sci 2021 Oct 12;22(20). Epub 2021 Oct 12.

Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan.

The molecular mechanisms by which mutation-mediated cell proliferation or tumorigenesis in aldosterone-producing adenomas (APAs) have not been elucidated. First, we investigated whether the APA-associated L104R mutation stimulated cell proliferation. Second, we aimed to clarify the molecular mechanisms by which the mutation-mediated cell proliferated. We performed transcriptome analysis in APAs with mutation. L104R mutation were modulated in human adrenocortical carcinoma (HAC15) cells (ATP1A1-mutant cells), and we evaluated cell proliferation and molecular signaling events. Transcriptome and immunohistochemical analysis showed that Na/K-ATPase (NKA) expressions in mutated APA were more abundant than those in non-functioning adrenocortical adenoma or mutated APAs. The significant increase of number of cells, amount of DNA and S-phase population were shown in ATP1A1-mutant cells. Fluo-4 in ATP1A1-mutant cells were significantly increased. Low concentration of ouabain stimulated cell proliferation in ATP1A1-mutant cells. ATP1A1-mutant cells induced Src phosphorylation, and low concentration of ouabain supplementation showed further Src phosphorylation. We demonstrated that NKAs were highly expressed in mutant APA, and the mutant stimulated cell proliferation and Src phosphorylation in ATP1A1-mutant cells. NKA stimulations would be a risk factor for the progression and development to an mutant APA.
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http://dx.doi.org/10.3390/ijms222010981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537586PMC
October 2021

Genotype-specific cortisol production associated with Cushing's syndrome adenoma with PRKACA mutations.

Mol Cell Endocrinol 2021 12 11;538:111456. Epub 2021 Sep 11.

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

The intracellular molecular mechanisms underlying the genotype of cortisol-producing adenoma (CPA) have not been fully determined. We analyzed gene expressions in CPA and the human adrenocortical cell line (HAC15 cells) with PRKACA mutation. Clustering analysis using a gene set associated with responses to cAMP revealed the possible differences between PRKACA mutant CPAs and GNAS and CTNNB1 mutant CPAs. The levels of STAR, CYP11A1, CYP17A1, CYP21A2, and FDX1 transcripts and cortisol levels per unit area in PRKACA mutant CPAs were significantly higher than those in GNAS mutant CPAs. PRKACA mutations led to an increase in steroidogenic enzyme expression and cortisol production in HAC15 cells. Transcriptome analysis revealed differences between PRKACA mutant CPAs and GNAS and CTNNB1 mutant CPAs. Cortisol production in PRKACA mutant CPAs is increased by the cAMP-PKA signaling pathway-mediated upregulation of steroidogenic enzymes transcription. The intracellular molecular mechanisms underlying these processes would be notably important in PRKACA mutant CPAs.
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http://dx.doi.org/10.1016/j.mce.2021.111456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551059PMC
December 2021

Subtype-specific trends in the clinical picture of primary aldosteronism over a 13-year period.

J Hypertens 2021 11;39(11):2325-2332

Clinical Research Institute of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, Kyoto.

Objective: Primary aldosteronism has two main clinically and biologically distinct subtypes: unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). We aimed to evaluate the changes of each subtype's clinical characteristics over a 13-year period.

Methods: This retrospective study involved time-trend analyses to identify changes in the clinical features of APA and BAH at diagnosis (2006-2018). A nationwide database from 41 Japanese referral centers was searched, which identified 2804 primary aldosteronism patients with complete baseline information and adrenal venous sampling (AVS) data.

Results: The proportion of patients with APA decreased from 51% in 2006-2009 to 22% in 2016-2018. Among the 1634 patients with BAH, trend analyses revealed decreases in hypertension duration (median 7--3 years; P < 0.01) and hypokalemia prevalence (18--11%; P < 0.01). However, among the 952 patients with APA, there were no significant changes in hypertension duration (median 8 years) and hypokalemia prevalence (overall 70%). Furthermore, the APA group had a trend towards increased use of multiple hypertensive drugs at diagnosis (30--43%; P < 0.01). When subtypes were reclassified according to the precosyntropin stimulation AVS data, APA patients tended to be diagnosed earlier and at milder forms, consistent with the trend in overall primary aldosteronism patients.

Conclusion: During 2006-2018, we identified marked subtype-specific trends in the clinical findings at the diagnosis of primary aldosteronism. Our results suggested that the emphasis on the implementing cosyntropin stimulation during AVS might lead to under-identification of APA, especially in patients with mild or early cases.
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http://dx.doi.org/10.1097/HJH.0000000000002924DOI Listing
November 2021

Update on Genetics of Primary Aldosteronism.

Biomedicines 2021 Apr 10;9(4). Epub 2021 Apr 10.

Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan.

Primary aldosteronism (PA) is the most common form of secondary hypertension, with a prevalence of 5-10% among patients with hypertension. PA is mainly classified into two subtypes: aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldosteronism. Recent developments in genetic analysis have facilitated the discovery of mutations in , , , , , , and in sporadic or familial forms of PA in the last decade. These findings have greatly advanced our understanding of the mechanism of excess aldosterone synthesis, particularly in APA. Most of the causative genes encode ion channels or pumps, and their mutations lead to depolarization of the cell membrane due to impairment of ion transport. Depolarization activates voltage-gated Ca channels and intracellular calcium signaling and promotes the transcription of aldosterone synthase, resulting in overproduction of aldosterone. In this article, we review recent findings on the genetic and molecular mechanisms of PA.
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http://dx.doi.org/10.3390/biomedicines9040409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069207PMC
April 2021

Should Adrenal Venous Sampling Be Performed in PA Patients Without Apparent Adrenal Tumors?

Front Endocrinol (Lausanne) 2021 12;12:645395. Epub 2021 Apr 12.

Department of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.

Introduction: Some aldosterone-producing micro-adenomas cannot be detected through image inspection. Therefore, adrenal venous sampling (AVS) is often performed, even in primary aldosteronism (PA) patients who have no apparent adrenal tumors (ATs) on imaging. In most of these cases, however, the PA is bilateral.

Objective: To clarify the clinical need for AVS in PA patients without apparent ATs, taking into consideration the rates of adrenalectomy.

Methods: This is a retrospective cross-sectional study assessing 1586 PA patients without apparent ATs in the multicenter Japan PA study (JPAS). We analyzed which parameters could be used to distinguish unilateral PA patients without apparent ATs from bilateral patients. We also analyzed the prevalences of adrenalectomy in unilateral PA patients.

Results: The unilateral subtype without an apparent AT was diagnosed in 200 (12.6%) of 1586 PA patients. Being young and female with a short hypertension duration, normokalemia, low creatinine level, low plasma aldosterone concentration, and low aldosterone-to-renin ratio (ARR) was significantly more common in bilateral than unilateral PA patients. If PA patients without apparent ATs were female and normokalemic with a low ARR (<560 pg/ml per ng/ml/h), the rate of unilateral PA was only 5 (1.1%) out of 444. Moreover, 77 (38.5%) of the 200 did not receive adrenalectomy, despite being diagnosed with the unilateral subtype based on AVS.

Conclusion: The low prevalence of the unilateral subtype in PA patients without apparent ATs suggests AVS is not indicated for all of these patients. AVS could be skipped in female normokalemic PA patients without apparent ATs if their ARRs are not high. However, AVS should be considered for male hypokalemic PA patients with high ARRs because the rates of the unilateral subtype are high in these patients.
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http://dx.doi.org/10.3389/fendo.2021.645395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072456PMC
December 2021

Association of aldosterone and blood pressure with the risk for cardiovascular events after treatments in primary aldosteronism.

Atherosclerosis 2021 05 29;324:84-90. Epub 2021 Mar 29.

Clinical Research Institute of Endocrinology and Metabolism, Kyoto Medical Center, National Hospital Organization, Endocrine Center, Ijinkai Takeda General Hospital, Kyoto, Japan.

Background And Aims: We used a dataset from a Japanese nationwide registry of patients with primary aldosteronism, to determine which of the parameters of hyperaldosteronism and blood pressure before or after treatments for primary aldosteronism (i.e., surgical adrenalectomy or a medication treatment) are important in terms of cardiovascular prognosis.

Methods: We assessed whether plasma aldosterone-to-renin ratio and pulse pressure levels before treatment and 6 months after treatment were associated with composite cardiovascular disease events during the 5-year follow-up period.

Results: The cohort included 1987 patients (mean age was 53.2 years, 52.0% were female, 37.2% had undergone surgical treatment, and the remainder had been treated with mineralocorticoid receptor antagonists). In the Cox proportional hazard model, the covariate-adjusted hazard ratio (95% confidence interval) for the composite cardiovascular disease events risk for each one-standard-deviation increase in the aldosterone-to-renin ratio or pulse pressure before treatment, those after treatment, or the duration of hypertension were 1.24 (1.05, 1.48), 0.74 (0.54, 1.02), and 1.07 (0.79, 1.44), 1.43 (1.07, 1.92), and 1.52 (1.19, 1.95), respectively. Patients with a high pre-treatment aldosterone-to-renin ratio of more than 603 and a large post-treatment pulse pressure of more than 49 mmHg showed approximately three-fold higher hazard ratios for cardiovascular events risk compared to those with a lower aldosterone-to-renin ratio and smaller pulse pressure.

Conclusions: Higher aldosterone-to-renin ratio before treatments, higher pulse pressure after treatments, and longer duration of hypertension were prognostic factors for cardiovascular diseases. Early intervention may be important for preventing cardiovascular disease among patients with primary aldosteronism.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.03.033DOI Listing
May 2021

Sex Differences in Renal Outcomes After Medical Treatment for Bilateral Primary Aldosteronism.

Hypertension 2021 02 28;77(2):537-545. Epub 2020 Dec 28.

Department of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, Japan (M.T., M.N.).

A higher incidence of bilateral primary aldosteronism in women is reported. Treatment of bilateral primary aldosteronism usually involves mineralocorticoid receptor antagonists. However, the impact of sex on renal outcomes is unknown. We compared renal outcomes between the sexes after mineralocorticoid receptor antagonist initiation by analyzing data obtained from 415 female and 313 male patients with bilateral primary aldosteronism who were treated with spironolactone or eplerenone in the JPAS (Japan Primary Aldosteronism Study). Over the course of 5 years, the temporal reduction in the estimated glomerular filtration rate was greater in women than in men (<0.001). Systolic blood pressure levels were equal between the sexes, despite higher doses of antihypertensive drugs in men. The mean of the annual decline in estimated glomerular filtration rate during what we termed the late phase, or 6 to 60 months after mineralocorticoid receptor antagonist initiation, was larger in women than in men after adjusting for patient characteristics (-1.33 mL/min per 1.73 m per year versus -1.04 mL/min per 1.73 m per year, <0.01). Female sex was a significant predictor of greater annual decline during the late phase in patients taking spironolactone but not in those taking eplerenone. Spironolactone use and diabetes were independent predictors of a greater annual decline in estimated glomerular filtration rate during the late phase in women. These findings suggest that female sex is associated with poorer renal outcomes in patients receiving mineralocorticoid receptor antagonist for bilateral primary aldosteronism.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16449DOI Listing
February 2021

Angiotensin-converting enzyme 2 expression is not induced by the renin-angiotensin system in the lung.

ERJ Open Res 2020 Oct 5;6(4). Epub 2020 Oct 5.

Dept of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

https://bit.ly/3fkopuO.
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http://dx.doi.org/10.1183/23120541.00402-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533374PMC
October 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044104PMC
October 2020

Variation in plasma glucagon levels according to obesity status in Japanese Americans with normal glucose tolerance.

Endocr J 2021 Jan 10;68(1):95-102. Epub 2020 Sep 10.

Department of Preventive Medicine for Diabetes and Lifestyle-related Diseases, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan.

Japanese Americans living in the United States are genetically identical to Japanese people, but have undergone a rapid and intense westernization of their lifestyle. This study investigated variability in glucagon secretion after glucose loading among Japanese Americans with normal glucose tolerance (NGT) according to obesity status. The 75-g oral glucose tolerance test (OGTT) was performed for 138 Japanese Americans (aged 40-75 years) living in Los Angeles. Plasma glucagon levels measured using the sandwich enzyme-linked immunosorbent assay were compared according to body mass index (BMI) categories among 119 individuals with NGT. The individuals were classified into three categories according to their BMI values: <22 kg/m (n = 37), 22-24.9 kg/m (n = 46), and ≥25 kg/m (n = 36). Fasting plasma glucagon levels and glucagon-area under the curve levels during the OGTT were the highest in the BMI ≥25 kg/m group. Fasting glucagon levels were correlated with BMI (r = 0.399, p < 0.001), fasting insulin levels (r = 0.275, p = 0.003) and the homeostasis model assessment-insulin resistance (r = 0.262, p = 0.004). In conclusion, our findings suggest that fasting hyperglucagonemia is associated with obesity and insulin resistance even during the NGT stage in the Japanese American population.
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http://dx.doi.org/10.1507/endocrj.EJ20-0366DOI Listing
January 2021

A Comparison of Adrenalectomy and Eplerenone on Vascular Function in Patients with Aldosterone-producing Adenoma.

J Clin Endocrinol Metab 2020 11;105(11)

Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

Context: It remains unclear whether adrenalectomy has more beneficial effects than treatment with a mineralocorticoid receptor antagonist on vascular function in patients with aldosterone-producing adenoma (APA).

Objective: The aim of this study was to compare the effects of adrenalectomy and treatment with eplerenone on vascular function in patients with APA.

Design, Setting, And Patients: Flow-mediated vasodilation (FMD), as an index of endothelium-dependent vasodilation, and nitroglycerine-induced vasodilation (NID), as an index of endothelium-independent vasodilation, were measured to assess vascular function before and after a 3-month treatment with eplerenone and at 3 months after adrenalectomy in 23 patients with APA.

Results: Flow-mediated vasodilation and NID after adrenalectomy were significantly higher than those before treatment with eplerenone (5.4 ± 2.6% vs 2.7 ± 1.9% and 14.8 ± 4.7% vs 9.6 ± 4.6%, P < 0.01, respectively) and those after treatment with eplerenone (5.4 ± 2.6% vs 3.1 ± 2.3% and 14.8 ± 4.7% vs 11.0 ± 5.3%, P < 0.01 and P = 0.03, respectively), while treatment with eplerenone did not alter FMD and NID compared with those before treatment with eplerenone. After adrenalectomy, the increase in FMD and NID were significantly correlated with a decrease in plasma aldosterone concentration and a decrease in the aldosterone-renin ratio. There were no significant relationships between FMD and changes in other parameters or between NID and changes in other parameters.

Conclusions: Adrenalectomy, but not treatment with eplerenone, improved vascular function in patients with APA. Adrenalectomy may be more effective than treatment with eplerenone for reducing the incidence of future cardiovascular events in patients with APA. Clinical Trial Information: URL for the clinical trial: http://UMIN; Registration Number for the clinical trial: UMIN000003409.
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http://dx.doi.org/10.1210/clinem/dgaa561DOI Listing
November 2020

A Case of Isolated Adrenocorticotropic Hormone Deficiency Caused by Pembrolizumab.

Case Rep Oncol 2020 Jan-Apr;13(1):200-206. Epub 2020 Mar 5.

Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Pembrolizumab (Keytruda®) is an anti-programmed cell death 1-specific monoclonal antibody that has become the standard second-line chemotherapy for unresectable advanced microsatellite instability-high colorectal cancer. Several immune-related adverse events (irAEs), particularly endocrinopathy, are linked to the administration of pembrolizumab. We report here a case of pembrolizumab-induced isolated adrenocorticotropic hormone deficiency in a patient with metastatic colon cancer. A 65-year-old woman visited our hospital for complaints of fatigue with a recent history of primary resection of cecal mucinous cancer and hepatectomy for liver metastasis 3 years ago. Peritoneal dissemination was detected 2 years after surgery. Several chemotherapeutic regimens of cytotoxic and molecular targeted drugs were administered; however, the metastases progressed gradually. Pembrolizumab monotherapy was started because of resistance to treatment. After 2 cycles of pembrolizumab, the patient was severely fatigued. Laboratory data demonstrated that the cortisol level was extremely low. All the other values were within the normal range. Magnetic resonance imaging indicated no mass in the pituitary gland. From multiple tolerance tests, we diagnosed isolated adrenocorticotropic hormone deficiency caused by pembrolizumab. The patient's symptoms improved promptly with cortisol treatment. An abdominal contrast-enhanced computed tomography scan after 5 cycles of pembrolizumab demonstrated that the size of the peritoneal dissemination remained unchanged. However, her serum level of carcinoembryonic antigen had decreased to normal levels. Endocrine disorders are very rarely seen as irAEs. Careful laboratory data follow-up is required to inhibit the progression of severe endocrine disorders.
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http://dx.doi.org/10.1159/000505687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154275PMC
March 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

Attempts to develop an enzyme converting DHIV to KIV.

Protein Eng Des Sel 2019 12;32(6):261-270

Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Blvd., MC 114-96, Pasadena, CA 91125, USA.

Dihydroxy-acid dehydratase (DHAD) catalyzes the dehydration of R-2,3-dihydroxyisovalerate (DHIV) to 2-ketoisovalerate (KIV) using an Fe-S cluster as a cofactor, which is sensitive to oxidation and expensive to synthesize. In contrast, sugar acid dehydratases catalyze the same chemical reactions using a magnesium ion. Here, we attempted to substitute the high-cost DHAD with a cost-efficient engineered sugar acid dehydratase using computational protein design (CPD). First, we tried without success to modify the binding pocket of a sugar acid dehydratase to accommodate the smaller, more hydrophobic DHIV. Then, we used a chemically activated substrate analog to react with sugar acid dehydratases or other enolase superfamily enzymes. Mandelate racemase from Pseudomonas putida (PpManR) and the putative sugar acid dehydratase from Salmonella typhimurium (StPutD) showed beta-elimination activity towards chlorolactate (CLD). CPD combined with medium-throughput selection improved the PpManR kcat/KM for CLD by four-fold. However, these enzyme variants did not show dehydration activity towards DHIV. Lastly, assuming phosphorylation could also be a good activation mechanism, we found that mevalonate-3-kinase (M3K) from Picrophilus torridus (PtM3K) exhibited adenosine triphosphate (ATP) hydrolysis activity when mixed with DHIV, indicating phosphorylation activity towards DHIV. Engineering PpManR or StPutD to accept 3-phospho-DHIV as a substrate was performed, but no variants with the desired activity were obtained.
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http://dx.doi.org/10.1093/protein/gzz042DOI Listing
December 2019

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

Elevated Plasma Renin Activity Caused by Accelerated-malignant Hypertension in a Patient with Aldosterone-producing Adenoma Complicated with Renal Insufficiency.

Intern Med 2019 Nov 10;58(21):3107-3111. Epub 2019 Jul 10.

Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan.

During the malignant phase of hypertension in patients with primary aldosteronism complicated with severe renal failure, the plasma renin activity may markedly increase with a false negative screening result for primary aldosteronism, thus potentially leading to a missed diagnosis of primary aldosteronism. We herein report the case of 37-year-old man who presented with accelerated-malignant hypertension complicated with severe renal insufficiency. The plasma renin activity was markedly increased in the malignant phase of hypertension, which were atypical results for primary aldosteronism. However, a plain abdominal computed tomography scan revealed a left adrenal nodule, which was diagnosed as aldosterone-producing adenoma by adrenal venous sampling.
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http://dx.doi.org/10.2169/internalmedicine.2327-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875448PMC
November 2019

Alteration of gut microbiota by a Westernized lifestyle and its correlation with insulin resistance in non-diabetic Japanese men.

J Diabetes Investig 2019 Nov 19;10(6):1463-1470. Epub 2019 Apr 19.

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

Aims/introduction: The severity of insulin resistance is higher in Japanese-American people with American lifestyles than in native Japanese people with Japanese lifestyles. Recently, the role of gut microbiota in the control of host metabolic homeostasis and organ physiology has been recognized. In addition, gut microbiota alterations have been suggested to contribute to pathogenesis of insulin resistance. The principle aim of the present study was to evaluate the impact of a Westernized lifestyle on the gut microbiota of Japanese-Americans versus native Japanese, and its correlation with insulin resistance.

Materials And Methods: A total of 14 native Japanese men living in Hiroshima, Japan, and 14 Japanese-American men living in Los Angeles, USA, were included. A 75-g oral glucose tolerance test was carried out for all participants to assess their glucose tolerance, and normal glucose tolerance was observed. We compared the insulin response with oral glucose load, the Matsuda Index, and the composition of the gut microbiota between the native Japanese and Japanese-American men.

Results: Japanese-American men showed higher area under the curve values for serum insulin concentrations during the oral glucose tolerance test and lower Matsuda Index than native Japanese men. Gut microbiota composition of the Japanese-American men was different; in particular, they showed a relatively lower abundance of Odoribacter than native Japanese men. The ratio between relative abundance of Odoribacter and Matsuda Index was positively correlated between the two groups.

Conclusions: Our findings suggest that Westernized lifestyles alter gut microbiota, and its alteration might induce insulin resistance in non-diabetic Japanese men.
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http://dx.doi.org/10.1111/jdi.13048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825921PMC
November 2019

Associations of nutrient intakes with obesity and diabetes mellitus in the longitudinal medical surveys of Japanese Americans.

J Diabetes Investig 2019 Sep 19;10(5):1229-1236. Epub 2019 Feb 19.

Department of Molecular and Internal Medicine, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Aims/introduction: Our previous survey of two Japanese populations, with different lifestyles but identical genetic dispositions, showed that Japanese Americans had different dietary intakes and higher prevalences of obesity and diabetes mellitus, compared with the native Japanese population. The present study examined whether Westernized dietary habits could affect the development of obesity or diabetes.

Materials And Methods: This study included 765 individuals with normal glucose tolerance at baseline medical examinations (1986 or 1989 in Los Angeles and in 1988 or 1992 in Hawaii) who subsequently completed follow-up medical examinations several years later. The participants were categorized at baseline as "lean" (576 individuals, body mass index of <25 kg/m ) or "obese" (189 individuals, body mass index of ≥25 kg/m ). Nutrient intakes were analyzed for associations with the development of obesity or diabetes using Cox's proportional hazard model.

Results: A total of 41 lean participants developed diabetes, which was not associated with any nutrient intakes (mean follow up 10.8 ± 6.6 years). A total of 36 obese participants developed diabetes, which was positively associated with intakes of animal protein, animal fat and saturated fatty acid (mean follow up 10.7 ± 6.3 years). A total of 85 lean participants became obese, which was positively associated with intakes of simple carbohydrates, sugar and fructose, as well as inversely associated with intakes of vegetable protein and complex carbohydrates (mean follow up 10.4 ± 6.5 years).

Conclusions: In the Japanese Americans, different nutrient intakes affected the development of obesity and diabetes. Furthermore, the associations of nutrient intakes with diabetes development varied according to the presence or absence of obesity.
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http://dx.doi.org/10.1111/jdi.13010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717818PMC
September 2019

Eplerenone improves endothelial function and arterial stiffness and inhibits Rho-associated kinase activity in patients with idiopathic hyperaldosteronism: a pilot study.

J Hypertens 2019 05;37(5):1083-1095

Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine.

Objective: Primary aldosteronism is one of the most common cause of secondary hypertension. It is well known that the incidence of cardiovascular events is higher in patients with primary aldosteronism than in patients with essential hypertension. In a previous study, we showed that aldosterone-producing adenoma is associated with vascular function and structure. The aim of this study was to evaluate the effects of eplerenone on vascular function in the macrovasculature and microvasculature, arterial stiffness and Rho-associated kinase (ROCK) activity in patients with idiopathic hyperaldosteronism (IHA).

Methods: Vascular function, including reactive hyperemia index (RHI), flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID), arterial stiffness including brachial-ankle pulse wave velocity (baPWV) and brachial intima-media thickness (IMT) and ROCK activity in peripheral leukocytes were measured before and after 12 weeks of treatment with eplerenone in 50 patients with IHA.

Results: After 12 weeks, eplerenone decreased the aldosterone renin ratio but did not alter SBP and DBP. Eplerenone treatment increased log RHI from 0.56 ± 0.25 to 0.69 ± 0.25 (P < 0.01) and NID from 12.8 ± 5.8 to 14.9 ± 6.9% (P = 0.02) and it decreased baPWV from 1540 ± 263 to 1505 ± 281 (P = 0.04) and ROCK activity from 1.20 ± 0.54 to 0.89 ± 0.42 (P < 0.01), whereas there was no significant change in FMD (increase from 4.6 ± 3.4 to 4.6 ± 3.6%, P = 0.99) or brachial IMT (decrease from 0.28 ± 0.07 to 0.28 ± 0.04 mm, P = 0.14).

Conclusion: Eplerenone improves microvascular endothelial function, vascular smooth muscle function, arterial stiffness and ROCK activity in patients with IHA.

Clinical Trial Registration Information: URL for Clinical Trial: http://UMIN; Registration Number for Clinical Trial: UMIN000003409.
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http://dx.doi.org/10.1097/HJH.0000000000001989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467648PMC
May 2019

Measurement of midnight ACTH levels is useful for the evaluation of midnight cortisol levels.

Steroids 2018 12 7;140:179-184. Epub 2018 Nov 7.

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

Objective: Elevated midnight cortisol levels induced by non-suppressed ACTH levels may lead to false-positive results for hypercortisolism in patients with adrenal incidentaloma. We investigated whether plasma ACTH-associated high midnight serum cortisol levels are correlated with other endocrinological findings with respect to hypothalamic-pituitaryadrenal function or hypercortisolism status.

Methods: Two-hundred-forty-six patients with adrenocortical adenoma were evaluated via measurements of midnight ACTH and cortisol levels, a 1-mg dexamethasone suppression test (DST), and a cosyntropin-releasing hormone (CRH) stimulation test. Patients were divided into four groups according to their midnight plasma ACTH levels.

Results: The groups with higher midnight ACTH levels had significantly higher basal ACTH levels. A positive relationship was observed between midnight serum cortisol and serum cortisol in the 1-mg DST for all groups; stronger associations were observed in the group with lower midnight ACTH. In the CRH test, peak, delta, and sigma ACTH had significant inverse relationships with midnight cortisol levels in the lowest and second lowest midnight ACTH groups. Patients with midnight cortisol levels >3.5 μg/dL were further divided into two groups according to whether their midnight plasma ACTH levels were below or above 10.0 pg/mL. There were significantly fewer patients with hypercortisolism in the higher ACTH group; midnight serum cortisol levels were associated with hypercortisolism only in the lower ACTH group.

Conclusion: We demonstrated that midnight ACTH-associated cortisol values were not correlated with other endocrinological findings or hypercortisolism state. Measurement of midnight ACTH levels is important, and careful evaluation is needed for patients with higher midnight ACTH levels.
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http://dx.doi.org/10.1016/j.steroids.2018.10.011DOI Listing
December 2018

Microvascular endothelial function is impaired in patients with idiopathic hyperaldosteronism.

Hypertens Res 2018 Nov 11;41(11):932-938. Epub 2018 Sep 11.

Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

The aims were to evaluate the relationship between idiopathic hyperaldosteronism (IHA) and grade of vascular function in the macrovasculature and microvasculature. Vascular function, including reactive hyperemia index (RIH), flow-mediated vasodilation (FMD), and nitroglycerine-induced vasodilation (NID) were evaluated in 52 patients with IHA, 53 patients with aldosterone-producing adenoma (APA), and 52 age-, sex-, and blood pressure-matched patients with essential hypertension (EHT). Log RHI was lower in the IHA and APA groups than in the EHT group (0.54 ± 0.25 and 0.55 ± 0.23 versus 0.79 ± 0.28; P < 0.01, respectively). FMD was lower in the APA group than in the EHT group (3.4 ± 2.1% versus 4.8 ± 2.8%; P = 0.02), whereas there was no significant difference in FMD between the IHA and the APA and EHT groups. NID was lower in the APA group than in the EHT group (10.0 ± 4.5% versus 12.5 ± 5.7%; P = 0.03), whereas there was no significant difference in NID between the IHA, APA, and EHT groups. Multiple regression analysis revealed an association of log RHI with plasma aldosterone concentration (t = -2.24; P = 0.03) and an association of FMD with plasma aldosterone concentration (t = -3.07; P < 0.01). Microvascular endothelial function was impaired in patients with IHA compared with that in patients with EHT.
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http://dx.doi.org/10.1038/s41440-018-0093-6DOI Listing
November 2018

Angiotensin 1-7 suppresses angiotensin II mediated aldosterone production via JAK/STAT signaling inhibition.

J Steroid Biochem Mol Biol 2019 01 17;185:137-141. Epub 2018 Aug 17.

Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.

Angiotensin 1-7 (Ang 1-7), which is a protein cleaved from angiotensin II (A-II), binds to the MAS receptor. Ang 1-7 has been demonstrated to exert protective effects against A-II-mediated cardiac, atherosclerotic, and renal damages. The aims of our study were to demonstrate the inhibitory role of Ang 1-7 in A-II-mediated aldosterone production by interacting with the MAS receptor in human adrenocortical carcinoma (HAC15) cells, and clarify the intracellular signaling mechanisms underlying the inhibition of aldosterone production by Ang 1-7. Ang 1-7 significantly suppressed A-II-stimulated aldosterone production, and partially abrogated A-II-induced upregulation of CYP11B2 expression. Treatment with a selective Ang 1-7 antagonist abrogated Ang 1-7-mediated inhibition of aldosterone production in HAC15 cells. Incubation of A-II-treated HAC15 cells with conditioned medium containing Ang 1-7 was demonstrated to suppress A-II-mediated aldosterone production and CYP11B2 expression. Proteomic analysis showed that Ang 1-7 predominantly inhibited the phosphorylation of JAK-STAT proteins in A-II stimulated HAC15 cells. Treatment of HAC15 cells with a STAT3 inhibitor partially but significantly repressed A-II-mediated aldosterone production by 63.2%. Similarly, treatment with a STAT5 inhibitor significantly abrogated A-II-stimulated aldosterone production in HAC15 cells by 60.7%. In conclusion, we demonstrated that Ang 1-7 negatively regulates A-II-mediated aldosterone production, and the observed inhibition of aldosterone production was associated with JAK/STAT signaling in human adrenal cells. Therefore, activation of Ang 1-7 or stimulation of the MAS receptor, which inhibits aldosterone production, is a promising therapeutic approach for the prevention of cardiovascular events that can directly affect the target organs.
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http://dx.doi.org/10.1016/j.jsbmb.2018.08.007DOI Listing
January 2019
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