Dataset Information

The Effects of Different Calcium Channel Blockers on Aldosterone-Producing Adenoma Cells.

ABSTRACT: Purpose: The aim of this study is to examine the effects of different kinds of calcium channel blockers (CCBs) on primary aldosterone-producing adenoma (APA) mainly with KCNJ5 mutations. Primary cultured APA cells were treated with different calcium channel blockers (L/T type CCB benidipine, T-type CCB mibefradil and L-type CCB nifedipine), and aldosterone secretagogues with or without nifedipine. Aldosterone level, aldosterone synthase (CYP11B2) mRNA expression and cell proliferation were detected. The results showed that all three CCBs significantly inhibit aldosterone secretion and CYP11B2 mRNA expression. Benidipine was relatively more effective than mibefradil or nifedipine. In addition, only mibefradil marginally inhibited cell proliferation. Adrenocorticotropin (ACTH) had a much stronger effect in stimulating aldosterone secretion and promoting cell proliferation from APA's than angiotensin II (ATII). Different from ACTH and ATII, potassium had no effect. Nifedipine inhibited the basal and ACTH-, ATII-elicited aldosterone secretion. Twenty three of 24 APAs had somatic KCNJ5 mutation. In conclusion, benidipine, mibefradil and nifedipine significantly inhibit aldosterone secretion in primary cultured APA cells.

SUBMITTER: Wang F

PROVIDER: S-EPMC7198795 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Effects of Different Calcium Channel Blockers on Aldosterone-Producing Adenoma Cells.

Wang Fen F Ma Xiaosen X Tong Anli A Zhang Yushi Y Wen Jin J Li Yuxiu Y

Frontiers in endocrinology 20200428

<b>Purpose:</b> The aim of this study is to examine the effects of different kinds of calcium channel blockers (CCBs) on primary aldosterone-producing adenoma (APA) mainly with <i>KCNJ5</i> mutations. Primary cultured APA cells were treated with different calcium channel blockers (L/T type CCB benidipine, T-type CCB mibefradil and L-type CCB nifedipine), and aldosterone secretagogues with or without nifedipine. Aldosterone level, aldosterone synthase (CYP11B2) mRNA expression and cell proliferat ...[more]

PMID: 32411097

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Project description:BACKGROUND: High blood pressure can cause kidney damage, which can increase blood pressure, leading to a vicious cycle. It is not clear whether the protective effects of T-type calcium channel blockers (T-type CCBs) on renal function are better than those of L-type CCBs or renin-angiotensin system (RAS) antagonists in patients with hypertension. METHODS AND FINDINGS: PUBMED, MEDLINE, EMBASE, OVID, Web of Science, Cochrane, CNKI, MEDCH, VIP, and WANFANG databases were searched for clinical trials published in English or Chinese from January 1, 1990, to December 31, 2013. The weighted mean difference (WMD) and 95% confidence interval (CI) were calculated and reported. A total of 1494 reports were collected, of which 24 studies with 1,696 participants (including 809 reports comparing T-type CCBs versus L-type CCBs and 887 reports comparing T-type CCB versus RAS antagonists) met the inclusion criteria. Compared with L-type CCBs, T-type CCBs resulted in a significant decline in aldosterone (mean difference?=?-15.19, 95% CI -19.65 - -10.72, p<1×10(-5)), proteinuria (mean difference?=?-0.73, 95% CI -0.88 - -0.57, p<1×10(-5)), protein to creatinine ratio (mean difference?=?-0.22, 95% CI -0.41 - -0.03, p?=?0.02), and urinary albumin to creatinine ratio (mean difference?=?-55.38, 95% CI -86.67 - -24.09, p?=?0.0005); no significant difference was noted for systolic blood pressure (SBP) (p?=?0.76) and diastolic blood pressure (DBP) (p?=?0.16). The effects of T-type CCBs did not significantly differ from those of RAS antagonists for SBP (p?=?0.98), DBP (p?=?0.86), glomerular filtration rate (p?=?0.93), albuminuria (p?=?0.97), creatinine clearance rate (p?=?0.24), and serum creatinine (p?=?0.27) in patients with hypertension. CONCLUSION: In a pooled analysis of data from 24 studies measuring the effects of T-type CCBs on renal function and aldosterone, the protective effects of T-type CCBs on renal function were enhanced compared with L-type CCBs but did not differ from RAS antagonists. Their protective effects on renal function were independent of blood pressure.

Project description:The endoplasmic reticulum (ER) plays a pivotal role in syntheses of proteins and steroid hormones and regulation of intracellular Ca2+ 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 (CLGN) was the most highly expressed ER-associated gene in APAs relative to nonfunctioning adrenocortical adenomas. Analysis with quantitative polymerase chain reaction revealed CLGN 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 CLGN mRNA levels. CLGN overexpression in HAC15 cells increased aldosterone levels but did not stimulate CYP11B2 mRNA levels. Pathway and gene ontology analyses using RNA sequencing results showed that tRNA aminoacyl metabolism was the most enriched pathway in CLGN-overexpressing cells. CYP11B2 (aldosterone synthase) and HSD3B2 (3 beta-hydroxysteroid dehydrogenase/delta 5->4-isomerase type 2) protein expression were more abundant in CLGN-overexpressing cells. CLGN 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 KCNJ5 mutation did not affect aldosterone production. To summarize, CLGN was upregulated and associated with aldosterone production via translational regulation of CYP11B2 in APAs.

Dataset Information

The Effects of Different Calcium Channel Blockers on Aldosterone-Producing Adenoma Cells.

Publications

The Effects of Different Calcium Channel Blockers on Aldosterone-Producing Adenoma Cells.

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