KCNJ5 Mutation Contributes to Complete Clinical Success in Aldosterone-Producing Adenoma: A Study From a Single Center

Zhang, Cui; Wu, Luming; Jiang, Lei; Su, Tingwei; Zhou, Weiwei; Xu, Zhi-Hong; Xie, Jing; Sun, Fenyong; Zhu, Yu; Jiang, Yiran; Wang, Weiqing

doi:10.1016/j.eprac.2021.01.007

Cited by 10 publications

(12 citation statements)

References 31 publications

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“…In addition, the abundance of pNCC was higher in mutation carriers, which implied that pNCC in uEVs might be an indicator of KCNJ5 mutations. Recently, several studies have indicated that somatic KCNJ5 mutations are an independent predictor of favorable outcomes after adrenalectomy ( 5 – 7 , 23 ). High pNCC expression in uEVs might, therefore, be an indicator of KCNJ5 mutations and AVS.…”

Section: Discussionmentioning

confidence: 99%

“…Potassium inwardly-rectifying channel subfamily J member 5 ( KCNJ5 ) was the first identified gene mutated in aldosterone-producing adenoma (APA) ( 4 ). Recent studies have suggested that KCNJ5 mutation is a protective factor for complete clinical success ( 5 – 7 ). To date, AVS is generally regarded as the gold standard test for distinguishing between unilateral and bilateral aldosteronism; the lateralization rate has been reported as 50-60%, but it is not widely available due to technical difficulties, cost, and the invasive nature of operation ( 8 – 10 ).…”

Section: Introductionmentioning

confidence: 99%

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The Role of Urinary Extracellular Vesicles Sodium Chloride Cotransporter in Subtyping Primary Aldosteronism

et al. 2022

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BackgroundAdrenal venous sampling (AVS) is recognized as the gold standard for subtyping primary aldosteronism (PA), but its invasive nature and technical challenges limit its availability. A recent study reported that sodium chloride cotransporter (NCC) in urinary extracellular vesicles (uEVs) is a promising marker for assessing the biological activity of aldosterone and can be treated as a potential biomarker of PA. The current study was conducted to verify the hypothesis that the expression of NCC and its phosphorylated form (pNCC) in uEVs are different in various subtypes and genotypes of PA and can be used to select AVS candidates.MethodsA total of 50 patients with PA were enrolled in the study. Urinary extracellular vesicles (uEVs) were isolated from spot urine samples using ultracentrifugation. NCC and pNCC expressions were tested in patients diagnosed with PA who underwent AVS. Sanger sequencing of KCNJ5 was performed on DNA extracted from adrenal adenoma.ResultspNCC (1.89 folds, P<.0001) and NCC (1.82 folds, P=0.0002) was more abundant in the uEVs in the high lateralization index (h-LI, ≥ 4) group than in the low LI (l-LI, < 4) group. Carriers of the somatic KCNJ5 mutations, compared with non-carriers, had more abundant pNCC expression (2.16 folds, P=0.0039). Positive correlation between pNCC abundance and plasma aldosterone level was found in this study (R = 0.1220, P = 0.0129).ConclusionsThe expression of pNCC in uEVs in patients with PA with various subtypes and genotypes was different. It can be used as biomarker of AVS for PA subtyping.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Role of Urinary Extracellular Vesicles Sodium Chloride Cotransporter in Subtyping Primary Aldosteronism

et al. 2022

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“…Bilateral CT was used to detect bilateral adrenal hyperplasia or nodules on CT. Adrenal venous sampling (AVS) was performed by an experienced radiologist. Cannulation was considered successful if the cortisol adrenal vein:cortisol peripheral vein ratio was greater than 3 without adrenal corticotropic hormone (ACTH) stimulation ( 17 ). Twenty-one patients underwent AVS with unilateral lateralization, and 3 patients were diagnosed with unilateral PA by CT scan.…”

Section: Methodsmentioning

confidence: 99%

“…Other mutations include CACNA1D, ATP1A1, and ATP2B3 ( 15 , 16 ). In China, KCNJ5 mutations occur in up to 70.7% of APAs ( 17 ) and account for most unilateral adrenal diseases. APAs appear as a single well-circumscribed nodule with various degrees of adrenal cortex remodeling, i.e., atrophic, with a diffuse hyperplasia or nodular hyperplasia ( 18 , 19 ).…”

Section: Introductionmentioning

confidence: 99%

Exploration of KCNJ5 Somatic Mutation and CYP11B1/CYP11B2 Staining in Multiple Nodules in Primary Aldosteronism

et al. 2022

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ObjectiveUnilateral primary aldosteronism (PA) includes aldosterone-producing adenoma (APA), unilateral adrenal hyperplasia, and unilateral multiple nodules. The correlation of multiple nodules, especially genotypic and pathological characteristics, remains unknown. KCNJ5 mutation accounts for 60–80% of unilateral PA, so we aimed to explore the correlation of KCNJ5 somatic mutation and CYP11B1/CYP11B2 staining in multiple nodules in unilateral PA.Design and MethodsA total of 56 microdissected nodules from 24 patients with unilateral PA were included. We assessed somatic KCNJ5 mutations, immunohistochemistry for aldosterone synthase (CYP11B2)/cortisol synthase (CYP11B1), and histological cellular composition of nodules together with adjacent adrenal cortical statements.ResultsKCNJ5 mutations were identified in 17 (17/56, 30.4%) nodules from 11 adrenals (11/24, 45.8%). All KCNJ5-mutant nodules were positive for CYP11B2 staining, 6 cases (6/11) had only one KCNJ5-mutant nodular, and the other 5 cases (5/11) had more than one KCNJ5-mutant nodules. Three cases (3/11) had different KCNJ5 mutations in individual nodules. Compared with KCNJ5-positive adrenals, the cortices adjacent to the nodules in KCNJ5-negative adrenals showed significant proliferation (p = 0.004). CYP11B2/CYP11B1 expression patterns revealed great heterogeneity in intensity and range both in KCNJ5-mutant nodules and KCNJ5-WT ones.ConclusionThere is great heterogeneity among nodules from patients with unilateral PA. Countable nodules could be considered as multiple APAs, featuring somatic KCNJ5 mutation, positive CYP11B2 staining, and lack of adjacent cortical proliferation in unilateral multiple nodules.

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“…Previous studies showed that unilateral PA patients carrying KCNJ5 mutations had a better hypertension prognosis after adrenalectomy than that of those non-mutant carriers [20,[47][48][49]. Therefore, how to identify whether APA patients harbor KCNJ5 mutation before surgery is an important topic.…”

Section: Pharmacology and Kcnj5 Mutationmentioning

confidence: 99%

Pathophysiological and Pharmacological Characteristics of KCNJ5 157-159delITE Somatic Mutation in Aldosterone-Producing Adenomas

Peng

Liao²,

Chueh

et al. 2021

Biomedicines

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Mutated channelopathy could play important roles in the pathogenesis of aldosterone-producing adenoma (APA). In this study, we identified a somatic mutation, KCNJ5 157-159delITE, and reported its immunohistological, pathophysiological and pharmacological characteristics. We conducted patch-clamp experiments on HEK293T cells and experiments on expression of aldosterone synthase (CYP11B2) and aldosterone secretion in HAC15 cells to evaluate electrophysiological and functional properties of this mutated KCNJ5. Immunohistochemistry was conducted to identify expressions of several steroidogenic enzymes. Macrolide antibiotics and a calcium channel blocker were administrated to evaluate the functional attenuation of mutated KCNJ5 channel in transfected HAC15 cells. The interaction between macrolides and KCNJ5 protein was evaluated via molecular docking and molecular dynamics simulation analysis. The immunohistochemistry analysis showed strong CYP11B2 immunoreactivity in the APA harboring KCNJ5 157-159delITE mutation. Whole-cell patch-clamp data revealed that mutated KCNJ5 157-159delITE channel exhibited loss of potassium ion selectivity. The mutant-transfected HAC15 cells increased the expression of CYP11B2 and aldosterone secretion, which was partially suppressed by clarithromycin and nifedipine but not roxithromycin treatment. The docking analysis and molecular dynamics simulation disclosed that roxithromycin had strong interaction with KCNJ5 L168R mutant channel but not with this KCNJ5 157-159delITE mutant channel. We showed comprehensive evaluations of the KCNJ5 157-159delITE mutation which revealed that it disrupted potassium channel selectivity and aggravated autonomous aldosterone production. We further demonstrated that macrolide antibiotics, roxithromycin, could not interfere the aberrant electrophysiological properties and gain-of-function aldosterone secretion induced by KCNJ5 157-159delITE mutation.

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KCNJ5 Mutation Contributes to Complete Clinical Success in Aldosterone-Producing Adenoma: A Study From a Single Center

Cited by 10 publications

References 31 publications

The Role of Urinary Extracellular Vesicles Sodium Chloride Cotransporter in Subtyping Primary Aldosteronism

The Role of Urinary Extracellular Vesicles Sodium Chloride Cotransporter in Subtyping Primary Aldosteronism

Exploration of KCNJ5 Somatic Mutation and CYP11B1/CYP11B2 Staining in Multiple Nodules in Primary Aldosteronism

Pathophysiological and Pharmacological Characteristics of KCNJ5 157-159delITE Somatic Mutation in Aldosterone-Producing Adenomas

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