{"doi":"10.1210/endocr/bqaf147","title":"Osmolarity Controls Oscillatory Calcium Signaling to Reduce Autonomous Aldosterone Production in Zona Glomerulosa Cells","abstract":"Primary aldosteronism (PA) is characterized by autonomous aldosterone (Aldo) production, resulting in blood volume/electrolyte imbalance and hypertension. Intracellular calcium (Ca2+) is the principal signal driving Aldo synthesis in adrenal zona glomerulosa (zG) cells, and mutations in ion transport genes that regulate Ca2+ are frequently mediators of PA. When organized in intact rosette structures, zG cells are voltage oscillators; stimulation by angiotensin II (AngII) or loss of TWIK-related acid-sensitive potassium (TASK) channel function evokes stereotypic Ca2+ oscillations with bursting activity proportional to increased steroidogenesis. Here, we delineate the role of the osmolar-volume regulatory axis in the control of Ca2+ and Aldo production in adrenal slices. Strikingly, in both pharmacological and genetic models of PA, extracellular osmolarity (OSMEC) potently and reversibly regulated Aldo secretion and Ca2+ signaling. Elevated OSMEC progressively suppressed Aldo production from AngII-stimulated adrenal slices and strongly inhibited autonomous production in both zG-specific TASK knockout slices and wild-type slices incubated with TASK inhibitors (TIs). To determine if the effects of OSMEC on Ca2+ dynamics were causative, we imaged adrenal slices expressing zG-specific GCaMP6f incubated in variable osmotic media with TIs or AngII. Consistent with Aldo suppression, increasing osmolarity proportionally reduced the number of active cells and the Ca2+ activity of bursting cells evoked by TASK loss of function or AngII stimulation. Collectively, our findings identify OSMEC as a broad regulator of zG excitability and adrenal steroidogenesis, and suggest that targeting volume-regulatory mechanisms such as the Na+-K+-2Cl- cotransporter may offer a novel strategy to suppress Aldo autonomy in PA.","journal":"Endocrinology","year":2025,"id":542485,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9514,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":940694,"name":"Molly R. Gerding","orcid":null,"position":1,"is_corresponding":false},{"id":253830,"name":"David T. Breault","orcid":"0000-0002-0402-4857","position":2,"is_corresponding":false},{"id":896853,"name":"Edward H. Nieh","orcid":null,"position":3,"is_corresponding":false},{"id":323068,"name":"Mark P. Beenhakker","orcid":"0000-0002-4541-0201","position":4,"is_corresponding":false},{"id":310378,"name":"Paula Q. Barrett","orcid":"0000-0003-2052-3899","position":5,"is_corresponding":false},{"id":310374,"name":"Nick A. Guagliardo","orcid":"0000-0003-2539-1346","position":6,"is_corresponding":false},{"id":1432062,"name":"Mohamed Diagne","orcid":null,"position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T02:52:55.809501Z","pmid":"41091658","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}