Osmolarity Controls Oscillatory Calcium Signaling to Reduce Autonomous Aldosterone Production in Zona Glomerulosa...

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.