title: Pathogenesis of Adrenal Aldosterone-Producing Adenomas Carrying Mutations of the Na(+)/K(+)-ATPase.
abstract: Aldosterone-producing adenoma (APA) is a major cause of primary aldosteronism, leading to secondary hypertension. Somatic mutations in the gene for the α1 subunit of the Na(+)/K(+)-ATPase were found in about 6% of APAs. APA-related α1 subunit of the Na(+)/K(+)-ATPase mutations lead to a loss of the pump function of the Na(+)/K(+)-ATPase, which is believed to result in membrane depolarization and Ca(2+)-dependent stimulation of aldosterone synthesis in adrenal cells. In addition, H(+) and Na(+) leak currents via the mutant Na(+)/K(+)-ATPase were suggested to contribute to the phenotype. The aim of this study was to investigate the cellular pathophysiology of adenoma-associated Na(+)/K(+)-ATPase mutants (L104R, V332G, G99R) in adrenocortical NCI-H295R cells. The expression of these Na(+)/K(+)-ATPase mutants depolarized adrenal cells and stimulated aldosterone secretion. However, an increase of basal cytosolic Ca(2+) levels in Na(+)/K(+)-ATPase mutant cells was not detectable, and stimulation with high extracellular K(+) hardly increased Ca(2+) levels in cells expressing L104R and V332G mutant Na(+)/K(+)-ATPase. Cytosolic pH measurements revealed an acidification of L104R and V332G mutant cells, despite an increased activity of the Na(+)/H(+) exchanger. The possible contribution of cellular acidification to the hypersecretion of aldosterone was supported by the observation that aldosterone secretion of normal adrenocortical cells was stimulated by acetate-induced acidification. Taken together, mutations of the Na(+)/K(+)-ATPase depolarize adrenocortical cells, disturb the K(+) sensitivity, and lower intracellular pH but, surprisingly, do not induce an overt increase of intracellular Ca(2+). Probably, the autonomous aldosterone secretion is caused by the concerted action of several pathological signaling pathways and incomplete cellular compensation.
authors.affiliation: Medical Cell Biology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Stindl
authors.affiliation: Medical Cell Biology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Tauber
authors.affiliation: Medical Cell Biology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Sterner
authors.affiliation: Medical Cell Biology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Tegtmeier
authors.affiliation: Medical Cell Biology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Warth
authors.affiliation: Medical Cell Biology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Bandulik
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology / Q000378:metabolism*; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism; D018246:Adrenocortical Adenoma / Q000235:genetics* / Q000378:metabolism; D018268:Adrenocortical Carcinoma / Q000235:genetics / Q000378:metabolism; D000450:Aldosterone / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D003600:Cytosol / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009154:Mutation; D018408:Patch-Clamp Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000378:metabolism
chemical_list: D017923:Sodium-Hydrogen Exchangers; D000450:Aldosterone; C499076:ATP1A1 protein, human; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium