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Aldosterone-producing adenoma (APA) is a major cause of primary aldosteronism, leading to secondary hypertension. Somatic mutations in the gene for the [alpha]1 subunit of the Na /K -ATPase were found in about 6% of APAs. APA-related [alpha]1 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 Ca2 -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 Ca2 levels in Na /K -ATPase mutant cells was not detectable, and stimulation with high extracellular K hardly increased Ca2 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 Ca2 . Probably, the autonomous aldosterone secretion is caused by the concerted action of several pathological signaling pathways and incomplete cellular compensation.

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