Impact of cellular ion- and pH homeostasis on the long-term regulation of adrenal aldosterone secretion and on the pathophysiology of primary aldosteronism

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The mineralocorticoid aldosterone plays a major role for the salt and water balance, and thereby, also for arterial blood pressure control. Accordingly, about 5-10% of hypertensive patients suffer from an inappropriately high synthesis of aldosterone in adrenocortical glomerulosa cells, a so-called primary aldosteronism (PA). A great majority of such cases is associated with recurrent mutations of genes coding for ion channels and transporters. The physiological stimulation of aldosterone production by angiotensin II or increased plasma K+ is mainly triggered by a membrane depolarisation and an increased cytosolic Ca2+ activtiy of glomerulosa cells. Fundamental data on the action of these parameters were obtained from acutely stimulated cells. By contrast, the expression of PA associated mutant genes causes a chronic autonomous stimulation of that signaling pathway including a variable increase of the Ca2+ activity. Moreover, a disturbed Na+- and pH homeostasis was found in the mutant cells. However, the role of these factors for the development of PA is still elusive. Our preliminary studies disclosed also dynamic changes of the cytosolic Ca2+ levels during physiological long-term stimulation and the results point to an important function of the cellular pH homeostasis for the regulation of aldosterone secretion. With our project, we want to figure out more precisely the complex interplay between the cytosolic Ca2+ as the known main regulatory factor and the homeostasis of cellular pH and Na+, as well of related signaling pathways during a chronic physiological stimulation of aldosterone synthesis. Based on that, we want to analyze how a disturbance of this regulatory network determines the pathophysiology of PA. Overall, we expect new insights into the long-term regulation of aldosterone synthesis and thereby a more comprehensive understanding of the pathophysiology of PA. Finally, we hope to identify new targets for the diagnosis and the medical treatment of this disease.