The mechanisms of osmo-sensitivity of adrenocortical cells and their relevance for the adrenal phenotype of the Task3 knockout mouse

• Applicant: Professor Dr. Richard Warth
• Subject Area: Anatomy and Physiology ; Endocrinology, Diabetology, Metabolism
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 403208210

The adrenal hormone aldosterone increases renal Na+ reabsorption and K+ secretion and, thereby, controls electrolyte homeostasis and long-term blood pressure. A pathological increase of aldosterone (primary aldosteronism) is believed to be disease-causing in 7-20% of patients with arterial hypertension. Thus, aldosterone secretion needs to be tightly regulated and adapted to dietary salt intake. It is already known for a long time that aldosterone secretion is strongly modulated by plasma osmolarity with hypertonicity inhibiting aldosterone secretion. Surprisingly, the relevance of this unique osmo-sensitivity has been largely neglected in recent concepts of aldosterone secretion. It appears plausible that impaired adrenal osmo-sensitivity contributes to autonomous aldosterone secretion and salt-sensitive hypertension. However, the molecular mechanisms underlying the adrenal osmo-sensitivity are poorly understood.In this proposal, we aim at investigating these mechanisms and their relevance for the salt-sensitive hypertension of Task3 potassium channel knockout mice. Specifically, we will address the following questions:1. Are electrical properties and cytosolic Ca2+ activity of excitable adrenocortical cells affected by changes of osmolarity?2. Do osmotic changes affect adrenocortical gene transcription and proteome?3. Does a defect of adrenal osmo-sensitivity contribute to the salt-sensitive hypertension phenotype of Task3 knockout mice?By addressing these questions successfully, we will shed light on the cellular mechanisms underlying osmo-sensitivity of adrenocortical cells and on the complex pathophysiology underlying primary aldosteronism.

• DFG Programme: Research Grants