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

肾上腺激素醛固酮增加肾脏对Na+的重吸收和K+的分泌，从而控制电解质平衡和长期血压。在7-20%的动脉高血压患者中，病理性的醛固酮升高(原发性醛固酮增多症)被认为是致病的。因此，需要严格调节醛固酮的分泌，并使之适应饮食中的盐摄入量。长期以来，人们已经知道，醛固酮的分泌受到血浆渗透压的强烈调节，高渗抑制了醛固酮的分泌。令人惊讶的是，在最近的醛固酮分泌概念中，这种独特的渗透敏感性在很大程度上被忽视了。肾上腺渗透压敏感性受损可能导致自主的醛固酮分泌和盐敏性高血压。然而，肾上腺渗透压敏感性的分子机制尚不清楚。在本研究中，我们旨在研究这些机制及其与Task3钾通道基因敲除小鼠盐敏感性高血压的相关性。具体地说，我们将解决以下问题：1.可兴奋的肾上腺皮质细胞的电特性和胞浆钙活性是否受到渗透压变化的影响？2.渗透压变化是否影响肾上腺皮质基因的转录和蛋白质组？3.肾上腺渗透压敏感性缺陷是否与Task3基因敲除小鼠的盐敏性高血压表型有关？通过成功地解决这些问题，我们将阐明肾上腺皮质细胞渗透压敏感性的细胞机制以及初级醛固酮增多症的复杂病理生理机制。

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.