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

肾上腺皮质细胞渗透敏感性的机制及其与Task3基因敲除小鼠肾上腺表型的相关性

• 批准号: 403208210
• 负责人: Professor Dr. Richard Warth
• 金额: --
• 依托单位: Lehrstuhl Medizinische Zellbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/403208210?language=en
• 关键词: mechanisms; osmo; sensitivity; adrenocortical; cells

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.

肾上腺激素醛固酮增加肾脏Na+重吸收和K+分泌，从而控制电解质稳态和长期血压。醛固酮的病理性增加（原发性醛固酮增多症）被认为是7-20%的动脉高血压患者的病因。因此，醛固酮分泌需要严格调节，并适应饮食中的盐摄入量。长期以来，人们已经知道醛固酮分泌受血浆渗透压的强烈调节，高渗抑制醛固酮分泌。令人惊讶的是，在最近的概念醛固酮分泌的这种独特的β-敏感性的相关性已在很大程度上被忽视。肾上腺皮质激素敏感性受损可能导致自发性醛固酮分泌和盐敏感性高血压。然而，肾上腺皮质激素敏感性的分子机制知之甚少，在这个提议中，我们的目的是调查这些机制及其与Task 3钾通道基因敲除小鼠的盐敏感性高血压的相关性。具体而言，我们将解决以下问题：1. 渗透压变化是否影响兴奋性肾上腺皮质细胞的电特性和胞浆Ca ~（2+）活性？2. 渗透压变化是否影响肾上腺皮质基因转录和蛋白质组？3. 肾上腺渗透压敏感性缺陷是否会导致Task 3基因敲除小鼠的盐敏感性高血压表型？通过成功地解决这些问题，我们将阐明肾上腺皮质细胞对β-肾上腺素敏感性的细胞机制和原发性醛固酮增多症的复杂病理生理机制。