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

细胞离子和 pH 稳态对肾上腺醛固酮分泌的长期调节以及原发性醛固酮增多症病理生理学的影响

• 批准号: 392121970
• 负责人: Dr. Sascha Bandulik
• 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: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/392121970?language=en
• 关键词: Impact; cellular; ion; pH; homeostasis

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.

盐皮质激素醛固酮对于盐和水的平衡起着重要作用，因此也对于动脉血压的控制起着重要作用。因此，约5-10%的高血压患者患有肾上腺皮质球细胞中醛固酮合成过高的问题，即所谓的原发性醛固酮增多症(PA)。绝大多数此类病例与离子通道和转运蛋白编码基因的反复突变有关。血管紧张素 II 或血浆 K+ 增加对醛固酮产生的生理刺激主要是由肾小球细胞膜去极化和胞浆 Ca2+ 活性增加触发的。这些参数作用的基本数据是从剧烈刺激的细胞中获得的。相比之下，PA 相关突变基因的表达会导致该信号通路的慢性自主刺激，包括 Ca2+ 活性的不同程度的增加。此外，在突变细胞中发现 Na+- 和 pH 稳态受到干扰。然而，这些因素对 PA 发展的作用仍不清楚。我们的初步研究还揭示了生理长期刺激过程中细胞质 Ca2+ 水平的动态变化，结果表明细胞 pH 稳态对于调节醛固酮分泌具有重要作用。通过我们的项目，我们希望更准确地弄清楚作为已知主要调节因子的胞质 Ca2+ 与细胞 pH 和 Na+ 的稳态之间的复杂相互作用，以及醛固酮合成的慢性生理刺激过程中的相关信号传导途径。在此基础上，我们想要分析该调节网络的紊乱如何决定 PA 的病理生理学。总的来说，我们期望对醛固酮合成的长期调节有新的见解，从而对 PA 的病理生理学有更全面的了解。最后，我们希望为该疾病的诊断和治疗找到新的靶点。