The Role of Chloride and Calcium Channels for Calcium Signalling in the Zona glomerulosa

氯离子和钙通道对肾小球带钙信号传导的作用

• 批准号: 413724788
• 负责人: Dr. Gabriel Stölting
• 金额: --
• 依托单位: Arbeitsgruppe Hypertension und molekulare Biologie endokriner Tumore
• 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/413724788?language=en
• 关键词: Role; Chloride; Calcium; Channels; Signalling

The outermost layer of the adrenal gland, the zona glomerulosa, is tasked with the production of the mineralocorticoid aldosterone. As aldosterone is highly lipophilic, its serum concentration must be regulated on the level of synthesis. In its target organs, e.g. the kidney, aldosterone associates with intracellular receptors and controls the expression of diverse genes to increase sodium chloride and water reabsorption while excreting potassium resulting in an increase of the arterial blood pressure. About 6% of all cases of arterial hypertension are the result of primary hyperaldosteronism caused by an unregulated, pathological synthesis of aldosterone. Recent studies suggest that changes to genes encoding ion channels and transporters—either as somatic mutations in aldosterone-producing adenomas or germline mutations in familial hyperaldosteronism—are underlying many cases of primary aldosteronism. Based on our recent contributions to this field, we will study the role of calcium and chloride ions in the electrical excitability of zona glomerulosa cells in general and the role of the calcium channels CaV1.3 and CaV3.2 as well as the chloride channel ClC-2 in particular. To this end, we established acute adrenal gland slice preparations to investigate zona glomerulosa function using calcium imaging and patch clamp electrophysiology as well as further supporting methods. Our access to knock-out and knock-in mouse models of many involved ion channels will allow us to unravel their contributions to zona glomerulosa physiology and pathophysiology on a cellular level.

肾上腺最外面的一层，即球状带，负责产生矿质皮质激素醛固酮。由于醛固酮是高度亲脂性的，其血清浓度必须在合成水平上进行调节。在其靶器官，如肾脏，醛固酮与细胞内受体结合，控制多种基因的表达，增加氯化钠和水的重吸收，同时排泄钾，导致动脉血压升高。在所有的动脉高血压病例中，约有6%是由醛固酮无规律的病理性合成引起的原发性醛固酮增多症所致。最近的研究表明，编码离子通道和转运蛋白的基因的变化-无论是产生醛固酮的腺瘤的体细胞突变还是家族性醛固酮增多症的生殖系突变-是许多原发性醛固酮增多症的基础。根据我们在这一领域的最新贡献，我们将研究钙离子和氯离子在肾小球带细胞电兴奋性中的作用，特别是钙通道CaV1.3和CaV3.2以及氯通道ClC-2的作用。为此，我们建立了急性肾上腺切片标本，利用钙成像和膜片钳电生理学以及进一步的支持方法来研究肾小球带的功能。我们获得了许多相关离子通道的敲除和敲入小鼠模型，这将使我们能够在细胞水平上揭示它们对肾小球透明带生理学和病理生理学的贡献。