OXGR1 in Renal Intercalated Cells, Salt Transport and Diuretic Efficacy

OXGR1在肾闰细胞、盐转运和利尿功效中的作用

• 批准号: 9913504
• 负责人: Eric J Delpire
• 金额: $ 82.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-05 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913504
• 关键词: Ablation; Affect; Alkalosis; Angiotensin II; Animals; Antihypertensive Agents; Apical; Bicarbonates; Biochemical; Biological; Blood Pressure; Calcineurin; Calcium; Cardiovascular Diseases; Cells; Chlorides; Chronic Kidney Failure; Data; Diagnostic; Diarrhea; Disease; Diuretics; Duct (organ) structure; Effectiveness; Electrolyte Balance; Electrophoretic Mobility Shift Assay; Essential Hypertension; Failure; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genetic; Genetic Transcription; Genomics; Health; Hypertension; Hypokalemia; In Vitro; Intercalated Cell; Investigation; Kidney; Knockout Mice; Knowledge; Lead; Light; Link; Liquid substance; Mediating; Medical; Metabolic; Molecular; Molecular Target; Mus; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Physiological; Physiology; Planets; Potassium; Process; Public Health; Publishing; Recombinants; Renal function; Resistance; Role; Sodium Chloride; Stimulus; System; Systems Biology; Testing; Therapeutic Effect; Thiazide Diuretics; Translating; Transport Process; United States; Urine; Vomiting; Work; absorption; alpha ketoglutarate; apical membrane; blood pressure reduction; cost effective; drug discovery; hypertension treatment; kidney cell; multidisciplinary; mutant; novel; paracrine; programs; promoter; receptor; response; salt balance; salt sensitive; thiazide; tool; trafficking; treatment strategy; urinary; wasting

Thiazides are one of the most cost-effective and medically beneficial first line antihypertensive agents. However, they don’t work for everyone, and in some patients they may lower blood pressure for a while but then wear off. The mechanisms responsible for thiazide resistance have been mysterious, until recently. Our recent systems-biology investigations revealed a salt-transport process is activated by a novel mechanism to limit urinary salt wasting when NCC, the thiazide target, is inhibited or hypokalemic intravascular volume depletion occurs. We discovered that a salt reabsorption pathway is created by the coordinate induction of a multi-gene transport system in non-α intercalated cells, highlighting the Cl/HCO3- exchanger, pendrin, alpha-ketoglutarate (α-KG) and the α-KG G-Protein Coupled Receptor, OXGR1. Our recently published and preliminary data strongly suggest that paracrine delivery of α-KG stimulates OXGR1 in non-α cells and this activates pendrin, stimulates salt reabsorption, and potentially lowers the diuretic response. Here, we have assembled a highly collaborative, multidisciplinary team to rigorously test the central tenants of the - KG /OXGR1/pendrin hypothesis (Aim 1), explore the underlying molecular mechanism(s) linking OXGR1 to pendrin activation (Aim 2), elucidate the physiological stimuli and consequences of the Renal α-KG/OxGR1 Paracrine system (Aim 3), building on our recent discoveries. We expect these investigations will have a major impact on understanding how the kidney controls salt balance in health and disease, in ways that illuminate the central underpinnings of the variable diuretic response. Ultimately, these studies will provide new information and diagnostic tools that lead to the better treatment of hypertension.

噻嗪类是最具成本效益和医学上有益的第一线之一 降压药。但是，它们并不适合所有人，在某些人中 患者可能会降低血压一段时间，但随后逐渐消失。这 负责噻嗪类抗性的机制一直是神秘的，直到 最近。我们最近的系统生物学调查显示了盐传输 当一种新型机制激活过程，以限制尿盐浪费 NCC是噻嗪类靶标的，被抑制或血管内血管内血管内体积 发生耗竭。我们发现盐吸收途径是由 在非α插入中的多基因运输系统的坐标诱导 细胞突出显示Cl/HCO3-交换器，Pendrin，α-酮戊二酸（α-KG） 和α-KG G蛋白偶联受体OXGR1。我们最近出版的 初步数据强烈表明α-kg的旁分泌递送刺激 非α细胞中的oxgr1并激活pendrin，刺激盐的吸收， 并可能降低利尿反应。在这里，我们组装了一个高度 协作，多学科团队，严格测试-的中心租户 kg /oxgr1 /pendrin假设（AIM 1），探索潜在的分子 将OXGR1与Pendrin激活联系起来的机制（AIM 2），阐明 肾α-KG/OXGR1旁分泌的生理刺激和后果 系统（AIM 3），基于我们最近的发现。我们期望这些 调查将对理解肾脏控制方式产生重大影响 健康和疾病的盐平衡，以照亮中心的方式 可变利尿反应的基础。最终，这些研究将 提供新的信息和诊断工具，从而更好地治疗 高血压。