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.

噻嗪类药物是最具成本效益和医疗效益的一线药物之一 抗高血压药。然而，它们并不适用于所有人，在某些情况下， 对病人来说，它们可能会降低血压一段时间，但随后就会消失。的 噻嗪类药物耐药性的机制一直是个谜， 最近我们最近的系统生物学研究揭示了盐的运输 这一过程被一种新的机制激活，以限制尿盐浪费， NCC，噻嗪类靶点，被抑制或低钾血症血管内容量 发生了损耗。我们发现盐重吸收途径是由 非α-intercalated多基因转运系统的协同诱导 细胞，突出显示Cl/HCO 3交换剂、pendrin、α-酮戊二酸（α-KG） 和α-KG G蛋白偶联受体，OXGR 1。我们最近出版的和 初步数据强烈提示旁分泌α-KG刺激 OXGR 1在非α细胞中，这激活了pendrin，刺激盐重吸收， 并可能降低利尿反应。在这里，我们聚集了一个高度 协作，多学科团队，严格测试的核心租户， KG /OXGR 1/pendrin假说（目的1），探索潜在的分子机制 OXGR 1与pendrin激活的联系机制（目的2），阐明了OXGR 1与pendrin激活的关系。 肾α-KG/OxGR 1旁分泌的生理刺激和后果 系统（目标3），建立在我们最近的发现。我们预计这些 研究将对了解肾脏如何控制 盐平衡在健康和疾病，在照亮中央的方式， 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