OXGR1 in Renal Intercalated Cells, Salt Transport and Diuretic Efficacy

噻嗪类药物是最具成本效益和医疗效益的第一线药物之一。 抗高血压药。然而，它们并不适用于所有人，而且在某些情况下 患者他们可能会降低血压一段时间，但随后就会消失。这个 造成噻嗪耐药性的机制一直是个谜，直到 最近。我们最近的系统生物学研究揭示了盐分的运输 一种新的机制激活了这一过程，以限制尿盐浪费 Thiazide靶标NCC被抑制或低钾血管内容量 耗尽就会发生。我们发现盐分重吸收途径是由 非α插层中多基因转运系统的协同诱导 细胞，突出氯/HCO3-交换器，侧链，α-酮戊二酸(α-KG) 和α-KG G蛋白偶联受体OXGR1.我们最近出版的和 初步数据强烈表明，旁分泌释放α-KG可刺激 OXGR1在非α细胞中的作用，这激活了侧翼蛋白，刺激了盐的重吸收， 并有可能降低利尿剂的反应。在这里，我们聚集了一个高度 协作的多学科团队严格测试的中央租户- Kg/OXGR1/Pendrin假说(目标1)，探索潜在的分子 氧合生长激素受体与悬挂蛋白激活的联系机制(目标2)，阐明 肾脏α-KG/OxGR1旁分泌的生理刺激及其后果 系统(目标3)，以我们最近的发现为基础。我们期待着这些 研究将对了解肾脏如何控制产生重大影响 健康和疾病中的盐平衡，以照亮中央的方式 可变利尿剂反应的基础。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。

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.