Role of basolateral K channels in renal salt handling and BP control

基底外侧钾离子通道在肾盐处理和血压控制中的作用

• 批准号: 10093524
• 负责人: Oleg Palygin
• 金额: $ 6.37万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093524
• 关键词: Affect; African American; Aldosterone; American; Attenuated; Blood; Blood Pressure; Cardiovascular system; Cells; Dahl Hypertensive Rats; Data; Development; Diet; Dietary Potassium; Dietary Supplementation; Disease; Distal; Distal convoluted renal tubule structure; Diuresis; Duct (organ) structure; Ductal Epithelial Cell; Electrolyte Balance; Electrolytes; Excretory function; FDA approved; Generations; Genes; Genetic; Homeostasis; Hormones; Human; Hypertension; Individual; Ion Channel; Ions; Kidney; Knock-out; Mediating; Membrane Potentials; Mineralocorticoid Receptor; Modeling; Molecular; Natriuresis; Nephrons; Nortriptyline; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Plasma; Play; Potassium; Potassium Channel; Publishing; Rattus; Regulation; Renal function; Renin-Angiotensin-Aldosterone System; Reporting; Research Proposals; Rest; Risk; Role; Serum; Severities; Side; Sodium; Sodium Chloride; Testing; Tricyclic Antidepressive Agents; Water; basolateral membrane; blood pressure regulation; clinically relevant; dietary; effective therapy; epithelial Na+ channel; experimental study; high salt diet; human disease; in vivo; inhibitor/antagonist; insight; novel; pressure; prevent; renal damage; salt intake; salt sensitive; salt sensitive hypertension; sensor; tool; urinary

Enhanced sensitivity of blood pressure to salt intake is present in nearly half of Americans affected by hypertension, including approximately 75% of African American hypertensive patients. Basolateral inwardly rectifying K+ (Kir) channels, specifically Kir4.1 and Kir4.1/Kir5.1 (encoded by Kcnj10 and Kcnj16 genes), play a dominant role in modulating water and electrolyte transport in the aldosterone-sensitive distal nephron. Renal Kir4.1/Kir5.1 heterotetramer is a primary basolateral channel at the distal and collecting ducts principal cells and plays an essential role in the regulation of plasma K+ level and Na+ reabsorption. The malfunction of this channel caused by genetic or medication-related factors can be directly involved in hypokalemic, hyperkalemic and hypertensive pathologies in humans. From the other side, precise pharmacological or genetic modulation of Kir4.1or Kir5.1 subunits may provide a new useful tool to the control of electrolyte balance in the body and will open new ways to treat and prevent the development of salt-sensitive hypertension and kidney damage. The Dahl Salt-Sensitive (SS) rat, a naturally occurring model of salt-sensitive hypertension, recapitulates many aspects of progressive human disease providing key insights into mechanisms underlying salt-sensitivity. We have created two rat models in which Kir4.1or Kir5.1 have been knocked out in the SS rat (SSKcnj10-/- and SSKcnj16- /- rats, respectively), enabling us to assess the role of both Kir4.1and Kir4.1/Kir5.1 channels in the control of K+ homeostasis and the development of salt-sensitive hypertension. Given the reported associations of Kir4.1/Kir5.1 with a variety of cardiorenal diseases, it is important to understand the mechanisms by which Kir4.1/Kir5.1 can influence electrolyte homeostasis, the activity of other channels and transporters, and blood pressure control in the setting of salt-induced hypertension. The Specific Aims of this proposal are 1) To define the dynamic interplay between Kir4.1/Kir5.1, NCC, ENaC channels/transporters and RAAS in the kidney and the role of these mechanisms in the control of electrolyte balance in the body. Changes in RAAS hormones under high salt and dietary potassium supplements, basolateral membrane potential in individual cells of DCT and CCD tubules, NCC and ENaC activity, sodium/potassium homeostasis, and the effect of a mineralocorticoid receptor inhibitors will be tested in SSKcnj10-/- and SSKcnj16-/- rats. 2) To determine if pharmacological inhibition of Kir4.1/Kir5.1 attenuates salt-induced hypertension. Our preliminary and published experiments revealed that nortriptyline, an FDA-approved second-generation tricyclic antidepressant, significantly decreases Kir4.1/Kir5.1-mediated K+- selective conductance and modulates ENaC activity in CCD cells. Using novel specific compounds, such as VU992, VU690, and VU726 in WT and SSKcnj16-/- rats, we will determine the viability of Kir4.1/Kir5.1 as a pharmacological target to regulate sodium-potassium homeostasis in the body. We hypothesize that direct modulation of basolateral Kir channel activity will play a protective role in the development of salt-induced hypertension and will lead to the discovery of more effective treatments for high blood pressure.

近一半的美国人的血压对盐摄入的敏感性增强 高血压，包括大约 75% 的非裔美国高血压患者。基底外侧向内 纠正 K+ (Kir) 通道，特别是 Kir4.1 和 Kir4.1/Kir5.1（由 Kcnj10 和 Kcnj16 基因编码），发挥 在醛固酮敏感的远端肾单位调节水和电解质转运中起主导作用。肾 Kir4.1/Kir5.1 异四聚体是远端的主要基底外侧通道和集合管主细胞和 在血浆 K+ 水平和 Na+ 重吸收的调节中起着重要作用。该通道故障 由遗传或药物相关因素引起的可直接参与低钾、高钾和 人类高血压病理学。另一方面，精确的药理或基因调节 Kir4.1或Kir5.1亚基可能为控制体内电解质平衡提供新的有用工具，并将 开辟治疗和预防盐敏感性高血压和肾脏损伤的新方法。这 Dahl 盐敏感 (SS) 大鼠是一种自然发生的盐敏感高血压模型，概括了许多 进行性人类疾病的各个方面为盐敏感性的潜在机制提供了重要的见解。我们 已经创建了两种大鼠模型，其中 SS 大鼠中的 Kir4.1 或 Kir5.1 已被敲除（SSKcnj10-/- 和 SSKcnj16- /- 大鼠），使我们能够评估 Kir4.1 和 Kir4.1/Kir5.1 通道在 K+ 控制中的作用 体内平衡和盐敏感性高血压的发展。鉴于报告的 Kir4.1/Kir5.1 关联 对于多种心肾疾病，了解 Kir4.1/Kir5.1 发挥作用的机制非常重要 影响电解质稳态、其他通道和转运蛋白的活性以及血压控制 盐诱发高血压的情况。该提案的具体目标是 1) 定义动态相互作用 肾脏中 Kir4.1/Kir5.1、NCC、ENaC 通道/转运蛋白和 RAAS 之间的关系及其作用 体内电解质平衡的控制机制。高盐和高盐条件下RAAS激素的变化 膳食钾补充剂，DCT 和 CCD 小管单个细胞的基底外侧膜电位， NCC 和 ENaC 活性、钠/钾稳态以及盐皮质激素受体抑制剂的作用 将在 SSKcnj10-/- 和 SSKcnj16-/- 大鼠中进行测试。 2) 确定Kir4.1/Kir5.1是否具有药理抑制作用 减轻盐引起的高血压。我们的初步和已发表的实验表明，去甲替林是一种 FDA 批准的第二代三环类抗抑郁药，显着降低 Kir4.1/Kir5.1 介导的 K+- 选择性电导并调节 CCD 细胞中的 ENaC 活性。使用新颖的特定化合物，例如 VU992、VU690 和 VU726 在 WT 和 SSKcnj16-/- 大鼠中，我们将确定 Kir4.1/Kir5.1 作为 调节体内钠钾稳态的药理学目标。我们假设直接 调节基底外侧Kir通道活性将在盐诱导的发育中发挥保护作用 高血压，并将导致发现更有效的高血压治疗方法。