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

基本信息

批准号：
10653811
负责人：
Oleg Palygin
金额：
$ 37.33万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10653811
关键词：
Affect African American Aldosterone American Attenuated Blood Blood Pressure Cardiorenal syndrome Cardiovascular system Cells Dahl Hypertensive Rats Data Development Diet Dietary Potassium Dietary Supplementation Distal Distal convoluted renal tubule structure Diuresis Duct (organ) structure Ductal Epithelial Cell Electrolyte Balance Electrolytes Event Excretory function FDA approved Generations Genes Genetic Homeostasis Hormones Human Hypertension Hypokalemia Individual Ion Channel Ions Kidney Knock-out Mediating Membrane Potentials Mineralocorticoid Receptor Modeling Molecular Natriuresis Nephrons Nortriptyline Pathology Patients Pharmaceutical Preparations 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 absorption basolateral membrane blood pressure control clinically relevant dietary effective therapy epithelial Na+ channel experimental study high salt diet human disease hyperkalemia hypertensive in vivo inhibitor insight novel pharmacologic pressure prevent renal damage salt intake salt sensitive salt sensitive hypertension sensor symporter tool urinary

项目摘要

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.

在近一半的美国人中，血压对盐摄入量的敏感性提高了高血压，包括大约75％的非裔美国人高血压患者。内外侧纠正K+（KIR）通道，特别是Kir4.1和Kir4.1/Kir5.1（由KCNJ10和KCNJ16基因编码），播放一个在调节醛固酮敏感远端肾单位中的水和电解质转运方面的主要作用。肾脏 Kir4.1/kir5.1异驱量是远端的主要基底外侧通道，并收集管道主要细胞和在血浆K+水平和Na+重吸收的调节中起着至关重要的作用。该渠道的故障由遗传或与药物相关的因素引起的可能直接参与降低性，高钾血症和人类的高血压病理。从另一侧，精确的药理学或遗传调节 Kir4.1或Kir5.1亚基可以为控制体内电解质平衡提供新的有用工具，并将开放新方法来治疗和防止对盐敏感的高血压和肾脏损害的发展。这 DAHL盐敏感（SS）大鼠是一种天然发生的盐敏感性高血压模型，概括了许多进行性人类疾病的各个方面提供了对盐敏感性基础机制的关键见解。我们已经创建了两个大鼠模型，其中Kir4.1或Kir5.1在SS大鼠中被淘汰（SSKCNJ10 - / - 和SSKCNJ16-- / - 大鼠，使我们能够评估Kir4.1和Kir4.1/Kir5.1渠道在控制K+中的作用稳态和盐敏感高血压的发展。考虑到Kir4.1/kir5.1的关联使用多种心脏疾病，重要的是要了解Kir4.1/Kir5.1的机制影响电解质稳态，其他通道和转运蛋白的活性以及血压控制盐引起的高血压的设置。该提案的具体目的是1）定义动态相互作用在Kir4.1/Kir5.1，NCC，肾脏中的ENAC频道/转运蛋白和RAAS之间控制体内电解质平衡的机制。高盐和 DCT和CCD小管单个细胞中的饮食钾补充剂，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）确定药理学抑制是否对Kir4.1/Kir5.1 减弱盐引起的高血压。我们的初步和发表的实验表明，诺特里普林线，这是一个 FDA批准的第二代三环抗抑郁药显着降低了Kir4.1/Kir5.1介导的K+ - 选择性电导和调节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的生存能力调节体内硫代钠稳态的药理靶标。我们假设这是直接的基底外侧KIR通道活动的调节将在盐引起的发展中起保护作用高血压，并将导致发现更有效的高血压治疗方法。