Mechanisms and Consequences of Defective Flow-Induced Potassium Secretion in the Metabolic Syndrome

代谢综合征中血流诱导钾分泌缺陷的机制和后果

• 批准号: 10202571
• 负责人: VIVEK BHALLA
• 金额: $ 41.55万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202571
• 关键词: Acute; Affect; Aldosterone; American; Arrhythmia; Blood; Calcium; Cardiovascular Diseases; Cardiovascular system; Cell Fractionation; Diet; Dietary Potassium; Disease; Distal; Diuretics; Duct (organ) structure; Equilibrium; Excretory function; Fatty acid glycerol esters; Feedback; Functional disorder; Furosemide; General Population; Goals; Grant; H(+)-K(+)-Exchanging ATPase; High Fat Diet; Immunoblotting; Immunofluorescence Immunologic; Impairment; Incidence; Individual; Insulin; Insulin Receptor; Insulin Resistance; Insulin deficiency; Ion Channel; KCNJ1 gene; Kidney; Knockout Mice; Learning; Life; MAP Kinase Gene; MAPK3 gene; Measures; Mediating; Metabolic syndrome; Methodology; Methods; Modeling; Mus; Nephrons; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Patients; Pharmacologic Substance; Pharmacology; Phenocopy; Phosphorylation; Phosphotransferases; Plasma; Potassium; Predisposition; Preparation; Prevention; Preventive; Pump; Reagent; Receptor Signaling; Regulation; Research; Research Personnel; Resources; Role; Signal Pathway; Signal Transduction; Signaling Protein; Sodium; Stretching; Sum; Syndrome; Techniques; Testing; Therapeutic; Tubular formation; United States National Institutes of Health; Urine; Vascular Smooth Muscle; Vasopressins; Wild Type Mouse; cell type; collecting tubule structure; dietary; high risk; hyperkalemia; iberiotoxin; in vivo; innovation; insulin secretion; insulin signaling; large-conductance calcium-activated potassium channels; mortality; mouse model; novel; patient subsets; paxilline; protein expression; receptor; response; uptake; voltage

PROJECT SUMMARY / ABSTRACT: The metabolic syndrome affects 50 million Americans, and is associated with obesity and insulin resistance. Hyperkalemia is associated with life-threatening cardiac arrhythmias and increased mortality, and patients with insulin resistance and Type 2 diabetes are susceptible to hyperkalemia. However, potential derangements in renal potassium (K) handling remain unexplored. As part of our ongoing NIH-sponsored studies of ion channel function in insulin resistance, we, the Investigators (PI and Co-I), uncovered that flow-induced K secretion (FIKS) in the distal nephron, mediated by BK channels, and renal K handling is defective. Deletion of BK channels leads to defective renal K handling, and impaired K adaptation. The objective of this proposal is to determine the mechanisms underlying the reduction in BK channel- mediated FIKS in the distal nephron and to determine the consequences for K adaptation and hyperkalemia in the insulin resistance syndrome. The R01 Grant will provide the necessary resources to test the hypothesis that insulin resistance in the distal nephron is a phenocopy for BK channel deficiency with decreased insulin signaling leading to disrupted BK channel activity, and thus, defective FIKS and K adaptation, and predisposition to hyperkalemia. To test this hypothesis, we propose two specific aims. Aim #1 is to determine the cellular mechanisms of distal nephron BK channel dysfunction in a mouse model of insulin resistance. Using control and insulin resistant mice, we will measure expression and subcellular localization of distal nephron BK and Ca2+- channels using two innovative methodologies, and will study the Ca2+ and voltage sensitivity of BK channels. We will also measure the impact of defective BK channels on K adaptation and hyperkalemia in the metabolic syndrome. Aim #2 is to determine whether impaired insulin receptor signaling in the distal nephron is sufficient to phenocopy the BK channel dysfunction of insulin resistance. Using a novel renal tubular insulin receptor knockout mouse, we will measure BK and Ca2+ channel expression, and subcellular localization using similar methods to Aim #1. We will study the Ca2+ and voltage sensitivity of BK channels in control and knockout mice and will measure the effect of deletion of insulin receptor signaling on K adaptation and hyperkalemia. We will also measure cell signaling pathways related to insulin and BK channels. We anticipate that these results will significantly advance the field by identifying appropriate dietary and pharmaceutical targets for the prevention and treatment of hyperkalemia in diseases associated with insulin resistance, such as obesity and Type 2 diabetes mellitus. The proposed research is innovative in that we will directly study the regulation of renal BK channels in insulin resistance and will employ novel reagents and cutting-edge techniques to understand the consequences of defective FIKS for hyperkalemia. Through the proposed studies, we will also learn about mechanisms of insulin signaling in the kidney in the insulin resistance syndrome and the role of diet in determining cardiovascular outcomes in this syndrome.

项目摘要 /摘要：代谢综合征会影响5000万美国人，并且有关联 具有肥胖和胰岛素抵抗。高钾血症与威胁生命的心律不齐和 死亡率增加，胰岛素抵抗和2型糖尿病患者易受高钾血症。 但是，肾脏（K）处理中的潜在危险仍未开发。作为我们正在进行的一部分 NIH赞助的对胰岛素抵抗中离子通道功能的研究，我们，研究者（PI和CO-I）， 发现了远端肾单位的流动诱导的K分泌（FIK），由BK通道介导，肾脏K 处理是有缺陷的。 BK通道的删除会导致肾脏K处理有缺陷，并且K适应受损。 该提案的目的是确定BK通道降低的基础机制。 远端肾单位中介导的FIK，并确定K适应和高钾血症的后果 胰岛素抵抗综合征。 R01赠款将提供必要的资源来检验假设 远端肾单位中的胰岛素耐药性是BK通道缺乏症的表观，胰岛素降低 信号导致BK通道活性中断，因此有缺陷的FIK和K适应，并且 高钾血症的易感性。为了检验这一假设，我们提出了两个具体目标。目的＃1是确定 胰岛素耐药性小鼠模型中远端NEPHRON BK通道功能障碍的细胞机制。 使用对照和胰岛素耐药小鼠，我们将测量远端的表达和亚细胞定位 Nephron BK和Ca2+ - 使用两种创新方法，并将研究Ca2+和电压 BK通道的敏感性。我们还将衡量有缺陷的BK渠道对K适应的影响 代谢综合征中的高钾血症。目标＃2是确定胰岛素受体信号是否受损 远端肾单位足以表观胰岛素抵抗的BK通道功能障碍。使用小说 肾小管胰岛素受体基因敲除小鼠，我们将测量BK和Ca2+通道表达，并且 使用类似的AIM＃1的亚细胞定位。我们将研究BK的Ca2+和电压灵敏度 控制和敲除小鼠中的通道，并将测量胰岛素受体信号缺失对K的影响 适应性和高钾血症。我们还将测量与胰岛素和BK通道有关的细胞信号通路。 我们预计这些结果将通过确定适当的饮食和 预防和治疗与胰岛素相关的疾病中高钾血症的药物靶标 抗性，例如肥胖和2型糖尿病。拟议的研究具有创新性，我们将 直接研究肾脏BK通道在胰岛素抵抗中的调节，并将采用新的试剂和 尖端的技术了解有缺陷的FIK对高钾血症的后果。通过 拟议的研究，我们还将了解胰岛素中肾脏中胰岛素信号的机制 抗性综合征和饮食在确定该综合征心血管结局中的作用。