ENaC Transport in Insulin Resistance: Role of Insulin & IGF-1 Receptors

ENaC 转运在胰岛素抵抗中的作用：胰岛素的作用

基本信息

批准号：
8912453
负责人：
VIVEK BHALLA
金额：
$ 36.37万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-06 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8912453
关键词：
1-Phosphatidylinositol 3-Kinase Adult Affect Attenuated Blood Pressure Blood pressure determination Cardiovascular Diseases Cells Collecting Cell Compensatory Hyperinsulinemia Conflict (Psychology)Data Development Disease Dose Duct (organ) structure Elements Epithelial Excretory function Functional disorder General Population Goals Grant Hormones Hyperinsulinism Hypertension In Vitro Incidence Individual Insulin Insulin Receptor Insulin Resistance Insulin-Like-Growth Factor I Receptor Kidney Knockout Mice Learning Measures Mediating Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Outcome Peripheral Peripheral Resistance Plasma Play Prevention Preventive Principal Investigator Process Receptor Activation Receptor Signaling Renal tubule structure Research Resources Role Signal Pathway Signal Transduction Sodium Sodium Channel Syndrome Techniques Testing Therapeutic Time United States Urine Wild Type Mouse Work base cell preparation collecting tubule structure defined contribution design epithelial Na+ channel hypertension treatment inhibitor/antagonist innovation mouse model novel receptor research study salt sensitive salt sensitive hypertension serum sodium transport inhibitor

项目摘要

DESCRIPTION (provided by applicant): Hypertension affects 60 million adults in the United States, and the insulin resistance syndrome induces a salt- sensitive form of hypertension in approximately half of these individuals. In the insulin resistance syndrome compensatory hyperinsulinemia provoked by peripheral resistance increases sodium retention and hence, blood pressure via direct effects on the renal tubule. The epithelial sodium channel (ENaC) expressed in principal cells of the collecting duct is fundamental to this process. However, the receptors in principal cells which propagate insulin-induced ENaC stimulation in the insulin resistance syndrome are not established. Experimental studies have yielded conflicting results on the role of the insulin receptor in mediating renal sodium reabsorption. On the other hand, several studies have suggested that activation of the insulin-like growth factor-1 (IGF-1) receptor can enhance sodium reabsorption via ENaC. The objective in this proposal is to determine the mechanisms that specifically regulate ENaC activity in models of insulin resistance. The R01 Grant will provide the necessary resources for the principal investigator (PI) to test the hypothesis that hyperinsulinemia provoked by peripheral insulin resistance induces salt-sensitive hypertension via activation of the insulin and/or the IGF-1 receptor, initiation of downstream signaling cascades, and enhancement of ENaC- mediated sodium transport. To test this hypothesis, two specific aims are proposed. Aim 1 is to define the contribution of the insulin and/or IGF-1 receptor to blood pressure, sodium reabsorption, and ENaC-mediated sodium transport in mouse models of insulin resistance. Using wild-type and principal cell-specific insulin or IGF-1 receptor knockout mice, the PI will induce insulin resistance in these mice and then measure systemic blood pressure, urine sodium excretion in the presence and absence of an ENaC-specific inhibitor, and sodium transport across in vitro microperfused collecting duct. Aim 2 is to determine the cellular mechanisms by which insulin-mediated activation of the insulin and/or IGF-1 receptor stimulates ENaC-mediated sodium transport in principal cells. The PI will measure receptor activation in control vs. insulin-resistant wild-type mice; measure ENaC expression in insulin-resistant wild-type vs. knockout mice; and compare ENaC-mediated currents and receptor signaling pathways using a novel technique to isolate principal cells from wild-type and knockout mice. The expected outcomes of the proposed aims are to identify the receptors and post-receptor signaling pathways required for stimulation of ENaC and hence, salt-sensitive hypertension in the insulin resistance syndrome. We anticipate that these results will significantly advance the field by identifying appropriate targets for the prevention and treatment of hypertension in diseases associated with insulin resistance, such as obesity and Type 2 diabetes mellitus. The proposed research is innovative in that we will directly compare the insulin and IGF-1 receptor and employ novel techniques to challenge the unilateral paradigm of hyperinsulinemia simply activating the insulin receptor in ENaC-expressing principal cells of the collecting duct.

描述（由申请人提供）：高血压影响着美国 6000 万成年人，其中大约一半的人因胰岛素抵抗综合征而诱发盐敏感型高血压。在胰岛素抵抗综合征中，外周阻力引起的代偿性高胰岛素血症会增加钠潴留，从而通过直接影响肾小管来增加血压。集合管主细胞中表达的上皮钠通道 (ENaC) 是这一过程的基础。然而，在胰岛素抵抗综合征中传播胰岛素诱导的 ENaC 刺激的主细胞中的受体尚未建立。关于胰岛素受体在介导肾脏钠重吸收中的作用，实验研究得出了相互矛盾的结果。另一方面，多项研究表明，胰岛素样生长因子-1 (IGF-1) 受体的激活可以通过 ENaC 增强钠的重吸收。本提案的目的是确定在胰岛素抵抗模型中特异性调节 ENaC 活性的机制。 R01 资助将为首席研究员 (PI) 提供必要的资源，以检验以下假设：外周胰岛素抵抗引起的高胰岛素血症通过激活胰岛素和/或 IGF-1 受体、启动下游信号级联而诱发盐敏感性高血压，并增强 ENaC 介导的钠转运。为了检验这一假设，提出了两个具体目标。目标 1 是确定胰岛素抵抗小鼠模型中胰岛素和/或 IGF-1 受体对血压、钠重吸收和 ENaC 介导的钠转运的影响。使用野生型和主要细胞特异性胰岛素或 IGF-1 受体敲除小鼠，PI 将诱导这些小鼠的胰岛素抵抗，然后测量全身血压、在存在或不存在 ENaC 特异性抑制剂的情况下的尿钠排泄量，以及钠通过体外微灌注集合管转运。目标 2 是确定胰岛素介导的胰岛素和/或 IGF-1 受体激活刺激主细胞中 ENaC 介导的钠转运的细胞机制。 PI 将测量对照小鼠与胰岛素抵抗野生型小鼠的受体激活情况；测量胰岛素抵抗野生型小鼠与基因敲除小鼠中 ENaC 的表达；并使用一种新技术从野生型和基因敲除小鼠中分离主细胞，比较 ENaC 介导的电流和受体信号传导途径。拟议目标的预期结果是确定刺激 ENaC 所需的受体和受体后信号通路，从而确定胰岛素抵抗综合征中的盐敏感性高血压。我们预计这些结果将通过确定适当的目标来预防和治疗与胰岛素抵抗相关的疾病（例如肥胖和2型糖尿病）中的高血压，从而显着推进该领域的发展。拟议的研究具有创新性，因为我们将直接比较胰岛素和 IGF-1 受体，并采用新技术来挑战高胰岛素血症的单方面范例，即简单地激活集合管表达 ENaC 的主细胞中的胰岛素受体。