Epithelial Na Channels and Regulation of Na Excretion

上皮钠通道和钠排泄的调节

• 批准号: 6846624
• 负责人: LAWRENCE G PALMER
• 金额: $ 39.36万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6846624
• 关键词: aldosterone; amiloride; angiotensin receptor; dietary sodium; hormone regulation /control mechanism; hypertension; insulin; laboratory mouse; laboratory rat; low salt diet; nutrition related tag; renal tubular transport; renin angiotensin system; saluresis; sodium channel; sodium hydrogen exchanger; thiazide

DESCRIPTION (provided by applicant): Epithelial Na channels are expressed in the distal parts of the mammalian nephron, and are known to be regulated by the renin-angiotensin-aldosterone axis. The role of these channels and their regulation by mineralocorticoids in the daily regulation of sodium excretion by the kidneys will be explored. Preliminary data indicate that when rats are given a low sodium diet, they can adjust their renal Na excretion within 15 hours and that increased reabsorption through Na channels can account for a large fraction of the reduced excretion rates. We will assess the role of the channels with different degrees of Na depletion, measuring both channel activity and overall urinary Na excretion. Channel activity will be measured as amiloride-sensitive whole-cell currents in the renal cortical collecting tubule as well as the medullary collecting duct and the connecting tubule to quantitate its contribution to renal Na handling. We will further test for the importance of Na channels by measuring Na excretion in rats treated with the channel blocker amiloride. Upregulation of other transport pathways will also be examined using thiazides to block NaCI cotransport and angiotensin receptor antagonists to prevent upregulation of Na/H exchange. We will also assess the roles of two putative signaling pathways for aldosterone secretion under these conditions, increased renin activity and elevated plasma K. We will explore the mechanisms of pathological upregulation seen in the Liddle's Syndrome form of human hypertension. This will be done using mice in which the channel subunit B-ENaC has been truncated to mimic the human mutation. Here we will test the idea that the mutation decreases the rate of downregulation of previously activated channels. Finally we will study the effects of insulin on the channels. We will examine the hypothesis that this hormone increases the open probability of channels inserted or activated by aldosterone. The results should help to understand the role of channel-mediated Na reabsorption under conditions of physiological (dietary) stress and hypertension.

描述（由申请人提供）：上皮NA通道在 哺乳动物肾单位的远端部分，已知由 肾素 - 血管紧张素 - 醛固酮轴。这些渠道及其的作用 矿物皮质激素在每天调节钠排泄的调节 将探索肾脏。初步数据表明当大鼠是 鉴于低钠饮食，他们可以在15次内调整肾脏Na排泄 小时和通过NA通道增加的吸收增加可以解释 排泄率降低的大部分。我们将评估 Na耗竭程度不同的通道，测量两个通道 活性和整体尿NA排泄。通道活动将被衡量为 肾皮质收集小管中的艾米洛德敏感全细胞电流 以及髓质收集管和连接小管 量化其对肾脏NA处理的贡献。我们将进一步测试 Na通道的重要性通过测量用治疗的大鼠中的Na排泄。 通道阻滞剂Amiloride。其他运输途径的上调也将 使用噻嗪类药物进行检查以阻断NACI共转运和血管紧张素受体 防止Na/H交换上调的拮抗剂。我们还将评估 这些醛固酮分泌的两个假定信号传导途径的作用 条件，肾素活性增加和等离子K。我们将探索 病理性上调的机制在Liddle综合征形式中看到 人类高血压。这将使用通道亚基的小鼠完成 B-ENAC已被截断以模仿人类突变。在这里，我们将测试 突变会降低以前的下调速率的想法 激活的通道。最后，我们将研究胰岛素对 频道。我们将研究这种激素增加开放的假设 通过醛固酮插入或激活的通道的概率。结果 应该有助于了解渠道介导的Na重吸收的作用 生理（饮食）压力和高血压的条件。