Role of Proximal Tubule NHE3 in Angiotensin II-induced Hypertension

近曲小管 NHE3 在血管紧张素 II 诱导的高血压中的作用

• 批准号: 10174160
• 负责人: Jia L. Zhuo
• 金额: $ 13.82万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-17 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10174160
• 关键词: Role; Proximal; Tubule; NHE3; Angiotensin

PROJECT SUMMARY In the United States, one in three adults will develop hypertension and require antihypertensive treatments in their lifetime. More importantly, only 50% of patients with hypertension have blood pressure controlled with current antihypertensive drugs. Poorly controlled hypertension is very prevalent in aging men and postmenopausal women with impaired pressure natriuresis response. The factors contributing to poorly controlled hypertension remain to be determined. It is clear, however, the development of all forms of hypertension will require continuously resetting of the pressure natriuresis response to higher pressures. Although previous studies have implicated the Na+/H+ exchanger 3 (NHE3) in the pressure natriuresis response and angiotensin II (ANG II)-dependent hypertension, whether NHE3 in the proximal tubules of the kidney is directly involved in the physiological pressure natriuresis response and its resetting in ANG II-induced hypertension has never been specifically investigated previously. We have strong preliminary evidence that conditional deletion of NHE3 selectively in the proximal tubules (PT-NHE3-KO), or pharmacological inhibition of NHE3 selectively in the kidney, primarily in the proximal tubules, with a novel orally absorbable NHE3 inhibitor significantly increases the pressure natriuresis response and attenuates ANG II- and salt-induced hypertension by restoring pressure natriuresis response in mice. In this revised proposal, we will test the hypotheses that NHE3 in the proximal tubules of the kidney is directly involved in the physiological pressure natriuresis response and its resetting in ANG II-induced hypertension, and that pharmacological inhibition of NHE3 selectively in the kidney, primarily in the proximal tubules, will attenuate hypertension in animal models of genetic-, ANG II-, aging-, and sex-associated hypertension by restoring pressure natriuresis responses. In Specific Aim 1, we will test whether deletion of NHE3 selectively in the proximal tubules will increase pressure natriuresis response and lower blood pressure by inhibiting proximal tubule Na+ reabsorption, whereas upregulation, via overexpression, of NHE3 selectively in the proximal tubules will impair and reset pressure natriuresis response to higher pressures by stimulating proximal tubule Na+ reabsorption and promoting salt sensitivity of blood pressure. In a revised Specific Aim 2, we will test whether NHE3 in the proximal tubules is directly involved in the physiological pressure natriuresis responses to acute saline volume expansion, natriuretic peptides, or activation of AT2 receptor/NO/cGMP signaling, and in the resetting of pressure natriuresis responses in ANG II-, L-NAME-, aging- and sex-associated hypertension. In Specific Aim 3, we will test whether inhibition of NHE3 selectively in the kidney, primarily in the proximal tubules, with an orally absorbable NHE3 inhibitor will attenuate genetic-, ANG II-, aging- and sex-associated hypertension by restoring pressure natriuresis responses. The successful outcomes of this proposal will help develop novel drugs to treat poorly controlled or resistant hypertension by selectively targeting NHE3 in the proximal tubules.

项目概要 在美国，三分之一的成年人会患高血压并需要抗高血压治疗 在他们的一生中。更重要的是，只有50%的高血压患者能够通过药物控制血压 目前的降压药。控制不佳的高血压在老年男性中非常普遍， 压力尿钠反应受损的绝经后妇女。导致成绩不佳的因素 控制高血压仍有待确定。然而，显而易见的是，各种形式的发展 高血压需要不断重置压力尿钠反应以适应更高的压力。 尽管之前的研究表明 Na+/H+ 交换器 3 (NHE3) 与压力尿钠反应有关 和血管紧张素 II (ANG II) 依赖性高血压，肾近曲小管中的 NHE3 是否存在 直接参与 ANG II 诱导的生理压力尿钠反应及其重置 以前从未对高血压进行过专门研究。我们有强有力的初步证据表明 在近曲小管中选择性地条件性删除 NHE3 (PT-NHE3-KO)，或通过药物抑制 NHE3 选择性地存在于肾脏中，主要是近端肾小管，采用新型口服可吸收 NHE3 抑制剂 显着增加压力尿钠反应并减弱 ANG II 和盐诱发的高血压 通过恢复小鼠的压力尿钠反应。在这个修订后的提案中，我们将测试以下假设： 肾脏近曲小管中的NHE3直接参与生理压力尿钠 ANG II 诱导的高血压的反应及其重置，以及 NHE3 的药理学抑制 选择性地作用于肾脏，主要是近端肾小管，将减轻动物模型中的高血压 通过恢复压力尿钠来治疗与遗传、ANG II、衰老和性别相关的高血压 回应。在具体目标 1 中，我们将测试近曲小管中选择性删除 NHE3 是否会影响 通过抑制近端肾小管 Na+ 重吸收来增加压力尿钠反应并降低血压， 而通过过度表达 NHE3 在近曲小管中的选择性上调将损害和重置 通过刺激近端肾小管 Na+ 重吸收和促进对较高压力的压力尿钠反应 血压对盐的敏感性。在修订后的具体目标 2 中，我们将测试近曲小管中的 NHE3 是否 直接参与对急性盐水容量扩张的生理压力尿钠反应， 利尿钠肽，或 AT2 受体/NO/cGMP 信号传导的激活，以及压力重置 ANG II-、L-NAME-、衰老和性别相关高血压的尿钠反应。在具体目标 3 中，我们将 测试口服药物是否能选择性地抑制肾脏（主要是近端肾小管）中的 NHE3 可吸收的 NHE3 抑制剂将通过以下方式减轻与遗传、ANG II、衰老和性别相关的高血压 恢复压力尿钠反应。该提案的成功结果将有助于开发新颖的 通过选择性靶向近曲小管中的 NHE3 来治疗控制不佳或难治性高血压的药物。