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.

项目摘要 在美国，三分之一的成年人将发展高血压，需要降压治疗 在他们的一生中。更重要的是，只有50％的高血压患者患有血压 当前的降压药。在老龄化男性中，控制不良的高血压非常普遍， 绝经后妇女的压力纳特里雷斯反应受损。导致不良的因素 受控的高血压仍有待确定。但是，很明显，所有形式的发展 高血压将需要不断重置对更高压力的压力反应。 尽管以前的研究已牵涉到Na+/h+交换器3（NHE3） 和血管紧张素II（ANG II）依赖性高血压，肾脏近端小管中的NHE3是否为 直接参与生理压力纳地尿反应及其在ANG II引起的重置 先前从未对高血压进行过专门研究。我们有大量的初步证据表明 NHE3在近端小管（PT-NHE3-KO）中有条件缺失或药理抑制 NHE3在肾脏中有选择地，主要在近端小管中，具有新颖的口服可吸收NHE3抑制剂 显着增加了纳地尿反应的压力，并减轻了Ang II-和盐诱导的高血压 通过恢复小鼠的压力纳地尿反应。在此修订的建议中，我们将检验以下假设 肾脏近端小管中的NHE3直接参与生理压力Natriuresis 反应及其在ANG II诱导的高血压中的重置，并且对NHE3的药理抑制作用 在肾脏中有选择地，主要在近端小管中，将减轻动物模型中的高血压 遗传，ANG II，衰老和性别相关的高血压通过恢复压力 回答。在特定的目标1中，我们将测试近端小管中NHE3的缺失是否会 通过抑制近端小管NA+重吸收，增加压力纳地尿反应并降低血压 近端小管中NHE3的上调，通过过表达会损害并重置 压力源自纳地钠对较高压力的反应，通过刺激近端小管Na+重吸收并促进 血压的盐敏感性。在修订的特定目标2中，我们将测试近端小管中的NHE3是否 直接参与了生理压力纳地硫硫硫次对急性生理盐水体积膨胀的反应， 亚钠肽或AT2受体/NO/CGMP信号的激活，并在压力重置时 ANG II-，L-NAME，衰老和性别相关的高血压中的Natriuresis反应。在特定的目标3中，我们将 测试是否在肾脏中有选择地抑制NHE3，主要是在近端小管中，口服 可吸收的NHE3抑制剂将减弱遗传，ANG II-，衰老和性别相关的高血压 恢复压力源自源反应。该提案的成功结果将有助于发展小说 通过选择性靶向近端小管中的NHE3来治疗不良控制或抗性高血压的药物。