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，三分之一的成年人会患上高血压，需要抗高血压治疗 在他们的一生中。更重要的是，只有50%的高血压患者的血压得到控制， 目前的抗高血压药物。控制不佳的高血压在老年男性中非常普遍， 压力性尿钠排泄反应受损的绝经后妇女。造成不良影响的因素 控制高血压仍有待确定。然而，很明显，各种形式的发展 高血压将需要持续地将压力尿钠排泄反应重新设定为更高的压力。 虽然以前的研究表明Na+/H+交换器3（NHE 3）参与了压力性尿钠排泄反应， 和血管紧张素II（ANG II）依赖性高血压，无论肾脏近端小管中的NHE 3是否 直接参与生理性压力利钠反应及其在ANG II诱导的 以前从未专门研究过高血压。我们有强有力的初步证据表明 在近端小管中选择性地条件性缺失NHE 3（PT-NHE 3-KO），或药理学抑制 NHE 3选择性地在肾脏中，主要在近端小管中，具有新型口服可吸收的NHE 3抑制剂 显著增加压力性尿钠排泄反应并减弱ANG II和盐诱导的高血压 通过恢复小鼠的压力性尿钠排泄反应。在这份修订后的提案中，我们将检验以下假设： 肾脏近端小管中的NHE 3直接参与生理性压力尿钠排泄 血管紧张素II诱导高血压反应及其重置，以及NHE 3的药理学抑制 选择性地在肾脏中，主要在近端小管中，将减轻动物模型中的高血压 通过恢复压力性尿钠排泄治疗遗传性、ANG II、衰老和性别相关性高血压 应答在具体目标1中，我们将测试在近端小管中选择性地缺失NHE 3是否会 通过抑制近曲小管Na+重吸收，增加压力性尿钠排泄反应，降低血压， 而通过过度表达选择性上调近端小管中的NHE 3， 通过刺激近端小管Na+重吸收和促进对较高压力的压力钠尿反应 血压的盐敏感性在修订后的特定目标2中，我们将测试近端小管中的NHE 3是否 直接参与对急性盐水容量扩张的生理压力尿钠排泄反应， 利钠肽或AT 2受体/NO/cGMP信号传导的激活，以及压力的重置 ANG II、L-NAME、衰老和性别相关性高血压的钠尿反应。在具体目标3中，我们 测试是否在肾脏中选择性抑制NHE 3，主要是在近端小管中， 可吸收的NHE 3抑制剂将通过以下方式减轻遗传性、ANG II、衰老和性别相关的高血压： 恢复压力性尿钠排泄反应。该提案的成功结果将有助于开发新的 通过选择性靶向近端小管中的NHE 3来治疗控制不良或顽固性高血压的药物。