The Na+/H+ Exchanger 3, Pressure Natriuresis, and Hypertension

Na /H 交换器 3、压力尿钠和高血压

• 批准号: 9336432
• 负责人: Jia L. Zhuo
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336432
• 关键词: Adult; Angiotensin II; Animals; Antihypertensive Agents; Attenuated; Bicarbonates; Blood Pressure; Chronic Kidney Failure; Congestive Heart Failure; Coronary Arteriosclerosis; Cyclic GMP; Data; Development; Diet; Dose; Endocytosis; Genes; Genetic; Guanosine; Human; Hydrostatic Pressure; Hydroxyeicosatetraenoic Acids; Hypertension; Hypotension; Kidney; Knock-out; Knockout Mice; Maintenance; Mediating; Molecular; Morbidity - disease rate; Mus; Mutant Strains Mice; Natriuresis; Outcome; Patients; Physiological; Proteins; Proximal Kidney Tubules; Rattus; Research Proposals; Resistant Hypertension; Risk Factors; Role; Small Interfering RNA; Sodium; Sodium Chloride; Stroke; Testing; United States; Up-Regulation; blood pressure reduction; blood pressure regulation; driving force; hypertension control; inhibitor/antagonist; interstitial; knock-down; lifetime risk; mortality; mouse model; mutant mouse model; novel; older patient; overexpression; paracrine; pressure; prevent; public health relevance; receptor; response; sodium-hydrogen exchanger 3

 DESCRIPTION (provided by applicant): In the United States, the lifetime risk for the development of hypertension is >80% and one in three adults will develop hypertension and require antihypertensive therapy. Only 50% of patients with hypertension attain adequate blood pressure control with current antihypertensive drugs. The reasons why hypertension is so difficult to control especially in elderly patients remain incompletely understood. There is evidence that regardless of the causes of the hypertension, the development and maintenance of hypertension are dependent upon the resetting of the pressure natriuresis relationship to higher pressures. However, the key factors and mechanisms responsible for resetting pressure natriuresis responses in hypertension remain unknown. We have recently shown that angiotensin II (ANG II) significantly increased the expression and/or activity of the sodium and hydrogen exchanger 3 (NHE3) in the proximal tubule of rats and mice via AT1a receptors. Further, we have powerful preliminary data that proximal tubule-selective deletion of NHE3 or AT1a receptors with the Cre/Lox approach markedly inhibits proximal tubule Na+ reabsorption, promotes pressure natriuresis, and attenuates blood pressure responses in ANG II-dependent hypertensive mice. In this proposal, we will test the hypothesis that increased Na+ reabsorption due to overexpression or upregulation of NHE3 selectively in the proximal tubule of the kidney in response to inappropriately elevated paracrine and intracellular ANG II contributes to the resetting of pressure natriuresis responses to higher pressures, and the development of hypertension. Further, we test the hypothesis that proximal tubule-selective deletion or inhibition of NHE3 will promote pressure natriuresis responses and attenuate genetic and ANG II-dependent hypertension. Three specific aims are proposed to test these hypotheses. In Specific Aim 1, we will determine whether the overexpression of NHE3 selectively in the proximal tubule will stimulate proximal tubule Na+ reabsorption, reset pressure natriuresis to higher pressure, and increase blood pressure, whereas deletion of NHE3 selectively in the proximal tubule will inhibit proximal tubule Na+ reabsorption, promote pressure natriuresis, and decrease blood pressure using proximal tubule-specific NHE3-KO mice. In Specific Aim 2, we will determine a subpressor dose of ANG II and a 2% Na+ diet will promote proximal tubule Na+ reabsorption, resets pressure natriuresis, and induces hypertension by increasing the expression of NHE3 in the proximal tubule, whereas deletion of NHE3 or AT1a receptors selectively in the proximal tubule will attenuate ANG II- dependent hypertension. In Specific Aim 3, we will determine whether an orally active, absorbable, specific NHE3 inhibitor to selectively inhibit NHE3 in the proximal tubule of the kidney will prevent the development of hypertension in young SHR and lower blood pressure in a subpressor ANG II-induced hypertensive mouse model. The successful outcome of this proposal will help develop novel proximal tubule-specific NHE3 inhibitors to treat patients with poorly-controlled hypertension.

 描述（由申请人提供）：在美国，发生高血压的终生风险>80%，三分之一的成年人将发生高血压并需要抗高血压治疗。只有50%的高血压患者在使用目前的降压药物后血压得到充分控制。为什么高血压如此难以控制，特别是在老年患者中，其原因仍不完全清楚。有证据表明，无论高血压的原因如何，高血压的发展和维持都依赖于将压力尿钠排泄关系重置为更高的压力。然而，高血压患者压力性尿钠排泄反应重置的关键因素和机制尚不清楚。我们最近发现，血管紧张素II（ANG II）显着增加的表达和/或活性的钠和氢交换器3（NHE 3）在大鼠和小鼠近端小管通过AT 1a受体。此外，我们有强有力的初步数据表明，近端小管选择性删除NHE 3或AT 1a受体与Cre/Lox的方法显着抑制近端小管Na+重吸收，促进压力尿钠排泄，并减弱血管紧张素II依赖性高血压小鼠的血压反应。在这个建议中，我们将测试的假设，增加Na+重吸收，由于过度表达或上调NHE 3选择性在近端肾小管的肾脏，以响应不适当的升高旁分泌和细胞内血管紧张素II有助于重置压力尿钠排泄反应更高的压力，和高血压的发展。此外，我们还检验了近端小管选择性缺失或抑制 NHE 3的表达将促进压力性尿钠排泄反应，并减轻遗传性和ANG II依赖性高血压。提出了三个具体目标来检验这些假设。在具体目标1中，我们将确定NHE 3在近端小管中的选择性过表达是否会刺激近端小管Na+重吸收，将压力尿钠排泄重置为更高的压力，并增加血压，而NHE 3在近端小管中的选择性缺失是否会抑制近端小管Na+重吸收，促进压力尿钠排泄，并使用近端小管特异性NHE 3-KO小鼠降低血压。在具体目标2中，我们将确定ANG II的降压剂量，2% Na+饮食将促进近端小管Na+重吸收，重置压力尿钠排泄，并通过增加近端小管中NHE 3的表达诱导高血压，而选择性缺失近端小管中的NHE 3或AT 1a受体将减弱ANG II依赖性高血压。在具体目标3中，我们将确定口服活性、可吸收、特异性NHE 3抑制剂选择性抑制肾脏近端小管中的NHE 3是否会预防年轻SHR中高血压的发展，并降低降压ANG II诱导的高血压小鼠模型中的血压。该提案的成功结果将有助于开发新的近端小管特异性NHE 3抑制剂来治疗控制不良的高血压患者。