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

Na /H 交换器 3、压力尿钠和高血压

基本信息

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
项目类别：
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

项目摘要

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，患高血压的终生风险>80%，三分之一的成年人会患高血压并需要抗高血压治疗，只有 50% 的高血压患者能够通过药物得到充分的血压控制。目前的抗高血压药物对高血压尤其是老年患者难以控制的原因尚不完全清楚。有证据表明，无论高血压的原因如何，高血压的发生和维持都取决于压力的恢复。然而，导致高血压中压力钠排泄反应重置的关键因素和机制仍然未知，我们最近发现血管紧张素 II (ANG II) 显着增加钠和氢交换器 3 的表达和/或活性。 (NHE3) 在大鼠和小鼠的近曲小管中通过 AT1a 受体进一步，我们有强有力的初步数据表明近曲小管选择性删除 NHE3 或 AT1a 受体。 Cre/Lox 方法显着抑制近端肾小管 Na+ 重吸收，促进压力尿钠排泄，并减弱 ANG II 依赖性高血压小鼠的血压反应。在本提案中，我们将测试由于 NHE3 选择性过度表达或上调而导致 Na+ 重吸收增加的假设。肾近端小管对旁分泌和细胞内 ANG II 不适当升高的反应有助于将压力尿钠反应重置为更高此外，我们测试了近端小管选择性缺失或抑制的假设。 NHE3 的表达将促进压力尿钠反应并减弱遗传性和 ANG II 依赖性高血压。在具体目标 1 中，我们将确定 NHE3 在近曲小管中选择性过度表达是否会刺激近曲小管 Na+。重吸收，将压力尿钠重置至更高压力，并升高血压，而选择性删除近端小管中的 NHE3 将抑制近端小管 Na+使用近端肾小管特异性 NHE3-KO 小鼠重吸收、促进压力尿钠并降低血压在特定目标 2 中，我们将确定 ANG II 的抑制剂量和 2% Na+ 饮食将促进近端肾小管 Na+ 重吸收，重置压力尿钠。，并通过增加近曲小管中NHE3的表达来诱导高血压，而选择性地缺失近曲小管中的NHE3或AT1a受体在特定目标 3 中，我们将确定选择性抑制肾近曲小管中 NHE3 的口服活性、可吸收、特异性 NHE3 抑制剂是否会预防年轻 SHR 发生高血压并降低血压。该提案的成功结果将有助于开发新型近端小管特异性 NHE3 抑制剂，以治疗控制不佳的高血压患者。