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（由适用提供）：在美国，高血压发展的终生风险> 80％，三分之一的成年人将患上高血压，需要降压治疗。高血压患者中只有50％可以通过当前的抗高血压药物获得足够的血压控制。高血压如此难以控制的原因，尤其是在老年患者中，尚不完全了解。有证据表明，不管高血压的原因如何，高血压的发展和维持都取决于纳地那二硫滋期与更高压力的关系的重置。但是，高血压中负责重置压力纳地尿反应的关键因素和机制尚不清楚。我们最近表明，血管紧张素II（ANG II）通过AT1A受体显着提高了大鼠和小鼠的近端小管中钠和氢交换器3（NHE3）的表达和/或活性。此外，我们拥有强大的初步数据，可以用CRE/LOX接近的NHE3或AT1A受体的管道选择性缺失明显抑制代理管Na+吸收na+吸收，从而促进压力Natriuresis，并抑制ANG II依赖性低血压下的血压反应。在该提案中，我们将检验以下假设：由于过表达或在肾脏近端的过度表达或更新而增加了Na+重吸收，这是因为响应不当升高的旁氨基和细胞内ANG II，有助于重置对较高压力的压力和高度发育的压力反应。此外，我们检验了近端管选择性缺失或抑制的假设 提出了三个特定目标来检验这些假设。在特定目的1中，我们将确定在近端管中选择性的NHE3的过表达是否会刺激Na+近端Na+吸收近端，将压力纳地硫酸重置为较高的压力，并增加血压，而NHE3在近端中选择性地缺失，而近端则可以促进NHE3的降压，并促进NAHE3的压力，并促进NHE3的促进nhe3近端管特异性NHE3-KO小鼠。 In Specific Aim 2, we will determine a subpressor dose of ANG II and a 2% Na+ diet will promote proximal tube Na+ reabsorption, resets pressure natriuresis, and induces hypertension by increasing the expression of NHE3 in the proximal tube, whereas deletion of NHE3 or AT1a receptors selectively in the proximal tube will Attenuate ANG II- dependent hypertension.在特定的目标3中，我们将确定在肾脏代理管中有选择性抑制NHE3的口服，可吸收，特异性NHE3抑制剂是否会防止年轻SHR中的高血压发展和降低亚种ANG II诱导的高血压高度诱导的高血压小鼠模型。该提案的成功结果将有助于开发新的代理管特异性NHE3抑制剂，以治疗患者控制不良的患者。