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: 8742716
• 负责人: Jia L. Zhuo
• 金额: $ 37.33万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-12 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8742716
• 关键词: Am 80; Angiotensin II; Animals; Attenuated; Bicarbonates; Blood Pressure; Cells; Chronic; Chronic Kidney Failure; Cyclic GMP; Data; Development; Diet; Diuretics; Dose; Elderly; Genes; Genetic; Genomics; Heart failure; Hydrostatic Pressure; Hydroxyeicosatetraenoic Acids; Hypertension; In Vitro; Infusion procedures; Kidney; Knowledge; Lead; Mediating; Modeling; Molecular; Mus; Natriuresis; Patients; Pharmaceutical Preparations; Play; Proteins; Proximal Kidney Tubules; Rattus; Risk Factors; Role; Sodium; Sodium Chloride; Stroke; Testing; Tissues; Treatment Efficacy; United States; Up-Regulation; blood pressure regulation; design; driving force; extracellular; hypertension control; inhibitor/antagonist; innovation; interstitial; lifetime risk; mouse model; older patient; overexpression; pressure; prevent; public health relevance; receptor; response; salt sensitive hypertension; sodium-hydrogen exchanger 3

DESCRIPTION (provided by applicant): Hypertension is the major risk factor for chronic heart failure, stroke, and chronic kidney diseases. Although many think hypertension is no longer a major concern, the lifetime risk for the development of hypertension is >80% and, still only 50% of hypertensive patients attain adequate blood pressure control. The factors contributing to the development of hypertension, and the reason why blood pressure is difficult to control in elderly patients remain incompletely understood. Although it is well recognized that regardless of genetic cause of the hypertension, the development of hypertension requires the resetting of the pressure natriuresis relationship to higher pressures, the mechanisms responsible for pressure natriuresis and its resetting in hypertension remain to be determined. We reason that increased sodium (Na+) reabsorption in the renal proximal tubule via the sodium and hydrogen exchanger 3 (NHE3) due to inappropriately elevated tissue angiotensin II (ANG II) may contribute to the resetting of pressure natriuresis responses in hypertension. We have recently demonstrated that both extracellular and intracellular ANG II increases the expression and activity of NHE3 in proximal tubule cells in vitro and in the proximal tubule of rats and mice via AT1a receptors. Further, we have generated exciting preliminary data that proximal tubule-selective deletion of NHE3 markedly attenuates pressure natriuresis and blood pressure responses in ANG II-induced hypertension. Using innovative molecular, genomic and pharmacological approaches, this proposal will test the hypothesis that NHE3 in the proximal tubule plays a critical role in mediating pressure natriuresis and that proximal tubule-selective deletion of NHE3 prevents the resetting pressure natriuresis and attenuate the development of ANG II-induced hypertension. Three specific aims are designed to test this hypothesis. 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, and promote the development of salt- sensitive hypertension, whereas deletion of NHE3 will inhibit proximal tubule Na+ reabsorption, blunt pressure natriuresis and decrease basal blood pressure using proximal tubule-specific NHE3-KO mice, tgNhe3-/-and SGLT2-Cre+Nhe3flox/flox. In Specific Aim 2, we will determine whether infusion of a subpressor dose of ANG II plus a high salt diet will stimulate proximal tubule Na+ reabsorption, resets pressure natriuresis, and induces hypertension by increasing the expression of NHE3 in the proximal tubule, whereas deletion of NHE3 will attenuate ANG II-induced hypertension using tgNhe3-/-and SGLT2-Cre+Nhe3flox/flox mice. In Specific Aim 3, we will test the therapeutic efficacy of molecular knockdown of the expression of NHE3 in the proximal tubule or pharmacological inhibition of NHE3 in a subpressor ANG II-induced hypertension model. The new knowledge generated by this project will help us better understand the renal mechanisms of hypertension and develop new NHE3 inhibitors to treat elderly patients with poorly-controlled hypertension.

描述（由申请人提供）：高血压是慢性心力衰竭、中风和慢性肾脏疾病的主要危险因素。尽管许多人认为高血压不再是一个主要问题，但终生患高血压的风险>80%，而且仍然只有 50% 的高血压患者血压得到充分控制。导致高血压发生的因素以及老年患者血压难以控制的原因仍不完全清楚。尽管人们普遍认识到，无论高血压的遗传原因如何，高血压的发展都需要将压力钠排泄关系重置为更高的压力，但高血压中压力钠排泄及其重置的机制仍有待确定。我们推断，由于组织血管紧张素 II (ANG II) 不适当升高，肾近曲小管通过钠氢交换器 3 (NHE3) 增加的钠 (Na+) 重吸收可能有助于重置高血压中的压力尿钠反应。我们最近证明，细胞外和细胞内 ANG II 通过 AT1a 受体增加体外近曲小管细胞以及大鼠和小鼠近曲小管中 NHE3 的表达和活性。此外，我们还获得了令人兴奋的初步数据，表明近曲小管选择性删除 NHE3 显着减弱 ANG II 诱导的高血压中的压力尿钠和血压反应。利用创新的分子、基因组和药理学方法，该提案将检验以下假设：近端小管中的 NHE3 在介导压力性尿钠排泄中发挥关键作用，并且近端小管选择性删除 NHE3 可防止重置压力性尿钠排泄并减弱 ANG II 的发展诱发高血压。设计了三个具体目标来检验这一假设。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、重置压力尿钠并促进盐敏感性高血压的发展，而NHE3的缺失将抑制近曲小管Na+重吸收，使用近端小管特异性 NHE3-KO 小鼠 tgNhe3-/-和 钝化压力尿钠并降低基础血压SGLT2-Cre+Nhe3flox/flox。在具体目标 2 中，我们将确定输注亚加压剂量的 ANG II 加高盐饮食是否会刺激近曲小管 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，而删除NHE3 将使用 tgNhe3-/- 和 SGLT2-Cre+Nhe3flox/flox 小鼠减轻 ANG II 诱导的高血压。在具体目标 3 中，我们将测试近曲小管中 NHE3 表达的分子敲低或 NH​​E3 在降压 ANG II 诱导的高血压模型中的药物抑制的治疗效果。该项目产生的新知识将帮助我们更好地了解高血压的肾脏机制，并开发新的NHE3抑制剂来治疗高血压控制不佳的老年患者。