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

 描述(申请人提供)：在美国，患高血压的终生风险为80%，三分之一的成年人会患上高血压，需要抗高血压治疗。只有50%的高血压患者通过目前的降压药物达到了足够的血压控制。高血压如此难以控制的原因，特别是在老年患者中，仍然不完全清楚。有证据表明，无论高血压的原因是什么，高血压的发展和维持都依赖于与更高压力的压力钠尿关系的重新设定。然而，高血压患者重置压力钠尿反应的关键因素和机制仍不清楚。我们最近发现血管紧张素II(Ang II)通过AT1a受体显著增加大鼠和小鼠近端肾小管钠氢交换蛋白3(NHE3)的表达和/或活性。此外，我们有强有力的初步数据表明，通过CRE/Lox方法选择性删除近端小管NHE3或AT1a受体显著抑制近端小管Na+的重吸收，促进压力钠尿，并减弱Ang II依赖型高血压小鼠的血压反应。在这个方案中，我们将检验这样一种假设，即由于NHE3在肾脏近端小管上选择性地过度表达或上调，以响应不适当的旁分泌和细胞内Ang II，导致Na+重吸收增加，从而有助于重置对更高压力的压力钠尿反应，并导致高血压的发生。此外，我们还检验了近端小管选择性缺失或抑制的假设 NHE3将促进压力钠尿反应，并减轻遗传性和Ang II依赖型高血压。为了检验这些假说，本文提出了三个具体目标。在特定的目标1中，我们将利用近端小管特异的NHE3-KO小鼠来确定NHE3选择性地在近端小管过表达是否会刺激近端小管的Na+重吸收，将压力钠尿重置为更高的压力，并增加血压，而选择性地在近端小管上缺失NHE3将抑制近端小管的Na+重吸收，促进压力钠尿，并降低血压。在特定的目标2中，我们将确定Ang II的降压剂量，2%的Na+饮食将促进近端小管Na+重吸收，重置压力钠排泄，并通过增加近端小管NHE3或AT1a的表达而诱导高血压，而选择性地删除近端小管上NHE3或AT1a受体将缓解Ang II依赖性高血压。在特定的目标3中，我们将确定口服活性的、可吸收的、特异的NHE3抑制剂选择性地抑制肾脏近端小管中的NHE3是否可以防止幼年SHR高血压的发展和在抑制物Ang II诱导的高血压小鼠模型中降低血压。该提案的成功结果将有助于开发新的近端小管特异性NHE3抑制剂来治疗控制不佳的高血压患者。

 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.