Role of Proximal Tubule NHE3 in Angiotensin II-induced Hypertension

项目总结 在美国，三分之一的成年人会患上高血压，需要抗高血压治疗 在他们的一生中。更重要的是，只有50%的高血压患者使用药物控制血压 目前的抗高血压药物。高血压控制不佳在老年男性中非常普遍， 绝经后女性压力性钠尿反应受损。导致成绩不佳的因素 可控高血压仍有待确定。然而，很明显，所有形式的 高血压将需要不断地重新调整对较高压力的压力排钠反应。 尽管以前的研究表明Na+/H+交换器3(NHE3)参与了压力性钠尿反应 和血管紧张素II(Ang II)依赖性高血压，无论NHE3在肾脏近端小管中是 直接参与血管紧张素Ⅱ诱导的生理压力性钠尿反应及其重置 高血压以前从未被专门研究过。我们有强有力的初步证据表明 有条件地选择性缺失近端小管NHE3(PT-NHE3-KO)，或药物抑制 NHE3选择性地在肾脏，主要是近端小管，与一种新的口服可吸收的NHE3抑制剂 显著增加压力钠尿反应，减轻血管紧张素转换酶II和盐诱导的高血压 通过恢复小鼠的压力性钠尿反应。在这份修订后的提案中，我们将检验以下假设 肾近端小管NHE3直接参与生理性压力性钠尿 血管紧张素Ⅱ诱导的高血压反应、重置及NHE3的药理抑制作用 选择性地在肾脏，主要是近端小管，将减轻动物模型中的高血压 通过恢复压力性钠尿治疗遗传性、血管紧张素II、增龄性和性别相关高血压 回应。在特定的目标1中，我们将测试近端小管中选择性缺失NHE3是否会 通过抑制近端肾小管钠离子重吸收，增加血压排钠反应，降低血压。 然而，通过NHE3的过度表达，NHE3在近端小管中的选择性上调将损害和重置 压力钠尿通过刺激近端小管钠离子重吸收和促进对压力升高的反应 血压的盐敏性。在修订的特定目标2中，我们将测试NHE3是否存在于近端小管 直接参与生理压力性钠尿对急性盐水量扩张的反应， 利钠肽，或AT2受体/NO/cGMP信号的激活，以及在血压重置中的作用 Ang II、L姓名、年龄和性别相关高血压患者的利钠反应。在具体目标3中，我们将 检测口服安慰剂对NHE3在肾脏，主要是近端小管的选择性抑制作用 可吸收的NHE3抑制剂将通过以下方式减轻遗传性、血管紧张素II、衰老和性别相关的高血压 恢复压力排钠反应。这一提议的成功结果将有助于开发新的 通过选择性靶向近端小管中的NHE3治疗控制不佳或顽固性高血压的药物。

PROJECT SUMMARY In the United States, one in three adults will develop hypertension and require antihypertensive treatments in their lifetime. More importantly, only 50% of patients with hypertension have blood pressure controlled with current antihypertensive drugs. Poorly controlled hypertension is very prevalent in aging men and postmenopausal women with impaired pressure natriuresis response. The factors contributing to poorly controlled hypertension remain to be determined. It is clear, however, the development of all forms of hypertension will require continuously resetting of the pressure natriuresis response to higher pressures. Although previous studies have implicated the Na+/H+ exchanger 3 (NHE3) in the pressure natriuresis response and angiotensin II (ANG II)-dependent hypertension, whether NHE3 in the proximal tubules of the kidney is directly involved in the physiological pressure natriuresis response and its resetting in ANG II-induced hypertension has never been specifically investigated previously. We have strong preliminary evidence that conditional deletion of NHE3 selectively in the proximal tubules (PT-NHE3-KO), or pharmacological inhibition of NHE3 selectively in the kidney, primarily in the proximal tubules, with a novel orally absorbable NHE3 inhibitor significantly increases the pressure natriuresis response and attenuates ANG II- and salt-induced hypertension by restoring pressure natriuresis response in mice. In this revised proposal, we will test the hypotheses that NHE3 in the proximal tubules of the kidney is directly involved in the physiological pressure natriuresis response and its resetting in ANG II-induced hypertension, and that pharmacological inhibition of NHE3 selectively in the kidney, primarily in the proximal tubules, will attenuate hypertension in animal models of genetic-, ANG II-, aging-, and sex-associated hypertension by restoring pressure natriuresis responses. In Specific Aim 1, we will test whether deletion of NHE3 selectively in the proximal tubules will increase pressure natriuresis response and lower blood pressure by inhibiting proximal tubule Na+ reabsorption, whereas upregulation, via overexpression, of NHE3 selectively in the proximal tubules will impair and reset pressure natriuresis response to higher pressures by stimulating proximal tubule Na+ reabsorption and promoting salt sensitivity of blood pressure. In a revised Specific Aim 2, we will test whether NHE3 in the proximal tubules is directly involved in the physiological pressure natriuresis responses to acute saline volume expansion, natriuretic peptides, or activation of AT2 receptor/NO/cGMP signaling, and in the resetting of pressure natriuresis responses in ANG II-, L-NAME-, aging- and sex-associated hypertension. In Specific Aim 3, we will test whether inhibition of NHE3 selectively in the kidney, primarily in the proximal tubules, with an orally absorbable NHE3 inhibitor will attenuate genetic-, ANG II-, aging- and sex-associated hypertension by restoring pressure natriuresis responses. The successful outcomes of this proposal will help develop novel drugs to treat poorly controlled or resistant hypertension by selectively targeting NHE3 in the proximal tubules.