The Role of The Proximal Nephron In Salt-Sensitive Hypertension

 描述(申请人提供)：高血压是世界范围内“健康丧失”的主要原因。多达50%的高血压是盐敏感的，这是一种疾病，由于肾脏缺陷，血压(BP)随着饮食中的盐的增加而增加。血管紧张素II(Ang II)是血压的关键调节因子，主要通过对肾脏的作用，包括近端小管(PT)。PT通过Na/H交换器3型(NHE3)和Na/K ATPase重吸收约70%的过滤后的Na。血管紧张素Ⅱ通过激活血管紧张素Ⅱ1型受体和经典蛋白激酶C亚型(α，β，γ)来刺激转运。当动物处于正常盐环境时，生理浓度的血管紧张素Ⅱ最大限度地刺激PT-Na的重吸收。当膳食盐水平升高时，Ang II水平下降~70%，尿钠排泄量(UNaV)增加，盐被排除。然而，如果面对高盐饮食，血管紧张素转换酶II的作用没有下降，盐就会保留下来，血压就会上升。 超过1500万美国人消耗的卡路里中有20%是果糖。饮食中的果糖会导致人类高血压。我们已经证明，当大鼠摄入20%的卡路里作为果糖(20%果糖饮食)时，它们会患上盐敏感型高血压，并且在开始高盐饮食后1-2天，血压开始上升。AT1受体阻滞剂降低果糖喂养大鼠的血压；然而，PT的作用和果糖导致盐敏感型高血压的机制尚不清楚。我们发现，果糖可以激活分离的、灌流的PTS中的PKCα/β，20%的果糖、高盐饮食使低浓度的Ang II能够刺激体外测量的PT转运，但不能增强最大作用。心钠素、多巴胺、一氧化氮不起作用。然而，果糖对PT的影响是否参与了果糖诱导的盐敏感型高血压及其机制尚不清楚。我们假设，20%的果糖饮食通过激活蛋白激酶Cα，从而使低浓度的血管紧张素Ⅱ(如高盐饮食引起的血管紧张素II)刺激PT-Na重吸收，从而钝化盐诱导的钠尿，并导致盐敏感型高血压。目的1测试20%果糖饮食是否能使高盐饮食引起的低浓度Ang II刺激NHE3和Na/K ATPase对PT-Na的重吸收。目的2将测试20%果糖饮食是否能提高基础蛋白激酶Cα活性，从而使低浓度血管紧张素转换酶II能充分提高蛋白激酶Cα活性，从而刺激钠重吸收。目标3 将测试20%果糖饮食对PT的影响是否会降低排出盐的能力 导致盐敏感型高血压。我们将在成像、生理学、分子生物学和基因转移方面使用最先进的技术。这个项目将对饮食中的果糖如何导致盐敏感型高血压产生新的见解。

 DESCRIPTION (provided by applicant): Hypertension is the leading cause of "loss of health" worldwide. As much as 50% of hypertension is salt- sensitive, a disease in which blood pressure (BP) increases with dietary salt due to a renal defect. Angiotensin II (Ang II) is a key regulator of BP primarily through actions on the kidney, including the proximal tubule (PT). The PT reabsorbs ~70% of the filtered Na via Na/H exchanger type 3 (NHE3) and Na/K ATPase. Ang II stimulates transport via activation of Ang II type 1 (AT1) receptors and classical protein kinase C (PKC) isoforms (α, β, γ). Physiological concentrations of Ang II when animals are on normal salt maximally stimulate PT Na reabsorption. When dietary salt is elevated, Ang II levels fall by ~70%, urinary Na excretion (UNaV) increases and the salt is eliminated. However, if the effects of Ang II don't decline in the face of a high-salt diet, salt is retained and BP increases. More than 15 million Americans consume >20% of their calories as fructose. Dietary fructose causes hypertension in humans. We have shown that when rats consume 20% of their calories as fructose (20% fructose diet) they develop salt-sensitive hypertension, and that BP begins to increase 1-2 days after beginning a high-salt diet. AT1 receptor blockers reduce BP in fructose-fed rats; however, the role of the PT and the mechanisms by which fructose causes salt-sensitive hypertension are unknown. We show that fructose can activate PKCα/β in isolated, perfused PTs and that a 20% fructose, high- salt diet enables low concentrations of Ang II to stimulate PT transport measured in vitro, but does not enhance the maximum effect. Atrial natriuretic factor, dopamine, nitric oxide do not play a role. However, whether the effects of fructose on the PT contribute to fructose-induced salt-sensitive hypertension and the mechanisms involved are unknown. We hypothesize that a 20% fructose diet blunts salt-induced natriuresis and causes salt-sensitive hypertension by activating PKCα thereby enabling low concentrations of Ang II such as those caused by a high-salt diet to stimulate PT Na reabsorption. Aim 1 will test whether a 20% fructose diet enables low concentrations of Ang II as caused by a high-salt diet to stimulate PT Na reabsorption by NHE3 and Na/K ATPase. Aim 2 will test whether a 20% fructose diet raises basal PKCα activity thereby enabling low concentrations of Ang II to elevate PKCα activity sufficiently to stimulate Na reabsorption. Aim 3 will test whether the effects of a 20% fructose diet on the PT reduce the ability to excrete a salt load and cause salt- sensitive hypertension. We will use state of the art techniques in imaging, physiology, molecular biology and gene transfer. This project will yield new insights into how dietary fructose causes salt-sensitive hypertension.