The role of the proximal nephron in salt-sensitive hypertension

美国果糖消费量的急剧上升反映了高血压发病率的增加。超过 1700万美国人消耗超过20%的卡路里作为果糖，交叉研究直接表明， 果糖增加血压（BP）。我们曾报道果糖可引起盐敏感性高血压， 而葡萄糖则不然。我们还发现，饮食果糖增强血管紧张素II（Ang II）的刺激作用， II）在近端肾单位Na重吸收上，唯一能够重吸收和代谢果糖的肾单位节段。 我们在这里表明，饮食果糖增强血管紧张素II刺激蛋白激酶C（PKC）活性的能力， 近端小管产生O2。然而，PKC激活和氧化应激在近端 肾单位在果糖诱导的高血压中的作用知之甚少。除了重新吸收70%的过滤后的 钠和水，近端肾单位的主要功能之一是分泌蛋白酶， 蛋白质，使其能够被重吸收。蛋白酶诱导的上皮Na通道（ENaC）激活 集合管在几种病理条件下引起Na潴留和高血压。近端 小管还没有被认为是尿蛋白酶的潜在来源。氧化应激刺激蛋白酶 从非肾细胞释放。在这里，我们表明，饮食果糖增强近端肾单位表达的两个 这些蛋白酶，胰蛋白酶和meprin β，并增加这些和尿激酶的尿排泄。我们还表明 抑制ENaC可以逆转果糖诱导的高血压。磷脂酶D和细胞内 Ca（Cai）参与许多蛋白质的分泌，并且两者都由Ang II刺激。因此，我们假设 饮食果糖通过增强血管紧张素II诱导的PKC活性增加而引起盐敏感性高血压 和近端肾单位的氧化应激。这种增加的氧化应激刺激胰蛋白酶、尿激酶和 从该节段表达和释放meprin β。这些蛋白酶在收集中切割并激活ENaC。 刺激钠重吸收。目的我将测试是否饮食果糖增强血管紧张素II的能力， 通过近端小管刺激PKC活性和O2产生，从而有助于盐潴留和升高 在BP。目的II将测试膳食果糖是否能增强胰蛋白酶、尿激酶和 近端小管通过O2-、磷脂酶D和CaI依赖性机制介导meprin β。Aim III将测试 果糖诱导的近端小管释放胰蛋白酶、尿激酶和meprin β通过 收集管道，从而有助于盐的保留和血压升高。我们将使用最先进的技术 在成像、生理学、分子生物学和基因转移方面。这个项目将产生新的见解，如何饮食 果糖导致盐敏感性高血压，目前用于治疗高血压的药物，如血管紧张素 II受体阻滞剂和利尿剂靶向集合管可能是最有效的。由于这些药物是 这些建议目前已获批准用于此类用途，可立即予以采纳。

The dramatic rise in U.S. fructose consumption mirrors the increase in the incidence of hypertension. More than 17 million Americans consume >20% of their calories as fructose and crossover studies directly show that fructose increases blood pressure (BP). We reported that fructose causes salt-sensitive hypertension while glucose does not. We also showed that dietary fructose enhances the stimulatory effect of angiotensin II (Ang II) on proximal nephron Na reabsorption, the only nephron segment able to reabsorb and metabolize fructose. We show here that dietary fructose enhances the ability of Ang II to stimulate protein kinase C (PKC) activity and O2- production by proximal tubules. However, the roles of PKC activation and oxidative stress in the proximal nephron in fructose-induced hypertension are poorly understood. In addition to reabsorbing ≈70% of the filtered Na and water, one of the primary functions of the proximal nephron is to secrete proteases that degrade filtered proteins so they can be reabsorbed. Protease-induced activation of the epithelial Na channel (ENaC) in the collecting duct causes Na retention and hypertension in several pathological conditions. Heretofore proximal tubules have not been thought of as a potential source for urinary proteases. Oxidative stress stimulates protease release from non-renal cells. Here we show that dietary fructose enhances proximal nephron expression of two such proteases, trypsin and meprin β, and augments the urinary excretion of these and urokinase. We also show that inhibition of ENaC reverses fructose-induced hypertension. Phospholipase D and increases in intracellular Ca (Cai) are involved in the secretion of many proteins, and both are stimulated by Ang II. Thus, we hypothesize that dietary fructose causes salt-sensitive hypertension by enhancing Ang II-induced increases in PKC activity and oxidative stress in the proximal nephron. This increased oxidative stress stimulates trypsin, urokinase and meprin β expression and release from this segment. These proteases cleave and activate ENaC in collecting ducts, stimulating Na reabsorption. Aim I will test whether dietary fructose enhances the ability of Ang II to stimulate PKC activity and O2- production by proximal tubules thereby contributing to salt retention and elevations in BP. Aim II will test whether dietary fructose enhances the expression and release of trypsin, urokinase and meprin β by proximal tubules via O2-, phospholipase D and Cai-dependent mechanisms. Aim III will test whether fructose-induced trypsin, urokinase and meprin β release from proximal tubules augments Na reabsorption by collecting ducts, thereby contributing to salt retention and elevations in BP. 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, and which drugs currently used to treat hypertension such as Ang II receptor blockers and diuretics targeting collecting ducts will likely be most efficacious. Since these drugs are currently approved for such use, the recommendations could be adopted immediately.