Role of Thick Ascending Limb Free Radicals in Angiotensin II-Dependent Hyperten

首席研究员/项目主任(最后、第一、中间)：加文，杰弗里·L，博士/蔡特奥，奥斯卡·A，医学博士 项目V 粗大升肢自由基在血管紧张素诱导高血压中的作用 项目调查员：杰弗里·L·加文博士 共同调查者：巴勃罗·A·奥尔蒂斯博士 共同调查者：帕特里克·J·帕加诺博士 共同调查者：杨晓平，医学博士 摘要 促进肾脏盐分和水分排泄的因素[即一氧化氮(NO)]和 血管紧张素II中有利于滞留的物质[即超氧化物(O2“)]。 形式，这种平衡有利于后者。肾脏不适当的食盐滞留可能导致或促成Ang II- 依赖型高血压。粗大的上肢吸收过滤后的NACI负荷的20%-30%。我们已经展示了 在粗大的升肢中，由内皮细胞或3型一氧化氮合酶(ENOS)特异性产生的NO起着 一种金龟子，抑制NaCI的吸收，因此可能会显著促进盐分和水分的排泄。 我们还发现，O2“刺激粗大的升肢对NaCI的吸收。 小剂量至中剂量血管紧张素转换酶II引起的高血压依赖于盐的摄入量。这些数据 表明肾脏在这种形式的高血压中起着重要作用。血管紧张性高血压期间肾脏 皮质eNOS表达增强，但我们的数据显示髓质厚的上肢表达 减少。相比之下，两个地区的活性氧(包括O2“)的生成量都有所增加。 目前，尚不清楚血管紧张性高血压如何影响髓质厚度对NaCI的净吸收。 这些效应是否由NO和O2~产生的变化所介导。因此，我们 假设在血管紧张素Ⅱ诱导性高血压期间， 粗大升肢中的利钠因子NO和抗利钠因子O2‘有利于后者 并增强盐分的吸收。目的I.假说：血管紧张素Ⅱ诱导的高血压减少血管内皮细胞一氧化氮的产生 粗大的升肢部分通过释放肿瘤坏死因子a(TNF A)减少eNOS的表达。 目的II.假设：激动剂诱导的eNOS激活在血管紧张性高血压中减少，原因是 抑制部位的磷酸化增加

Principal Investigator/Program Director (Last, First, Middle): Garvin, Jeffrey L, Ph.D./CaiTeterO, Oscar A., M.D. PROJECT V Role of Thick Ascending Limb Free Radicals in Angiotensin ll-lnduced Hypertension Project Investigator: Jeffrey L. Garvin, Ph.D. Co-Investigator: Pablo A. Ortiz, Ph.D. Co-Investigator: Patrick J. Pagano, Ph.D. Co-Investigator: Xiao-Ping Yang, M.D. Abstract There is a balance between factors promoting renal salt and water excretion [i.e., nitric oxide (NO)] and those favoring retention [i.e., superoxide (O2")]. In angiotensin II (Ang Independent hypertension and other forms, this balance favors the latter. Inappropriate salt retention by the kidney may lead or contribute to Ang II- dependent hypertension. The thick ascending limb absorbs 20-30% of the filtered NaCI load. We have shown that NO specifically produced by endothelial or type 3 NO synthase (eNOS) in the thick ascending limb acts as an autacoid, inhibiting NaCI absorption, and may thereby contribute significantly to salt and water excretion. We have also shown that O2" stimulates NaCI absorption in the thick ascending limb. Ang ll-induced hypertension caused by infusion of low to moderate doses of Ang II is dependent on salt intake. These data indicate a significant role of the kidney in this form of hypertension. During Ang ll-induced hypertension renal cortical eNOS expression is enhanced, but our data show that medullary thick ascending limb expression decreases. In contrast, production of reactive oxygen species (including O2") is elevated in both regions. Currently, it is unclear how Ang ll-induced hypertension affects net NaCI absorption by the medullary thick ascending limb, or whether these effects are mediated by changes in NO and O2~ production. Thus we hypothesize that during Ang ll-induced hypertension there is a shift in the balance between the natriuretic factor NOand the antinatriuretic factor O2'in the thick ascending limb that favors the latter and enhances salt absorption. Aim I. Hypothesis: Ang ll-induced hypertension diminishes NOproduction in the thick ascending limb in part by reducing eNOS expression via release of tumor necrosis factor a (TNF a). Aim II. Hypothesis: Agonist-induced eNOS activation is reduced in Ang ll-induced hypertension due to increased phosphorylation at the inhibitory