ISOPROSTANES IN LIVER DISEASE-INDUCED RENAL DYSFUNCTION

异前列腺素在肝病引起的肾功能障碍中的作用

• 批准号: 6634778
• 负责人: LUIS A. JUNCOS
• 金额: $ 12万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634778
• 关键词: acetylcholine; angiotensin II; antioxidants; arachidonate; arterioles; cholanate compound; disease /disorder model; hemodynamics; kidney circulation; kidney circulation disorder; laboratory rat; liver disorder; molecular pathology; nitric oxide; nitroferricyanide; oxidative stress

DESCRIPTION (adapted from the application) Liver disease induces a spectrum of renal abnormalities. Early on there is redistribution of intrarenal RBF; that is there is cortical vasoconstriction with shunting of RBF towards the juxtamedullary nephrons, which may contribute to enhanced sodium and water retention. However, the mechanisms leading to these alterations are not clear. Recent studies have described a new family of prostaglandin-like compounds, F2-isoprostanes, that are formed in vivo by free-radical catalyzed peroxidation of arachidonic acid. These compounds are markers of oxidant injury, possess biological activity and are markedly elevated in liver disease. Yet their role in the associated renal dysfunction is poorly understood. We hypothesize that elevated oxidative stress in liver disease increases F2-isoprostanes, which in turn contribute to the altered renal hemodynamics. In our first aim, we examine whether oxidative stress via F2-isoprostanes contributes to the redistribution of intrarenal RBF induced by chronic bile duct ligation (c-BDL). The rationale for this aim is that c-BDL increases oxidative stress and causes redistribution of RBF. Thus, using micro-CT technology, we will examine whether by acutely or chronically blocking oxidative stress or the F2-isoprostanes receptor reverses or prevents the redistribution of RBF. The next aims assess the direct actions of isoprostanes, and what role oxidative stress via isoprostanes plays in the renal vascular abnormalities of the c-BDL rats. For this, we will study vascular reactivity in isolated microperfused afferent arterioles dissected from the superficial and juxtamedullary cortex (s-Af-Arts and jm-Af-Arts respectively), of control and c-BDL rats. In aim #2 we test the hypothesis that s-Af-Arts are more sensitive than jm-Af-Arts isoprostane-induced vasoconstriction, which thus may explain why renal medullary perfusion is preserved despite marked cortical hypoperfusion. In aim #3 we test the hypothesis that vascular reactivity of s-Af-Art but not jm-Af-Arts is enhanced in c-BDL compared to controls (contributing to the above-mentioned redistribution of RBF). If we find that Af-Art reactivity is altered, we will test the hypothesis that the enhanced reactivity is due to oxidative stress via increased isoprostanes by determining whether treatment with antioxidants or isoprostane antagonists improves the vascular parameters. Finally, because bile acids are very elevated in c-BDL, and can themselves promote oxidative stress, aim #4 tests the hypothesis that the elevated bile acids themselves contribute to the enhanced Af-Art reactivity via their pro-oxidant actions. We will examine the effects that bile acids have on s- and jm-Af-Art diameter, and reactivity (as in aim #2). This information will complement that obtained in aim #2 (where the exposure to bile acids is chronic in vivo rather than acute in vitro). Our proposed application therefore characterizes the renal vascular actions of oxidative stress and isoprostanes, and evaluates their role in the c-BDL rats.

描述（根据应用程序改编） 肝病诱导肾异常。早些时候 重新分布肾内RBF；那是皮质血管收缩 随着RBF向近来的肾上腺脱骨，这可能有助于 以增强钠和保水。但是，导致的机制 这些更改尚不清楚。最近的研究描述了一个新家庭 前列腺素状化合物，F2-异前列腺，由体内形成 蛛网膜酸的自由基催化过氧化。这些化合物是 氧化剂损伤的标志物，具有生物学活性，明显 肝病升高。然而它们在相关的肾功能障碍中的作用 理解很差。我们假设肝脏中氧化应激升高 疾病增加了F2-异前列腺，进而有助于改变 肾脏血流动力学。在我们的第一个目标中，我们检查是否通过 F2-异前列腺有助于重新分布由肾内RBF的重新分布 慢性胆管连接（C-BDL）。这个目标的理由是C-BDL 增加氧化应激并导致RBF的重新分布。因此，使用 Micro-CT技术，我们将通过急性或长期阻塞检查 氧化应激或F2-异前列腺受体逆转或防止 RBF的重新分布。下一个目标评估异丙烷的直接行动， 以及通过异前列腺在肾血管中发挥的作用氧化应激 C-BDL大鼠的异常。为此，我们将研究血管反应性 从浅表和 对照和控制和 C-BDL大鼠。在AIM＃2中，我们检验了S-AF-Arts更敏感的假设 比JM-AF-ARTS异丙烷引起的血管收缩，因此可以解释 为什么尽管有明显的皮质 灌注不良。在AIM＃3中，我们检验了以下假设 与对照组相比 （有助于上述RBF的重新分布）。如果我们发现 Af-Af-Art反应性发生了改变，我们将检验以下假设。 反应性是由于通过确定的氧化应激通过增加的氧化应激引起的 用抗氧化剂或异丙烷拮抗剂治疗是否可以改善 血管参数。最后，由于胆汁酸在C-BDL中非常升高，所以 并可以促进氧化应激，目标＃4检验了以下假设 升高的胆汁酸本身有助于增强的AF-AF-ART反应性 通过他们的氧化作用。我们将研究胆汁酸具有的影响 在S-和JM-AF-ART直径以及反应性（如AIM＃2中）。此信息 会补充AIM＃2中获得的补充（其中暴露于胆汁酸是 慢性体内而不是体外急性）。因此，我们提出的申请 表征了氧化应激和异丙烷的肾血管作用， 并评估它们在C-BDL大鼠中的作用。