Renal Medullary COX2 in Blood Pressure Regulation

肾髓质 COX2 在血压调节中的作用

• 批准号: 7455306
• 负责人: CHUAN-MING HAO
• 金额: $ 26.74万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7455306
• 关键词: Animals; Anti-Inflammatory Agents; Anti-inflammatory; Blood Pressure; Blood flow; Coxibs; Diet; Epithelial Cells; Equilibrium; Excretory function; Exhibits; Homeostasis; Hypertension; Kidney; Limb structure; Luciferases; Macula densa; Mediating; Patients; Pharmaceutical Preparations; Play; Prostaglandin Receptor; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Renal Interstitial Cell; Reporter; Rofecoxib; Role; Sodium; Sodium Chloride; Stream; Techniques; Testing; Thick; Tissues; Transgenic Mice; absorption; blood pressure regulation; celecoxib; cyclooxygenase 1; cyclooxygenase 2; inhibitor/antagonist; interstitial; interstitial cell; kidney medulla; progesterone 11-hemisuccinate-(2-iodohistamine); prostaglandin EP2 receptor; receptor

DESCRIPTION (provided by applicant): As opposed to other tissues, the kidney exhibits abundant constitutive expression of inducible cyclooxygenase-2 (COX2) (18). Within the kidney, the vast majority of COX2 resides in the stromal/interstitial cells, with some COX2 expressed in the cortex in epithelial cells on macula densa and its adjacent fragment of cortical thick ascending limb. Studies indicate cyclooxygenase inhibiting non-steroidal anti-inflammatory drugs (NSAIDs), including newly developed COX2 selective inhibitors (celecoxib, rofecoxib), cause sodium retention and hypertension in certain subsets of patients (21, 63, 64), pointing to an important role of renal COX2 mediated prostaglandins in regulating salt absorption and systemic blood pressure. Animal studies show renal medullary COX2 is markedly induced by high salt diet (69), consistent with the role of renal medullary COX2 in maintaining body sodium homeostasis. The present proposal will examine the hypothesis that high salt induced renal medullary interstitial (stromal) COX2 plays an important role in regulating renal medullary blood flow, salt excretion and maintaining systemic blood pressure. Defining the role of COX2 in renal interstitial cells should provide valuable information in identifying target molecule(s) or receptor(s) of renal COX2 mediated PGs. The proposed studies will have three specific aims: Specific Aim I: To examine the mechanism underlying high salt diet induced COX2 expression. Specific Aim II: To examine the role of renal medullary interstitial cell COX2 in modulating sodium excretion and maintaining blood pressure following high salt loading. Specific Aim III: To define the down-stream target of activated renal medullary COX2 expression.

描述（由申请人提供）：与其他组织相反，肾脏表现出丰富的诱导型环氧合酶-2 (COX2) 组成型表达 (18)。在肾脏内，绝大多数 COX2 驻留在基质/间质细胞中，一些 COX2 在皮质中的致密斑及其邻近的皮质厚升肢片段的上皮细胞中表达。研究表明，抑制环氧合酶的非甾体类抗炎药 (NSAID)，包括新开发的 COX2 选择性抑制剂（塞来考昔、罗非考昔），会导致某些患者亚群出现钠潴留和高血压 (21,63,64)，这表明肾脏 COX2 介导的前列腺素在调节盐吸收和全身血压方面发挥着重要作用。动物研究表明，高盐饮食可显着诱导肾髓质 COX2 (69)，这与肾髓质 COX2 在维持体内钠稳态中的作用一致。本提案将检验以下假设：高盐诱导的肾髓质间质（基质）COX2 在调节肾髓质血流、盐排泄和维持全身血压方面发挥重要作用。定义 COX2 在肾间质细胞中的作用应该为识别肾 COX2 介导的 PG 的靶分子或受体提供有价值的信息。拟议的研究将有三个具体目标： 具体目的一：探讨高盐饮食诱导COX2表达的机制。 具体目标 II：检查肾髓质间质细胞 COX2 在高盐负荷后调节钠排泄和维持血压中的作用。 具体目标 III：确定激活肾髓质 COX2 表达的下游靶点。