Renal Medullary COX2 in Blood Pressure Regulation

描述（由申请人提供）：与其他组织相反，肾脏表现出诱导型环氧合酶-2（COX 2）的丰富组成型表达（18）。在肾脏内，绝大多数COX 2存在于基质/间质细胞中，其中一些COX 2在致密斑上的上皮细胞中的皮质中及其皮质厚升支的相邻片段中表达。研究表明，抑制环氧合酶的非甾体抗炎药（NSAID），包括新开发的COX 2选择性抑制剂（塞来昔布，罗非昔布），在某些患者亚群中引起钠潴留和高血压（21，63，64），这表明肾脏COX 2介导的前列腺素在调节盐吸收和全身血压中的重要作用。动物研究表明，高盐饮食显著诱导肾髓质C 0X 2（69），这与肾髓质C 0X 2在维持体内钠稳态中的作用一致。目前的建议将检查的假设，高盐诱导的肾髓质间质（基质）COX 2起着重要的作用，在调节肾髓质血流，盐排泄和维持全身血压。确定COX 2在肾间质细胞中的作用将为鉴定肾COX 2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I：研究高盐饮食诱导COX 2表达的机制。 具体目标二：探讨高盐负荷后肾髓质间质细胞COX 2在调节钠排泄和维持血压中的作用。 具体目的III：确定活化的肾髓质COX 2表达的下游靶点。

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.