Renal Medullary COX2 in Blood Pressure Regulation

描述(申请人提供)：与其他组织不同，肾脏表现出丰富的诱导型环氧合酶-2(COX2)的结构性表达(18)。在肾脏内，COX2主要分布在间质/间质细胞中，部分COX2表达于肾皮质致密黄斑及其邻近的皮质粗大升支上皮细胞中。研究表明，环氧合酶抑制非类固醇抗炎药(NSAIDs)，包括新开发的COX2选择性抑制剂(塞来昔布、罗非昔布)，在某些亚组患者(21，63，)中会导致钠滞留和高血压，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，高盐饮食可显著诱导肾髓质COX2的表达，这与肾髓质COX2在维持体内钠稳态中的作用一致。本研究将验证高盐诱导的肾脏髓质间质(间质)COX2在调节肾脏髓质血流、排盐和维持全身血压方面的重要作用的假说。明确COX2在肾间质细胞中的作用，将为鉴定COX2介导的PGs的靶分子(S)或受体(S)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COX2表达的机制。 目的II：研究肾髓质间质细胞COX2在高盐负荷后调节钠排泄和维持血压中的作用。 特异性目的III：确定激活的肾脏髓质COX2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.