Renal Medullary COX2 in Blood Pressure Regulation

描述（由申请人提供）：与其他组织不同，肾脏具有丰富的诱导型环氧合酶-2 （COX2）组成表达（18）。在肾脏内，COX2绝大多数存在于间质细胞中，部分COX2表达于黄斑致密区及其邻近皮质厚升肢片段的皮层上皮细胞中。研究表明，环氧化酶抑制非甾体抗炎药（NSAIDs），包括新开发的COX2选择性抑制剂（塞来昔布，罗非昔布），在某些亚群患者中引起钠潴留和高血压（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重要作用。动物研究表明，高盐饮食可显著诱导肾髓质COX2(69)，这与肾髓质COX2在维持机体钠稳态中的作用一致。本研究将探讨高盐诱导肾髓质间质COX2在调节肾髓质血流、盐排泄和维持全身血压中发挥重要作用的假说。明确COX2在肾间质细胞中的作用将为鉴定肾COX2介导的PGs的靶分子或受体提供有价值的信息。建议的研究将有三个具体目标：

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.