Interstitial Cell COXs in Renal Development and Disease

间质细胞 COX 在肾脏发育和疾病中的作用

• 批准号: 6780924
• 负责人: CHUAN-MING HAO
• 金额: $ 15.1万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-23 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6780924
• 关键词: connective tissue cells; diabetic nephropathy; enzyme activity; gene deletion mutation; gene targeting; genetically modified animals; immunocytochemistry; in situ hybridization; kidney function; laboratory mouse; nephrogenesis; polycystic kidney; prostaglandin endoperoxide synthase; prostaglandins; renal tubule; tissue /cell culture

DESCRIPTION (provided by applicant): Of all organs tested, the kidney exhibits the greatest level of expression of the inducible form of cyclooxygenase-2 (COX2) (Guan Am J. Physiol 1997), and within the kidney, the vast majority of COX2 resides in the interstitial cell. The interstitial cell is situated between the renal microvascular and epithelial compartments and so, COX2 derived prostaglandins elaborated by medullary interstitial cells are in an ideal location to modulate the functions of both renal tissues. Accumulating evidence suggests that renal interstitial/stromal cells are involved in virtually all functions of healthy kidney, and in many pathological events of the kidney [Grupp, 1999 #144]. However because COX2 is also expressed in the renal macula densa and COX1 is expressed in the collecting duct, the exact role of these renal interstitial cell COX2 derived prostanoids in the kidney is not precisesly known. The present proposal will focus on the role of renal interstitial/stromal COX mediated prostanoids in normal and diseased kidney including diabetic and polycystic kidney disease. Elucidating the bio-activity of renal prostaglandins will be important not only in understanding the maintenance of normal renal function but also in determining their potential as therapeutic targets in disease. The proposed studies will have two specific aims: Specific Aim 1: Generating and characterizing renal interstitial cell selective COX2 deficient mouse. Conventional COX2 gene disruption results in kidney dysgenesis, suggesting COX2 plays an important role in the kidney development, it remains uncertain whether interstitial or epithelial (i.e. nacent macula densa) derived COX2 is necessary for normal renal development. Futhermore examination of the role of COX2 in the adult COX2 null mouse is complicated by this renal dysgensis. Conditional COX2 knockout mice will allow this problem to be circumvented. Furthermore, the conditional COX2 knockout mouse will make it possible to study selectively the role of renal interstitial cell COX2 in the kidney. Specific Aim 2: Examine the role of renal interstitial COX2 and COX1 in maintenance of normal function and in the pathogenesis of disease such as diabetic nephropathy and polycystic kidney disease. The proposed studies will examine the effect of selective renal interstitial cell COX2 deletion on the (1) ability of renal papilla to survive hypertonic stress; (2) development of diabetic kidney disease; (3) on rate of expansion of cyst.

描述（由申请人提供）：在所有测试的器官中，肾脏表现出诱导型环氧合酶 2 (COX2) 的最高水平表达 (Guan Am J. Physiol 1997)，并且在肾脏内，绝大多数 COX2 存在于间质细胞中。间质细胞位于肾微血管和上皮室之间，因此，由髓质间质细胞产生的 COX2 衍生的前列腺素处于调节两个肾组织功能的理想位置。越来越多的证据表明肾间质/基质细胞几乎参与健康肾脏的所有功能以及肾脏的许多病理事件[Grupp, 1999 #144]。然而，由于COX2也在肾致密斑中表达，COX1在集合管中表达，这些肾间质细胞COX2衍生的前列腺素在肾脏中的确切作用尚不清楚。目前的提案将重点关注肾间质/基质 COX 介导的前列腺素类药物在正常和患病肾脏（包括糖尿病和多囊肾病）中的作用。阐明肾前列腺素的生物活性不仅对于理解正常肾功能的维持很重要，而且对于确定它们作为疾病治疗靶点的潜力也很重要。拟议的研究将有两个具体目标： 具体目标 1：生成并表征肾间质细胞选择性 COX2 缺陷小鼠。传统的COX2基因破坏会导致肾脏发育不全，表明COX2在肾脏发育中发挥重要作用，但仍不确定间质或上皮（即新生致密斑）来源的COX2是否是正常肾脏发育所必需的。进一步检查 COX2 在成年 COX2 缺失小鼠中的作用因这种肾发育不全而变得复杂。有条件的COX2基因敲除小鼠将可以避免这个问题。此外，条件性COX2敲除小鼠将使选择性研究肾间质细胞COX2在肾脏中的作用成为可能。 具体目标2：检查肾间质COX2和COX1在维持正常功能以及糖尿病肾病和多囊肾等疾病发病机制中的作用。拟议的研究将检查选择性肾间质细胞 COX2 缺失对 (1) 肾乳头生存高渗应激能力的影响； (2) 糖尿病肾病的发展； (3)对囊肿扩张速度的影响。