Interstitial Cell COXs in Renal Development and Disease

描述(申请人提供)：在所有被测试的器官中，肾脏表现出最高水平的诱导形式的环氧合酶-2(COX2)(Guan Am J.Physiol 1997)，并且在肾脏内，绝大多数COX2驻留在间质细胞中。间质细胞位于肾微血管和上皮室之间，因此，由髓质间质细胞分泌的COX2衍生前列腺素处于调节两种肾组织功能的理想位置。越来越多的证据表明，肾间质/基质细胞几乎参与了健康肾脏的所有功能，并参与了肾脏的许多病理事件(Grupp，1999#144)。然而，由于COX2也在肾脏致密斑区表达，COX1在集合管表达，这些肾间质细胞COX2衍生的前列腺素类化合物在肾脏中的确切作用尚不清楚。目前的建议将集中在肾间质/间质COX介导的前列腺素在正常和疾病肾脏中的作用，包括糖尿病和多囊肾病。阐明肾脏前列腺素的生物活性不仅对于理解正常肾功能的维持具有重要意义，而且对于确定其作为疾病治疗靶点的潜力也具有重要意义。拟议的研究将有两个具体目标： 特异性目的1：建立和鉴定肾间质细胞选择性COX2缺陷小鼠。传统的COX2基因突变导致肾脏发育不全，提示COX2在肾脏发育中起重要作用，但尚不确定COX2来源于间质还是上皮性(即密集黄斑)对正常肾脏发育是必需的。此外，在成年COX2缺失小鼠中检测COX2的作用也会因这种肾脏发育不全而变得复杂。有条件的COX2基因敲除小鼠可以绕过这个问题。此外，条件性COX2基因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。 具体目的2：研究肾间质COX2和COX1在维持正常功能和糖尿病肾病、多囊肾病等疾病发病机制中的作用。建议的研究将检查选择性肾间质细胞COX2缺失对(1)肾乳头在高渗应激下存活的能力；(2)糖尿病肾病的发展；(3)对囊性扩张速度的影响。

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.