Interstital Cell COXs in Renal Development and Disease

Vanderbilt University, Nashville TN

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Abstract

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.