THE ROLE OF CYCLOXGENISE 2 IN PROGRESSIVE NEPHRON DESTRU

Vanderbilt University, Nashville TN

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Abstract

Description: (Taken directly from the application) Cyclooxygenase-2 (COX-2) expression increases in the kidney cortex in both inflammatory and "non-inflammatory" progressive renal injury. We and others have identified three sites in kidney cortex that exhibit increased COX-2 expression in progressive injury: infiltrating leukocytes in glomerulus, the macula densa and surrounding cTALH and tubulointerstitium and glomerular podocytes. The three Specific Aims of this proposal are designed to address mechanisms of regulation of COX-2 expression and the pathophysiologic consequences of increased expression in these cell types. We will utilize three mouse models of progressive renal injury: a model of progressive glomerulosclerosis and tubulointerstitial injury secondary to loss of functioning renal mass, a model of diabetic nephropathy and a model of crescenteric glomerulonephritis In Specific Aim #1, we will examine COX-2 expression in these models of progressive renal injury and will determine the effect of specific COX-I and COX-2 inhibitors on disease progression. Leukocyte infiltration of glomerulus and tubulointerstitium is a hallmark of both inflammatory and non-inflammatory progressive renal injury. In this aim, we will also define the potential role of leukocyte-generated prostanoids derived from COX-2 by subjecting mice to lethal irradiation and bone marrow transplant with cells derived from COX-2-/-mice in order block COX-2 expression in infiltrating cells. In Specific Aim #2, we will examine the effect of increased COX-2 in the macula densa and surrounding cTALH on renal hemodynamics in hyperfiltering states and determine pathophysiologic mechanisms underlying this increased expression. In Specific Aim #3, we propose to examine the role of COX-2 expression on glomerular podocyte function under basal conditions and in response to glomerular injury. For these studies, we will either selectively overexpress COX-2 in podocytes by developing transgenic mice in which increased COX-2 expression is directed by the nephrin promoter or selectively delete podocyte COX-2 by developing and crossing loxP targeted COX-2 mice with nephrin-Cre mice.