(Taken directly from the application) Cyclooxygenases (COXs) play a critical role in regulating cell function through the enzymatic production of prostaglandins, a family of bioactive unsaturated fatty acids. The recent discovery of a second, mitogen inducible isoform, COX2, was quickly followed by the realization that as compared to COX1, COX2 derived prostanoids played a dramatic role in neoplastic proliferation and inflammation. Constitutive expression of COX2 in the kidney is greater than in almost any other tissue and the bulk of renal COX2 is in the interstitium. The goal of this proposal is to establish the role of renal interstitial COX2 expression in normal physiologic processes and disease. Renal dysgenesis is the dominant phenotype of the COX2 knockout.
Specific Aim 1 will examine how COX2 derived prostaglandins promote renal development. The synthetic profile of COX1 and COX2 derived prostaglandins (i.e., PGE2 TxA2, PG12, PGF2a and PGD2) during nephrogenesis as well as the down-stream prostanoid receptors through which they promote development, will be determined. These studies will utilize several locally generated knockout mice including EP1, EP2 and EP4 receptor knockouts as well as COX1, and COX2 null mice.
Specific Aim 2 will examine the role of tubulointerstitial prostanoids in the pathogenesis of in diabetic nephropathy in the db/db mouse. Potential protective effects of COX1 gene disruption as well as EP2 and EP4 receptor, disruption on the progression of diabetic nephropathy will be determined in the db/db mouse. Finally Specific Aim 3 will examine the role of interstitial cells in maintaining blood pressure and renal medullary blood flow. A critical relationship between blood pressure and medullary interstitial cells has long been suggested. These studies will utilize a novel COX2 conditional knockout (i.e., COX2 a floxed allele) and an interstitial cell specific Cre to establish a cell specific knockout of COX2. The role of interstitial cells cyclooxygenase products in regulating renal medullary blood flow and its potential link to blood pressure regulation will thereby be determined. Through the information gained, we hope to establish new therapeutic targets within the prostaglandin pathway for treating renal disease.
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