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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/R1751    most recent 90985.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Seta, F. Articles by Funk, C. D. PubMed PubMed Citation Articles by Seta, F. Articles by Funk, C. D.

HEMODYNAMICS AND CARDIORENAL INTEGRATION

Renal and cardiovascular characterization of COX-2 knockdown mice

Departments of ¹Physiology and ⁵Biochemistry, and ³Cancer Research Institute, Queen's University, Kingston, Ontario, Canada; ²Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada; and ⁴Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania

Submitted 4 December 2008 ; accepted in final form 2 April 2009

Selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) increase the incidence of cardiovascular and cerebrovascular events. Complete disruption of the murine gene encoding COX-2 (Ptgs2) leads to renal developmental problems, as well as female reproductive anomalies and patent ductus arteriosus of variable penetrance in newborns, thus rendering this genetic approach difficult to compare with coxib administration. Here, we created hypomorphic Ptgs2 (COX-2^Neo/Neo) mice in which COX-2 expression is suppressed to an extent similar to that achieved with coxibs, but not eliminated, in an attempt to circumvent these difficulties. In LPS-challenged macrophages and cytokine-stimulated endothelial cells obtained from COX-2^Neo/Neo mice, COX-2 expression was reduced 70–90%, and these mice developed a mild renal phenotype compared with COX-2 mice possessing an active site mutation (COX-2^Y385F/Y385F), with minimal signs of renal dysfunction as measured by FITC-inulin clearance and blood urea nitrogen. These COX-2 knockdown mice displayed an increased propensity for thrombogenesis compared with their wild-type (COX-2^+/+) littermates observed by intravital microscopy in cremaster muscle arterioles upon ferric chloride challenge. Measurement of urinary prostanoid metabolites indicated that COX-2^Neo/Neo mice produced 50% less prostacyclin but similar levels of PGE₂ and thromboxane compared with COX-2^+/+ mice in the absence of any blood pressure and ex vivo platelet aggregation abnormalities. COX-2^Neo/Neo mice, therefore, provide a genetic surrogate of coxib therapy with disrupted prostacyclin biosynthesis that predisposes to induced arterial thrombosis.

prostaglandin synthase; thrombosis; prostacyclin; macrophage; induced mutant mice; kidney