PROSTAGLANDIN-SYNTHASE-2 GENE DISRUPTION CAUSES SEVERE RENAL PATHOLOGY IN THE MOUSE

The prostaglandin endoperoxide H synthase isoform 2, cyclooxygenase 2 (COX-2), is induced at high levels in migratory and other responding c ells by proinflammatory stimuli. COX-2 is generally considered to be a mediator of inflammation. Its isoform, COX-1, is constitutively expre ssed in most tissues and is thought to mediate ''housekeeping'' functi ons. These two enzymes are therapeutic targets of the widely used nons teroidal anti-inflammatory drugs (NSAIDs). To investigate further the different physiologic roles of these isoforms, we have used homologous recombination to disrupt the mouse gene encoding COX-2 (PtgsS). Mice lacking COX-2 have normal inflammatory responses to treatments with te tradecanoyl phorbol acetate or with arachidonic acid. However, the; de velop severe nephropathy and are susceptible to peritonitis.