Cyclooxygenase-2 in the kidney.

Prostaglandins are produced constitutively by many tissues in the body, including brain, gut, and kidney, and their synthesis increases at sites of inflammation. Cyclooxygenase (COX), the enzyme responsible for the initial rate-limiting metabolism of arachidonic acid to prostaglandin G2 and subsequently to prostaglandin H2, was first purified in ram seminal vesicles and was cloned in 1988 by DeWitt and Smith (1). This enzyme has been renamed cyclooxygenase-1 (COX-1) to indicate that it encodes the constitutive enzyme. Prostaglandins play myriad roles as local mediators of inflammation and as modulators of physiologic functions, such as maintenance of gastric mucosal integrity and modulation of renal microvascular hemodynamics, renin release, and tubular salt and water reabsorption (2). After the recognition that COX was the target of aspirin (3), the pharmaceutical industry developed a substantial number of nonsteroidal anti-inflammatory drugs (NSAID), whose mechanism of action involves competitive or noncompetitive inhibition of COX activity. However, by the early 1990s, experimental studies began to suggest that COX-1 might not be the enzyme responsible for increased prostanoid production in inflammatory states. In cultured cells and tissue, COX activity increased rapidly in response to mitogens and cytokines (4–6), although COX-1 mRNA and immunoreactive protein were not altered. Furthermore, glucocorticoid administration was shown to decrease COX activity in peritoneal macrophages after lipopolysaccharides (7) but not to affect constitutive renal medullary COX activity. These results led Needleman and co-workers (7) to postulate the existence of a second, inflammatory-mediated COX isoform. Shortly after the Needleman hypothesis was formulated, Xie and co-workers (8) detected the presence of a second avian COX mRNA species, and Kujubu and co-workers (9) identified a phorbol ester-activated immediate early murine gene (TIS10) that possesses similar COX activity but shares only approximately 66% homology in amino acid sequence. This second COX isoform has subsequently been renamed cyclooxygenase-2 (COX-2), and a vast amount of research has identified it to be an inducible and glucocorticoid-sensitive gene that is highly expressed in many tissues in response to inflammation. Expression of recombinant enzymes and determination of the crystal structure of COX-2 have provided insights into the observed physiologic and pharmacologic similarities to and differences from COX-1 (10,11). The identification of COX-2 has also led to the development and marketing of both relatively and highly selective COX-2 inhibitors for use as analgesics, antipyretics, and anti-inflammatory agents. In addition to its central role in inflammation, aberrantly upregulated COX-2 expression is increasingly implicated in the pathogenesis of a number of epithelial cell carcinomas, including colon, esophagus, breast, and skin, and in Alzheimer’s disease and possibly other neurologic conditions (12–14).