Physiologic and pathophysiologic roles of cyclooxygenase-2 in the kidney.

In the mammalian kidney, prostaglandins are important mediators of physiologic processes, including modulation of vascular tone and salt and water. Prostaglandins arise from enzymatic metabolism of free arachidonic acid (AA), which is cleaved from membrane phospholipids by phospholipase A2 activity. The cyclooxygenase (COX) enzyme system is a major pathway for metabolism of arachidonic acid in the kidney. Cyclooxygenases are the enzymes responsible for the initial conversion of AA to PGG2 and subsequently to PGH2, which serves as the precursor for subsequent metabolism by specific prostaglandin and thromboxane synthases. In addition to high levels of expression of the "constitutive" rate-limiting enzyme responsible for prostanoid production, COX-1, the "inducible" isoform of cyclooxygenase, COX-2, is also constitutively expressed in the kidney and is highly regulated in response to alterations in intravascular volume. Prostaglandins and thromboxane A2 exert their biological functions predominantly through activation of specific 7-transmembrane G-protein-coupled receptors. We and others have shown that COX-2-derived prostaglandins exert important physiologic functions in maintenance of renal blood flow, mediation of renin release, and regulation of sodium excretion. In addition to physiologic regulation of prostanoid production in the kidney, increases in prostanoid production are also observed in a variety of inflammatory renal injuries, and we have found a role for COX metabolites to serve as mediators of inflammatory injury in renal disease.