Physiological regulation of cyclooxygenase-2 in the kidney

In adult mammalian kidney, cyclooxygenase-2 (COX-2) expression is found in a restricted subpopulation of cells. The two sites of renal COX-2 localizat ion detected in all species to date are the macula densa (MD) and associate d cortical thick ascending limb (cTALH) and medullary interstitial cells (M ICs). Physiological regulation of COX-2 in these cellular compartments sugg ests functional roles for eicosanoid products of the enzyme. COX-2 expressi on increases in high-renin states (salt restriction, angiotensin-converting enzyme inhibition, renovascular hypertension), and selective COX-2 inhibit ors significantly decrease plasma renin levels, renal renin activity, and m RNA expression. There is evidence for negative regulation of MD/cTALH COX-2 by angiotensin If and by glucocorticoids and mineralocorticoids. Conversel y, nitric oxide generated by neuronal nitric oxide synthase is a positive m odulator of COX-2 expression. Decreased extracellular chloride increases CO X-2 expression in cultured cTALH, an effect mediated by increased p38 mitog en-activated protein kinase activity, and, in vivo, a sodium-deficient diet increases expression of activated p38 in MD/cTALH. In contrast to COX-2 in MD/cTALH, COX-2 expression increases in MICs in response to a high-salt di et as well as water deprivation. Studies in cultured MICs have confirmed th at expression is increased in response to hypertonicity and is mediated, at least in part, by nuclear factor-kappaB activation. COX-2 inhibition leads to apoptosis of MICs in response to hypertonicity in vitro and after water deprivation in vivo. In addition, COX-2 metabolites appear to be important mediators of medullary blood flow and renal salt handling. Therefore, ther e is increasing evidence that COX-2 is an important physiological mediator of kidney function.