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 localization detected in all species to date are the macula densa (MD) and associated cortical thick ascending limb (cTALH) and medullary interstitial cells (MICs). Physiological regulation of COX-2 in these cellular compartments suggests functional roles for eicosanoid products of the enzyme. COX-2 expression increases in high-renin states (salt restriction, angiotensin-converting enzyme inhibition, renovascular hypertension), and selective COX-2 inhibitors significantly decrease plasma renin levels, renal renin activity, and mRNA expression. There is evidence for negative regulation of MD/cTALH COX-2 by angiotensin II and by glucocorticoids and mineralocorticoids. Conversely, nitric oxide generated by neuronal nitric oxide synthase is a positive modulator of COX-2 expression. Decreased extracellular chloride increases COX-2 expression in cultured cTALH, an effect mediated by increased p38 mitogen-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 diet as well as water deprivation. Studies in cultured MICs have confirmed that 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, there is increasing evidence that COX-2 is an important physiological mediator of kidney function.
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George M. O'Brien Kidney and Urologic Diseases Center and Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, and Veterans Affairs Medical Center, Nashville, Tennessee 37232, USA. Ray.Harris@mcmail.vanderbilt.edu
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D000818:Animals; D051546:Cyclooxygenase 2; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology / Q000502:physiology*; D007672:Kidney Cortex / Q000201:enzymology; D007679:Kidney Medulla / Q000201:enzymology; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases