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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
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-
B 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.
prostaglandin; macula densa; medullary interstitial cell; renin; hypertonicity
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