CaR-mediated COX-2 expression in primary cultured mTAL cells.
Primary cultures of medullary thick ascending limb (mTAL) cells retain the capacity to express calcium-sensing receptor (CaR) mRNA and protein. Increases in cyclooxygenase-2 (COX-2) mRNA accumulation, protein expression, and PGE(2) synthesis were observed in a dose- and time-dependent manner after exposure of these cells to extracellular calcium (Ca(o)(2+)). Moreover, transfection of mTAL cells with a CaR overexpression vector significantly enhanced COX-2 expression and PGE(2) production in response to calcium compared with cells transfected with an empty vector. Challenge with the CaR-selective agonist poly-L-arginine (PLA) also increased COX-2 mRNA accumulation, protein expression, and PGE(2) synthesis. Furthermore, Ca(o)(2+)- and PLA-mediated PGE(2) production was abolished in the presence of NS-398 or nimesulide, two different COX-2-selective inhibitors. These data suggest that intracellular signaling mechanisms initiated via activation of CaR contribute to COX-2-dependent PGE(2) synthesis in the mTAL. Because Ca(o)(2+) concentration varies along Henle's loop, calcium may contribute to salt and water balance via a COX-2- and CaR-dependent mechanism. Thus novel calcimimetics might be useful in conditions such as hypertension in which manipulation of extracellular fluid volume provides beneficial effects.
Wang
D
D
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
An
S J
SJ
Wang
W H
WH
McGiff
J C
JC
Ferreri
N R
NR
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D008138:Loop of Henle / Q000166:cytology / Q000201:enzymology*; D008297:Male; D009578:Nitrobenzenes / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D009578:Nitrobenzenes; D010455:Peptides; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D013449:Sulfonamides; C473605:extracellular calcium cation-sensing receptor, rat; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C015462:polyarginine; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D002118:Calcium; C012655:nimesulide