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Am J Physiol Renal Physiol 281: F658-F664, 2001;
0363-6127/01 $5.00
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Vol. 281, Issue 4, F658-F664, October 2001

CaR-mediated COX-2 expression in primary cultured mTAL cells

Dairong Wang, Shao-Jian An, Wen-Hui Wang, John C. McGiff, and Nicholas R. Ferreri

Department of Pharmacology, New York Medical College, Valhalla, New York 10595

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 PGE2 synthesis were observed in a dose- and time-dependent manner after exposure of these cells to extracellular calcium (Ca<UP><SUB>o</SUB><SUP>2+</SUP></UP>). Moreover, transfection of mTAL cells with a CaR overexpression vector significantly enhanced COX-2 expression and PGE2 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 PGE2 synthesis. Furthermore, Ca<UP><SUB>o</SUB><SUP>2+</SUP></UP>- and PLA-mediated PGE2 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 PGE2 synthesis in the mTAL. Because Ca<UP><SUB>o</SUB><SUP>2+</SUP></UP> 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.

cyclooxygense-2; calcium-sensing receptor; medullary thick ascending limb


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