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. Increa ses in cyclooxygenase-2 (COX-2) mRNA accumulation, protein expression, and PGE(2) synthesis were observed in a dose- and time-dependent manner after e xposure of these cells to extracellular calcium (Ca-o(2+)). Moreover, trans fection of mTAL cells with a CaR overexpression vector significantly enhanc ed COX-2 expression and PGE(2) production in response to calcium compared w ith cells transfected with an empty vector. Challenge with the Call-selecti ve agonist poly-L-arginine (PIA) also increased COX-2 mRNA accumulation, pr otein expression, and PGE(2) synthesis. Furthermore, Ca-o(2+) and PLA-media ted PGE(2) production was abolished in the presence of NS-398 or nimesulide , two different COX-2-selective inhibitors. These data suggest that intrace llular signaling mechanisms initiated via activation of Call contribute to COX-2-dependent PGE(2) synthesis in the mTAL. Because Ca-o(2+) concentratio n varies along Henle's loop, calcium may contribute to salt and water balan ce via a COX-2- and Call-dependent mechanism. Thus novel calcimimetics migh t be useful in conditions such as hypertension in which manipulation of ext racellular fluid volume provides beneficial effects.