Regulation of cyclooxygenase isoforms in the renal thick ascending limb: Effects of extracellular calcium

We previously showed that primary cultures of mTAL cells express cyclooxyge nase 2 (COX-2) when challenged with tumor necrosis factor alpha (TNF alpha) or phorbol myristate acetate (PMA). Moreover, expression of COX-2 was link ed to decreases in TNF alpha -mediated Rb-86 uptake, an in vitro correlate of natriuresis. mTAL cells in primary culture express calcium sensing recep tor (CaR), a G-protein coupled receptor that senses changes in extracellula r calcium concentration and ultimately increases intracellular calcium conc entration ([Ca2+](i)) and protein kinase C (PKC) activity. PGE, synthesis b y mTAL cells increases In a dose- and time-dependent manner after exposure of these cells to extracellular Ca2+ Similar effects were observed when cel ls were challenged with the CaR-selective agonist, poly-l-arginine. These d ata suggest that intracellular signaling mechanisms initiated via activatio n of CaR contribute to mTAL PGE, synthesis. As TNF production is calcium-se nsitive in some cells types, we postulate that these effects involve the re gulation of COX-2 expression via a TNF-dependent mechanism. The functional implications of these studies relate to a cytokine-mediated mechanism that contributes to salt and water balance, and suggests that small changes in C a-o(2+) may contribute to the regulation of these events. The possibility t hat the effects of Cao2+ involve activation of CaR suggests that novel calc imimetic molecules might be useful in conditions, such as hypertension or o ther conditions, in which manipulation of extracellular fluid volume provid es beneficial effects.