Regulation of cyclooxygenase isoforms in the renal thick ascending limb: effects of extracellular calcium.
We previously showed that primary cultures of mTAL cells express cyclooxygenase 2 (COX-2) when challenged with tumor necrosis factor alpha (TNFalpha) or phorbol myristate acetate (PMA). Moreover, expression of COX-2 was linked to decreases in TNFalpha-mediated 86Rb uptake, an in vitro correlate of natriuresis. mTAL cells in primary culture express calcium sensing receptor (CaR), a G-protein coupled receptor that senses changes in extracellular calcium concentration and ultimately increases intracellular calcium concentration ([Ca2+]i) and protein kinase C (PKC) activity. PGE2 synthesis by mTAL cells increases in a dose- and time-dependent manner after exposure of these cells to extracellular Ca2+. Similar effects were observed when cells were challenged with the CaR-selective agonist, poly-L-arginine. These data suggest that intracellular signaling mechanisms initiated via activation of CaR contribute to mTAL PGE2 synthesis. As TNF production is calcium-sensitive in some cells types, we postulate that these effects involve the regulation 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 Ca(2+)o may contribute to the regulation of these events. The possibility that the effects of Ca(2+)o involve activation of CaR suggests that novel calcimimetic molecules might be useful in conditions, such as hypertension or other conditions, in which manipulation of extracellular fluid volume provides beneficial effects.
Wang
D
D
Department of Pharmacology, New York Medical College, Valhalla 10595, USA.
McGiff
J C
JC
Ferreri
N R
NR
D000818:Animals; D001120:Arginine / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D006706:Homeostasis; D006801:Humans; D006934:Hypercalcemia / Q000378:metabolism; D008138:Loop of Henle / Q000201:enzymology / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism*; D020033:Protein Isoforms
D002135:Calcium-Binding Proteins; D011453:Prostaglandins; D020033:Protein Isoforms; D001120:Arginine; D011451:Prostaglandin-Endoperoxide Synthases; D002118:Calcium