Hypertonic induction of COX2 expression requires TonEBP/NFAT5 in renal epithelial cells.
TonEBP/NFAT5 transcription factor is a master regulator of genes involved in osmoprotection. Cyclooxygenase 2 (COX2) has been reported to be a cytoprotective molecule in the inner renal medulla, where cells are physiologically exposed to the highest osmolality of the body. Our aim was to study whether COX2 expression requires TonEBP/NFAT5. Incubation of MDCK cells in hypertonic NaCl medium (500 mOsm/kg H2O) caused fully translocation of TonEBP/NFAT5 from cytoplasm to nucleoplasm and significantly increased COX2 mRNA, protein and activity levels. TonEBP/NFAT5-siRNA prevented hypertonic induction of COX2 mRNA and protein, leading to a depressed-prostaglandin synthesis and to a decreased cell survival. By using COX2-siRNA and COX2 specific inhibitor NS398, we found that cell survival does not depend on endogenous COX2-induced prostaglandin synthesis, but that cytoprotection strongly correlates with COX2 protein levels. These results demonstrate a new function for TonEBP/NFAT5, i.e., to mediate hypertonic-induced COX2 expression, and suggest that osmoprotection strongly depends on COX2 protein levels.
Favale
N O
NO
Department of Biological Sciences, School of Pharmacy and Biochemistry, University of Buenos Aires, IQUIFIB-CONICET, Ciudad Autónoma de Buenos Aires, Junín 956, 1er piso, (C1113AAD), Argentina.
Casali
C I
CI
Lepera
L G
LG
Pescio
L G
LG
Fernández-Tome
M C
MC
D000818:Animals; D002470:Cell Survival; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004285:Dogs; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009997:Osmotic Pressure; D012462:Saline Solution, Hypertonic / Q000494:pharmacology; D012965:Sodium Chloride / Q000494:pharmacology*
D050778:NFATC Transcription Factors; D012462:Saline Solution, Hypertonic; D012965:Sodium Chloride; D051546:Cyclooxygenase 2