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Celecoxib Induces Heme‐Oxygenase Expression in Glomerular Mesangial Cells
Author(s) -
HOU CHUNCHENG,
HUNG SULI,
KAO SHUHUEI,
CHEN TSO HSIAO,
LEE HORNGMO
Publication year - 2005
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1338.026
Subject(s) - heme oxygenase , protein kinase b , celecoxib , chemistry , protein kinase a , kinase , mapk/erk pathway , mesangial cell , wortmannin , pharmacology , heme , phosphorylation , biochemistry , biology , enzyme , in vitro
A bstract : Nonsteroidal anti‐inflammatory drugs (NSAIDs) are frequently used as analgesics. They inhibit cyclooxygenases (COX), preventing the formation of prostaglandins, including prostacyclin and thromboxane. A serious side effect of COX‐1 and COX‐2 inhibitors is renal damage. To investigate the molecular basis of the renal injury, we evaluated the expression of the stress marker, heme oxygenase‐1 (HO‐1), in celecoxib‐stimulated mesangial cells. We report here that a COX‐2 selective NSAID, celecoxib, induced a concentration‐ and time‐dependent increase of HO‐1 expression in glomerular mesangial cells. Celecoxib‐induced HO‐1 protein expression was inhibited by actinomycin D and cycloheximide, suggesting that de novo transcription and translation are required in this process. N ‐acetylcysteine, a free radical scavenger, strongly decreased HO‐1 expression, suggesting the involvement of reactive oxygen species (ROS). Celecoxib‐induced HO‐1 expression was attenuated by pretreatment of the cells with SP 600125 (a specific JNK inhibitor), but not SB 203580 (a specific p38 MAPK inhibitor), or PD 98059 (a specific MEK inhibitor). Consistently, celecoxib activated c‐Jun N‐terminal kinase (JNK) as demonstrated by kinase assays and by increasing phosphorylation of this kinase. N ‐acetylcysteine reduced the stimulatory effect of celecoxib on stress kinase activities, suggesting an involvement of JNK in HO‐1 expression. On the other hand, LY 294002, a phosphatidylinositol 3‐kinase (PI‐3K)‐specific inhibitor, prevented the enhancement of HO‐1 expression. This effect was correlated with inhibition of the phosphorylation of the PDK‐1 downstream substrate Akt/protein kinase B (PKB). In conclusion, our data suggest that celecoxib‐induced HO‐1 expression in glomerular mesangial cells may be mediated by ROS via the JNK‐PI‐3K cascade.