The selective cyclooxygenase-2 inhibitor celecoxib modulates the formation of vasoconstrictor eicosanoids and activates PPARgamma. Influence of albumin.
OBJECTIVE
Selective cyclooxygenase (COX)-2 inhibitors do not adversely affect renal function in experimental cirrhosis. In the current study, we investigated the molecular mechanisms underlying the effects of the selective COX-2 inhibitor, celecoxib, and assessed the influence of albumin on its actions.


METHODS
Rat mesangial cells (RMC) were incubated with celecoxib in the absence or presence of albumin, and levels of selected vasoconstrictor eicosanoids, renin release and alpha-smooth muscle actin (alpha-SMA) expression were determined. The effects of celecoxib on PPARgamma were assessed in RMC co-transfected with PPARgamma and luciferase reporter constructs.


RESULTS
Under resting conditions, RMC expressed COX-1, COX-2 and 12/15-lipoxygenase and mainly generated prostaglandin (PG)E2, thromboxane (TX)B2, 12-hydroxyeicosatetraenoic acid (12-HETE) and 8-epi-PGF2alpha. Celecoxib, in addition to reducing PGE2, significantly decreased 8-epi-PGF2alpha formation. In the presence of albumin, celecoxib also reduced TXB2 and 12-HETE. Albumin per se inhibited PGE2 as well as renin release. In trans-activation assays, celecoxib acted as a PPARgamma agonist whereas albumin inhibited PPARgamma as well as 15d-PGJ2-induced PPARgamma activation. Finally, celecoxib and albumin potentiated the inhibitory effect of 15d-PGJ2 on alpha-SMA expression.


CONCLUSIONS
These data provide novel molecular mechanisms of celecoxib and their modulation by albumin, that may be relevant to prevent renal dysfunction in conditions of unbalanced effective blood volume.
López-Parra
Marta
M
DNA Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Villarroel 170, Barcelona 08036, Spain.
Clària
Joan
J
Titos
Esther
E
Planagumà
Anna
A
Párrizas
Marcelina
M
Masferrer
Jaime L
JL
Jiménez
Wladimiro
W
Arroyo
Vicente
V
Rivera
Francisca
F
Rodés
Joan
J
D000199:Actins / Q000032:analysis; D000418:Albumins / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015777:Eicosanoids / Q000096:biosynthesis*; D008297:Male; D047495:PPAR gamma / Q000187:drug effects*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
C477819:15-deoxyprostaglandin J2; D000199:Actins; D000418:Albumins; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D047495:PPAR gamma; D011720:Pyrazoles; D013449:Sulfonamides; D016718:Arachidonic Acid; D012083:Renin; D000068579:Celecoxib; D015230:Prostaglandin D2