The selective cyclooxygenase-2 inhibitor celecoxib modulates the formation of vasoconstrictor eicosanoids and activates PPARγ. Influence of albumin

Background/Aims 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 α-smooth muscle actin (α-SMA) expression were determined. The effects of celecoxib on PPARγ were assessed in RMC co-transfected with PPARγ 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-PGF2α. Celecoxib, in addition to reducing PGE2, significantly decreased 8-epi-PGF2α 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 PPARγ agonist whereas albumin inhibited PPARγ as well as 15d-PGJ2-induced PPARγ activation. Finally, celecoxib and albumin potentiated the inhibitory effect of 15d-PGJ2 on α-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.