15- Deoxy-Δ12,14-prostaglandin J2 upregulates COX-2 expression and PGE2 in mouse mesangial cells through a mechanism independent of PPARγ.

15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an endogenous cyclooxygenase-derived lipid mediator and natural ligand of peroxisome proliferator-activated receptor gamma (PPARγ), plays important roles in inflammatory regulation and renal pathophysiology. However, the effect of 15d-PGJ2 on cyclooxygenase-2 (COX-2) expression in mesangial cells and the involvement of PPARγ in this process remain unclear. In this study, we investigated the regulation of COX-2 expression and prostaglandin E2 (PGE2) production by 15d-PGJ2 in primary cultured mouse mesangial cells and determined the role of PPARγ using pharmacological and genetic approaches. Treatment with 15d-PGJ2 significantly increased COX-2 mRNA and protein expression, accompanied by a marked elevation of PGE2 production. Pharmacological inhibition of PPARγ using the selective antagonist GW9662 did not affect 15d-PGJ2-induced COX-2 expression or PGE2 production. Similarly, overexpression of dominant-negative PPARγ, siRNA-mediated knockdown, and Cre-mediated genetic deletion of PPARγ failed to attenuate the induction of COX-2 by 15d-PGJ2. Functional reporter assays confirmed effective modulation of PPARγ transcriptional activity under these conditions, indicating that the lack of effect was not due to insufficient inhibition. These findings demonstrate that 15d-PGJ2 induces COX-2 expression and enhances PGE2 production in mouse mesangial cells via a mechanism independent of PPARγ. This PPARγ-independent action suggests alternative signaling pathways through which endogenous lipid mediators regulate inflammatory responses in the kidney. Our results provide new insight into the complex role of prostaglandin metabolites in renal inflammatory signaling and highlight the importance of receptor-independent actions of electrophilic lipid mediators.