Relaxin Family Peptide Receptor 1 Activation Stimulates Peroxisome Proliferator-Activated Receptor Gamma

Abstract

Relaxin (RLX) has antifibrotic effects in a number of tissues. Many of these effects are similar to those induced by the activators of peroxisome proliferator-activated receptor gamma (PPARgamma), raising the possibility that a mechanism for RLX's antifibrotic effects may involve activation of the PPARgamma pathway. This study investigated the effect of RLX on PPARs and their mechanism of upregulation. It shows that RLX stimulates ligand-independent PPAR activation in a dose-dependent manner. The combined effect of RLX and PPARgamma agonists was superadditive, suggesting that both agents might be used together for an increased antifibrotic effect. RLX caused increased expression of the PPARgamma target genes CD36 and LXRalpha. RLX's effect was mimicked by forskolin and partially blocked by pertussis toxin, suggesting that RLX works through a cAMP/protein kinase A pathway to activate PPARgamma. A better understanding of this pathway might help in the amelioration of fibrotic diseases.