| Relaxin is a polypeptide hormone of the insulin superfamily involved in extracellular matrix remodeling. Relaxin signals through the Relaxin Family Peptide 1 (RXFP1) receptor, a G protein-coupled receptor that triggers multiple signaling pathways, including the cAMP/protein kinase A pathway (PKA). Relaxin plays a role in the prevention and treatment of fibrosis in a number of tissues. Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that regulate gene expression through binding to PPAR response elements (PPRE). Three types of PPARs (PPARalpha, /delta and gamma) have been identified. Recent studies have implicated PPARs in the control of fibrosis. In particular, agonists of PPARgamma reduce many of the same fibrotic markers as relaxin. Due to these common properties, we hypothesized that one mechanism for relaxin effects may be activation of the PPARgamma pathway.;We found that in cells overexpressing RXFP1 (HEK-RXFP1), relaxin increased transcriptional activity through a PPAR response element (PPRE) that was reduced by PPARgamma knockdown and its dominant-negative PPARgamma. Results using GW9662, an inhibitor of PPARgamma ligand binding, suggested that relaxin activates PPARgamma via a ligand-independent mechanism. These studies represent the first report that relaxin can activate the transcriptional activity of PPARgamma.;Our results suggest that relaxin-induced PPARgamma activity is mediated through accumulation of cAMP followed by PKA activation. In HEK-RXFP1 and LX2 cells, PKA activated CREB directly as well as partially indirectly through p38 MAPK. Relaxin increased the expression of PGC1alpha, and the effects of relaxin on PGC1alphaa expression and PPARgamma activity were completely abrogated in HEK-RXFP1 cells transfected with a dominant-negative form of CREB. Collectively, these findings suggest that relaxin, through cAMP, induces CREB activation to increase PGC1 expression that subsequently regulates PPARgamma activity.;In summary, this is the first report of relaxin activation of the PPARgamma pathway. The finding that the combined effect of relaxin and PPARgamma agonists was superadditive suggests the possibility that both agents might be used together for an increased antifibrotic effect. Furthermore, relaxin activation of PGC1alpha is a novel finding. These findings could have implications in metabolic diseases. |
