U.S. Department of Veterans Affairs

 

Date of this Version

2010

Document Type

Article

Citation

Molecular and Cellular Endocrinology 315 (2010) 239–245; doi:10.1016/j.mce.2009.08.014

Abstract

Relaxin is a polypeptide hormone that triggers multiple signaling pathways through its receptor RXFP1 (relaxin family peptide receptor 1). Many of relaxin’s functions, including vascular and antifibrotic effects, are similar to those induced by activation of PPARγ. In this study, we tested the hypothesis that relaxin signaling through RXFP1 would activate PPARγ activity. In cells overexpressing RXFP1 (HEK-RXFP1), relaxin increased transcriptional activity through a PPAR response element (PPRE) in a concentrationdependent manner. In cells lacking RXFP1, relaxin had no effect. Relaxin increased both the baseline activity and the response to thePPARγ agonists rosiglitazone and 15d-PGJ2, but not to agonists of PPARα or PPARγ. In HEK-RXFP1 cells infected with adenovirus expressing PPARγ, relaxin increased transcriptional activity through PPRE, and this effect was blocked with an adenovirus expressing a dominant-negative PPARγ. Knockdown of PPARγ using siRNA resulted in a decrease in the response to both relaxin and rosiglitazone. Both relaxin and rosiglitazone increased expression of the PPARγ target genes CD36 and LXRα in HEK-RXFP1 and in THP-1 cells naturally expressing RXFP1. Relaxin did not increase PPARγ mRNA or protein levels. Treatment of cells with GW9662, an inhibitor of PPARγ ligand binding, effectively blocked rosiglitazone-induced PPARγ activation, but had no effect on relaxin activation of PPARγ. These results suggest that relaxin activates PPARγ activity, and increases the overall response in the presence of PPARγ agonists. This activation is dependent on the presence of RXFP1. Furthermore, relaxin activates PPARγ via a ligand-independent mechanism. These studies represent the first report that relaxin can activate the transcriptional activity of PPARγ.

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