Relaxin-a pleiotropic hormone and its emerging role for experimental and clinical therapeutics.

The insulin-related peptide hormone relaxin (Rlx) is known as pregnancy hormone for decades. In the 1980s, researchers began to recognize the highly intriguing fact that Rlx plays a role in a multitude of physiological processes far beyond pregnancy and reproduction. So, Rlx's contribution to the regulation of vasotonus, plasma osmolality, angiogenesis, collagen turnover, and renal function has been established. In addition, the peptide has been demonstrated to represent a mediator of cardiovascular pathology. The ongoing efforts to identify Rlx receptors eventually precipitated the discovery of the G protein-coupled receptors (GPCR) LGR7 and LGR8 as membrane receptors for human Rlx-2 in 2002. This review will summarize the current state of insight into this rapidly evolving field, which has further been expanded by the discovery of GPCR135 and GPCR142 as receptors for Rlx-3. In addition, Rlx has also been shown to activate the human glucocorticoid receptor (GR). There is evidence from Rlx and Rlx receptor knockouts suggesting that LGR7 is the only relevant receptor for mouse Rlx-1 (corresponding to human Rlx-2) in vivo and that insulin-like peptide (INSL)-3 represents the physiological ligand for LGR8. Regarding Rlx signal transduction, the cyclic adenosine monophosphate (cAMP) and nitric oxide (NO) pathways will be characterized as major cascades. Investigation of downstream signaling remains an important field for future research. Finally, the current state of therapeutical strategies using Rlx in animal models as well as in humans is summarized.