Relaxin in hepatic fibrosis: What is known and where to head?

Abstract

Relaxin (RLX) is a heterodimeric, polypeptide hormone that has natural anti-fibrotic activity in many organs. During the chronic liver injury, hepatic stellate cells (HSCs) are phenotypically transformed into myofibroblasts. This process is known as activation of HSCs. Activated HSCs play a central role in hepatic fibrosis. Quiescent HSCs were shown to express low levels of RLX receptors such as RXFP1 and RXFP2. Upon chronic liver injury, HSCs are activated and express high levels of the RLX receptors. ML290, an agonist of RXFP1 has been reported to have antifibrotic effect in vitro as well as in vivo. Serelaxin, a recombinant human RLX-2 treatment has reduced hepatic fibrosis and portal hypertension in experimental models due to its vasodilation properties by inducing intrahepatic nitric oxide level. Serelaxin has also produced a neutral effect when studied against human cirrhosis-related portal hypertension in clinical trials. RLX is a potent collagen synthesis inhibitor and it has extracellular matrix (ECM) remodeling properties by promoting matrix metalloproteinases and downregulating expression of metalloproteinases inhibitors. Available reports suggest that RLX could induce ECM remodeling and suppress the profibrogenic transforming growth factor-β signaling and thereby regress hepatic fibrosis. Though RLX has natural antifibrotic activity, its antifibrotic molecular mechanisms especially in hepatic fibrosis condition are not reported. This review exclusively focuses antifibrotic effect of RLX on hepatic fibrosis.