Inhibition of markers of hepatic stellate cell activation by the hormone relaxin.
Hepatic fibrosis results from excess extracellular matrix produced primarily by hepatic stellate cells (HSC). In response to injury, HSC differentiate to a myofibroblastic phenotype expressing smooth muscle actin and fibrillar collagens. Relaxin is a polypeptide hormone shown to have antifibrotic effects in fibrosis models. In this study, activated HSC from rat liver were treated with relaxin to determine if relaxin can reverse markers of HSC activation. Relaxin treatment resulted in a decrease in the expression of smooth muscle actin, but had no effect on cell proliferation rate. The levels of total collagen and type I collagen were reduced, while the synthesis of new collagen was inhibited. Furthermore, relaxin caused an increase in the expression and secretion of rodent interstitial collagenase (MMP-13), but there was no effect on the gelatinases MMP-2 or MMP-9. Relaxin also increased secretion of TIMP-1 and TIMP-2. The effective concentration of relaxin to induce these effects was consistent with action through the relaxin receptor. In conclusion, relaxin reversed markers of the activated phenotype of HSC including the production of fibrillar collagen. At the same time, the activity of a fibrillar collagenase was increased. These data suggest that relaxin not only inhibits HSC properties that contribute to the progression of hepatic fibrosis, but also promotes the clearance of fibrillar collagen. Therefore, relaxin may be a useful approach in the treatment of hepatic fibrosis.
Bennett
Robert G
RG
Department of Medical Research, Veterans Affairs Medical Center, 4101 Woolworth Ave., Omaha, NE 68105, USA. rgbennet@unmc.edu
Kharbanda
Kusum K
KK
Tuma
Dean J
DJ
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012065:Relaxin / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*
D015415:Biomarkers; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D012065:Relaxin; D003094:Collagen; D017364:Collagenases