The role of relaxin in the regulation of human liver and kidney fibrosis

Liver fibrosis has a range of aetiologies and is a global cause of mortality. A<br/>critical effect of liver fibrosis which also increases mortality is portal<br/>hypertension. The hepatic stellate cell is accepted as a major progenitor of liver<br/>myofibroblasts, which have been shown to be a major source of collagen and<br/>extracellular matrix proteins that disrupt liver architecture and function. Relaxin<br/>is a hormone involved in remodelling of extracellular matrix in the uterus and<br/>cervix and is known to increase renal blood flow in pregnancy. It has been<br/>implicated in the regulation of fibrosis in animal models and to modify the cell<br/>biology of hepatic stellate cells in vitro. I have demonstrated the profile of<br/>expression of relaxin receptors in primary human stellate cells (HSC), showing<br/>them to express RXFP-1, 3 and 4. Using a cAMP assay I confirm these receptors<br/>to be functional, with RXFP-1 positively and RXFP-3 and 4 negatively coupling<br/>to cAMP. The expression of RXFP-1 is coupled with the level of activation,<br/>demonstrating a possible role for H2-relaxin in the regulation of HSC. I have<br/>established a dynamic regulation of fibrotic mediators and HSC activation<br/>markers, including a reduction in ?-SMA, TIMP-1 and TGF-? with increases in<br/>MMP-1 and MMP-2, consistent with H2-relaxin having potentially therapeutic<br/>antifibrotic effects by increasing the fibrolytic phenotype. In addition through<br/>the use of gel contraction assays I demonstrate that H2-relaxin reduces serum or<br/>endothelin-1 induced HSC contraction. Through the use of siRNA I have<br/>confirmed that H2-relaxin mediates its regulation of fibrotic mediators and HSC<br/>activation markers as well as the inhibition of gel contraction through the relaxin<br/>receptor RXFP-1. I have evidence to suggest that the inhibition of contraction<br/>may in part be via nitric oxide release in HSC. In conclusion I propose that<br/>RXFP-1 is a potential therapeutic target in end stage human liver disease,<br/>targeting fibrosis and portal blood hypertension via both resolution of the<br/>phenotypic collagen deposition and vascular constriction associated with the<br/>human hepatic stellate cell.

Name dc:type.qualificationname

Ph.D.

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of Southampton

Year dc:date.issued

2009

Author dc:creator

• Hayden, Annette Louise

Advisors dc:contributor.advisor

• Collins, J.E.
• Princivalle, M.
• Iredale, J.P.