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


Hayden, Annette Louise (2009) The role of relaxin in the regulation of human liver and kidney fibrosis. University of Southampton, School of Medicine, Doctoral Thesis , 358pp.

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Description/Abstract

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

Item Type: Thesis (Doctoral)
Subjects: R Medicine > RB Pathology
Q Science > QP Physiology
Divisions: University Structure - Pre August 2011 > School of Medicine > Infection, Inflammation and Repair
ePrint ID: 67633
Date Deposited: 28 Aug 2009
Last Modified: 27 Mar 2014 18:48
URI: http://eprints.soton.ac.uk/id/eprint/67633

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