RELAXIN IS A RENAL VASODILATOR IN EXPERIMENTAL MODELS OF CIRRHOSIS AND A POTENTIAL NOVEL THERAPY FOR HEPATORENAL SYNDROME (HRS) IN HUMANS

Background: HRS is a feared complication of cirrhosis with a high
mortality rate and limited treatment options. The hallmark of HRS
is profound renal vasoconstriction, resulting in functional renal
failure but normal kidney histology. The peptide hormone relaxin
(RLN) mediates maternal haemodynamic adaptations to pregnancy,
including increased renal blood flow (RBF) and glomerular filtration
rate (GFR). We hypothesised that RLN could modulate RBF in
cirrhosis.
Methods: Cirrhosis was induced in rats by 16 weeks i.p. carbon
tetrachloride (CCl4) and decompensated biliary cirrhosis by 3 weeks
bile duct ligation (BDL). We measured the effect of acute i.v.
and extended (72 hr) s.c. RLN on systemic haemodynamics, RBF,
GFR and organ histology. Subgroups of rats were co-treated with
the nitric oxide (NO) synthase inhibitor L-NAME. Blood oxygen
dependent-magnetic resonance imaging (BOLD-MRI) was used to
quantify changes in renal oxygenation. Tissue expression and
distribution of RLN receptor (RXFP1) was determined by qPCR and
immunohistochemistry. Expression of vasoconstrictor genes was
quantified by qPCR array.
Results: RXFP1 was detected in glomerular podocytes, renal
pericytes, renal, segmental and interlobar arteries of cirrhotic rats.
In CCl4 cirrhosis, acute i.v. RLN (4 mg) induced a 50% increase in RBF
after 60 minutes (p < 0.01 vs. placebo, n = 6). BOLD-MRI showed
increased tissue oxygenation at the same timepoint in renal cortex
and medulla. Extended s.c. RLN increased RBF by 54% in CCl4
(p < 0.01 vs. placebo, n = 8) and 87% in BDL (p < 0.05 vs. placebo,
n = 3) and increased GFR by 138% in CCl4 (p < 0.01 vs. placebo, n = 8)
and 70% in BDL (p < 0.05 vs. placebo, n = 3). Mean arterial pressure
was unaffected by RLN. L-NAME (250 mg/L) p.o. abrogated the effect
of RLN on RBF and GFR. Relative expression of vasoconstrictor genes
in kidney was markedly reduced by RLN treatment.
Conclusion: RLN increased RBF in experimental cirrhosis. Critically,
RLN also improved renal function and oxygenation but did not
induce systemic hypotension even in decompensated disease.
The effects of RLN were mediated via augmentation of NO and
downregulation of vasoconstrictor genes known to be important in
the pathogenesis of HRS. RLN has potential as a treatment for HRS
and further translational studies are warranted.