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

V. K. Snowdon, A. Pellicoro, P. Ramachandran, W. Mungall, M. Jansen, R. Lennen, R. Aucott, T. Kendall, J. Hughes, J. P. Iredale, J. A. Fallowfield

Research output: Contribution to journalMeeting abstractpeer-review

Abstract

Introduction Hepatorenal syndrome (HRS) is a feared complication of cirrhosis with a high mortality rate and limited treatment options. The hallmark features of HRS are profound renal vasoconstriction, resulting in a functional renal failure but with 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 beneficially modulate RBF in cirrhosis and HRS.

Methods Cirrhosis, with reduced RBF, was induced in rats by 16 weeks of intraperitoneal (i.p.) carbon tetrachloride (CCl4) and decompensated biliary cirrhosis by 3 weeks bile duct ligation (BDL). We measured the effect of acute intravenous (i.v.) and extended (72 hr) subcutaneous (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 distri- bution of RLN receptor (RXFP1) was determined by qPCR and immunofluorescence. Expression of vasoconstrictor genes was quantified by qPCR array.

Results RXFP1 was detected on glomerular podocytes, renal peri- cytes, and endothelial cells of the renal, segmental and interlobar arteries of cirrhotic rats. In CCl4 cirrhosis, acute i.v. RLN (4❍g) induced a 50% increase in RBF after 60 minutes (p  0.01 vs. pla-cebo, 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 57%
in BDL (p  0.001 vs. placebo, n = 5) and increased GFR by 138% in CCl4 (p  0.01 vs. placebo, n = 8) and 103% in BDL (p  0.05 vs. pla- cebo, n = 5). Mean arterial pressure was unaffected by RLN. L-NAME (250mg/L) orally (p.o.) abrogated the effect of RLN on RBF and GFR. The relative expression of vasoconstrictor genes in the kidney was markedly reduced by RLN treatment.
Conclusion RLN increases RBF in experimental cirrhosis. Cru- cially, RLN also improves renal function and oxygenation but does not induce systemic hypotension even in decompensated disease. The effects of RLN are 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.
Original languageEnglish
Article numberPWE-146
Pages (from-to)A190-A191
Number of pages2
JournalGut
Volume62
DOIs
Publication statusPublished - Jun 2013
EventAnnual General Meeting of the British-Society-of-Gastroenterology - Glasgow, United Kingdom
Duration: 24 Jun 201327 Jun 2013

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