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PWE-146 Relaxin Is a Renal Vasodilator in Experimental Models of Cirrhosis and A Potential Novel Therapy for Hepatorenal Syndrome in Humans
  1. V K Snowdon1,
  2. A Pellicoro1,
  3. P Ramachandran1,
  4. W Mungall2,
  5. M Jansen3,
  6. R Lennen3,
  7. R Aucott1,
  8. T Kendall1,
  9. J Hughes1,
  10. J P Iredale1,
  11. J A Fallowfield1
  1. 1MRC/Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh
  2. 2Biomedical Research Resources, University of Edinburgh
  3. 3Edinburgh Preclinical Imaging, BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK

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 distribution 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 pericytes, and endothelial cells of the renal, segmental and interlobar arteries of cirrhotic rats. In CCl4 cirrhosis, acute i.v. RLN (4µg) 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 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. placebo, 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. Crucially, 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.

Disclosure of Interest None Declared.

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