Relaxin is a selective renal vasodilator improving renal function in experimental models of cirrhosis and is a potential novel therapy for hepatorenal syndrome in man

VK Snowdon1, A Pellicoro1, W Mungall2, R Lennen3, A Thomson3, M Jansen3, P Ramachandran1, T Kendall1, J Hughes1, JP Iredale1, JA Fallowfield1. 1MRC/Centre for Inflammation Research,Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK, 2Biomedical Research Resources, University of Edinburgh, Edinburgh, UK, 3BHF/University Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK

Introduction: With advancing cirrhosis, there is progressive renal arterial vasoconstriction. The pathogenesis involves portal hypertension, systemic vasodilatation and endothelial dysfunction leading to activation of potent vasoconstrictors which act predominantly on the renal circulation. Hepatorenal syndrome (HRS), a frequent complication of cirrhosis with a dismal prognosis and very limited treatment options, occurs when the arterial vasoconstriction results in a critical reduction in renal blood flow (RBF), the development of functional renal failure (fall in glomerular filtration rate (GFR)), but with preservation of normal kidney histology.

The peptide hormone relaxin (RLN) mediates maternal haemodynamic adaptations to pregnancy, including renal vasodilatation, increasing RBF and GFR. We hypothesised that RLN could be used therapeutically to correct renal vasoconstriction in experimental cirrhosis.

Methods: Cirrhosis, with reduced RBF, was induced in male Sprague Dawley rats by 16 weeks of intraperitoneal (i.p). carbon tetrachloride (CCl4) at a dose of 0.1mg/100grams for two weeks and 0.05mg/100grams thereafter, and biliary cirrhosis by 3 weeks bile duct ligation (BDL). We measured the effect of acute i.v. (4 µg) and extended s.c. (72 hr 4µg/hour) RLN on systemic haemodynamics, RBF, GFR and organ histology. Subgroups of rats were co-treated with the nitric oxide (NO) synthase inhibitor L-NAME (250mg/L) in drinking water. Blood oxygen dependent-magnetic resonance imaging (BOLD-MRI) was used to quantify changes in renal oxygenation. Doppler USS was used to non-invasively monitor changes in the heart (cardiac output, ejection fraction and stroke volume) and kidney (renal resistive index and velocity time index) in response to acute bolus RLN or placebo. Tissue expression and distribution of RLN receptor (RXFP1) was determined by qPCR and immunofluorescence. Expression of vasoconstrictor genes was quantified by qPCR array in whole kidney.

Results: RXFP1 expression in the liver and kidney increases in cirrhosis. Kidney RXFP1 was detected on the glomerular podocytes, renal pericytes and endothelial cells of the renal vasculature. In CCl4 cirrhosis, acute i.v. RLN 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 the renal cortex and medulla (p<0.05, n=6). Doppler USS showed no significant change in cardiac output but a significantly reduced renal resistive index at 60 minutes (p<0.05, n=6). 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 abrogated the effect of RLN on RBF and GFR. In advanced cirrhosis there was upregulation of potent vasoconstrictor genes in the kidney, treatment with RLN resulted in a significant reduction in their relative expression.

Conclusion: RLN increases RBF in experimental cirrhosis. Crucially, RLN also improves renal function and oxygenation but does not induce systemic hypotension. 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.