OC-031 Relaxin Modulates Cirrhosis-induced Renal Vascular Endothelial Dysfunction

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Abstract

Introduction

Hepatorenal syndrome (HRS) is a feared complication of cirrhosis characterised by intense renal vasoconstriction. The pathophysiology remains unclear, pharmacotherapy is limited and mortality is high. We investigated vascular responsiveness and the pathogenesis of renal vasoconstriction in models of advanced rat cirrhosis. Additionally,we determined the mechanism of action of the vasoactive peptide relaxin (RLN), previously shown to increase renal blood flow (RBF) in experimental cirrhosis (Snowdon V et al ., BSG 2013).

Methods

We induced cirrhosis,reduced RBF and renal dysfunction in male SD rats by carbon tetrachloride (16 wk) or bile duct ligation (4 wk). Arteries from renal (renal, segmental, interlobar) and splanchnic circulation were isolated for functional assessment using wire myography. qPCR array for vasoactive signalling genes,western blot for eNOS signalling proteins and NOS activity assay were undertaken in cirrhotic and control kidneys. Markers of oxidative stress and inflammatory cytokines were measured in serum by ELISA. We studied the effects of s.c. infusion of recombinant human RLN(seralaxin;72 h, 4 µg/h) on these parameters. Doppler USS measured changes in cardiac output (CO) and renal arterial resistive index (RRI) in response to i.v. RLN (4 µg). Kidney endothelial morphology was assessed by electron microscopy, H+E and PAS stained kidney by light microscopy.

Results

In renal arteries from control and cirrhotic rats endothelial vasodilatation was eNOS-dependent. In cirrhotic rats endothelium-dependent relaxation (acetylcholine; 10–9–3 × 10–5 M) was dramatically reduced (p < 0.0001) in all renal arteries,with only a modest reduction seen in the mesenteric arteries. Endothelium-independent relaxation (sodium nitroprusside; 10–9–3 × 10–5 M) and vasoconstriction (phenylephrine; 10–9–3 × 10–5 M) were unaltered. In cirrhotic kidneys,total eNOS expression was up-regulated,as were arginase2 and caveolin1 (negative regulators of eNOS),and NOS activity was reduced (p < 0.05). Acute RLN had no effect on CO but decreased RRI (p < 0.05). Extended RLN restored endothelium-dependent relaxation, increased kidney NOS activity (p < 0.05), increased phosphorylated Akt and eNOS, and reduced serum TNFα levels.

Conclusion

Renal vascular endothelial dysfunction characterises experimental cirrhosis, through a reduction in renal eNOS activity. This impairment may contribute to the renal vasoconstriction seen in cirrhosis and is a promising target for therapeutic modulation. RLN treatment restored renal endothelial vasodilatation. The potential for recombinant forms of RLN as a haemodynamic modulator in human cirrhosis and HRS merits investigation in translational studies.

Disclosure of Interest

None Declared.

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