Endothelin is an important determinant of renal function in a rat model of acute liver and renal failure.
OBJECTIVE
Renal failure occurs in approximately 55% of patients with acute liver failure. We have previously shown that plasma endothelin 1 concentrations are elevated in patients with acute liver failure and the hepatorenal syndrome. There are few reported satisfactory animal models of liver failure together with functional renal failure. In this study, a rat model of acute liver failure induced by galactosamine that also develops renal failure was first characterised. This model was used to investigate the hypothesis that endothelin 1 is an important mediator involved in the pathogenesis of renal impairment that occurs in acute liver failure.


METHODS
Acute liver failure was induced in male Sprague-Dawley rats by intraperitoneal injection of galactosamine together with treatment with the endothelin receptor antagonist Bosentan. Twenty four hour urine collections were made using a metabolic cage. Renal blood flow was measured in anaesthetised animals.


RESULTS
This model developed renal failure and liver failure in the absence of any significant renal pathology, and with an accompanying fall in renal blood flow. Plasma concentrations of endothelin 1 were increased twofold following the onset of liver and renal failure (p<0.05), and there was significant upregulation of the endothelin receptor A (ET(A)) in the renal cortex (p<0.05). Administration of Bosentan prevented the development of renal failure when given before or 24 hours after the onset of liver injury (p<0.05) but had no effect on liver injury itself, or on renal blood flow.


CONCLUSIONS
This study demonstrates that this animal model has many of the features needed to be regarded as a model of renal failure that occurs in acute liver failure. The observation that plasma levels of endothelin 1 and ET(A) receptors are increased and upregulated, and that renal failure is prevented by an endothelin antagonist supports the hypothesis originally put forward that ET(A) is important in the pathogenesis of renal failure that occurs in patients with acute liver failure.
Anand
R
R
Department of Medicine, Royal Free and University College Medical School, London, UK.
Harry
D
D
Holt
S
S
Milner
P
P
Dashwood
M
M
Goodier
D
D
Jarmulowicz
M
M
Moore
K
K
D000208:Acute Disease; D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D015415:Biomarkers; D000077300:Bosentan; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D005688:Galactosamine; D006530:Hepatorenal Syndrome / Q000209:etiology / Q000378:metabolism*; D008297:Male; D008854:Microscopy, Electron; D009994:Osmolar Concentration; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation
D000959:Antihypertensive Agents; D015415:Biomarkers; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D013449:Sulfonamides; D005688:Galactosamine; D000077300:Bosentan