Endothelin is an important determinant of renal function in a rat model of acute liver and renal failure

Abstract

Background and aims: 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.

Evaluation of the therapeutic effect of <em>Nigella sativa</em> crude oil and its blend with omega-3 fatty acid-rich oils in a modified hepatorenal syndrome model in rats

“…ET-1 showed a significant elevation in the MHRS model in the present study, which supports the previous proposal of being a biomarker of HRS (Anand et al, 2002) due to the increased endothelin (A) of the renal cortex which is important in the pathogenesis of renal failure that occurs in patients with acute liver failure or HRS. Urinary NAG was significantly elevated in the MHRS model in the present study reflecting tubular dysfunction and kidney parenchymal damage as reported by Skálová (2005).…”

Protective effects of ellagic acid in d-galactosamine-induced kidney damage in rats

“…It has also been determined that a patient with a liver disease had a decline in renal blood flow that indicated renal vasoconstriction (Guarner et al 1987). Anand et al (2002) also showed that treatment of DGalN results in renal failure that manifests itself through the decrease in the renal blood flow, creatinine clearance, along with a rise in plasma endothelin-1 (ET-1) concentration, and also upregulation of ET-1 receptors in renal cortex. Catal and Bolkent (2008) reported that animals administered 500 mg/kg D-GalN had distinct degenerative changes, particularly in the proximal tubular cells and glomerulus when compared to the kidney tissues of control groups.…”

“…GalN-induced liver injury has also been linked to renal failure (Javle et al 1998). Anand et al (2002) showed that treatment of D-GalN results in renal failure manifested by the decrease in renal blood flow, creatinine clearance in renal cortex. It was also reported that a patient suffering from liver disease showed a decrease in the renal blood flow, indicating renal vasoconstriction (Guarner et al 1987).…”

Brassica nigraplays a remedy role in hepatic and renal damage

“…Classically, HRS is associated with the end-stage liver cirrhosis and it has been observed that renal failure occurs with this liver disease in about 50% of patients. Anand et al (2002) reported that d-GalN intoxication causes liver injury followed by renal impairment which is manifested by the decrease in renal blood flow and creatinine clearance. Renal dysfunction due to d-GalN administration was also manifested by the increase in serum urea and creatinine levels and kidney TBARS and MPO activity together with degenerative changes in kidney histology (Tunc et al, 2010).…”

“…Progressive impairment of liver cells due to oxidative stress would lead to life threatening complications if left untreated (Wolf, 1999). Anand et al (2002) reported d-galactosamine-induced acute liver failure results in renal damage and is mediated by endothelin receptors. Recently, the term hepatorenal syndrome (HRS) has been introduced to define the development of renal failure related with hepatocellular dysfunction (Epstein, 1996).…”