Tumor necrosis factor-alpha-induced reduction of glomerular filtration rate in rats with fulminant hepatic failure

Abstract

The mechanism of renal failure during fulminant hepatic failure (FHF) or end-stage of liver disease is not fully understood. The present study aims to delineate the mechanisms of decreased glomerular filtration rate (GFR) in acute hepatic failure. A rat model of renal insufficiency in severe liver injury was established by lipopolysaccharide (LPS) plus D-galactosamine (GalN) exposure. GFR was evaluated by continuous infusion of fluorescein isothiocyanate-inulin with implanted micro-osmotic pumps. GalN/LPS intoxication resulted in severe hepatocyte toxicity as evidenced by liver histology and biochemical tests, whereas renal morphology remained normal. GFR was reduced by 33% of the controls 12 h after GalN/LPS exposure, accompanied with a decreased serum sodium levels, a marked increase in serum TNF-a and ET-1 levels as well as significantly upregulated renal type 1 inositol 1,4,5-trisphosphate receptor (IP 3 R1) expression. The upregulated IP 3 R1 expression was abrogated by the treatment of anti-TNF-a antibodies, but not by 2-aminoethoxydiphenylborate (2-APB), which blocks the inositol 1,4,5-trisphosphate signaling pathway. Treatments with either TNF-a antibodies or 2-APB also significantly improved the compromised GFR, elevated serum urea nitrogen and creatinine levels, and reversed the decrease in glomerular inulin space and the increase in glomerular calcium content in GalN/LPS-exposed rats. The extent of acute liver injury as reflected by serum ALT levels was much more attenuated by anti-TNF-a antibodies than by 2-APB. Liver histology further confirmed that anti-TNF-a antibodies conferred better protection than 2-APB in GalN/LPS-exposed rats. LPS-elicited TNF-a over-production is responsible for decreased GFR through IP 3 R1 overexpression, and the compromised GFR resulted in the development of acute renal failure in rats with FHF.

High expression of type I inositol 1,4,5-trisphosphate receptor in the kidney of rats with hepatorenal syndrome

“…Semi-quantitative Western blot analysis demonstrated that IP 3 RI protein expression was low in normal kidney tissue. Following treatment with D-GalN plus LPS, IP 3 RI protein expression began to rise at 3 h and reached a peak at 12 h. Interestingly, liver and kidney dysfunction and hepatocyte necrosis were most severe and blood TNF-α and ET-1 levels were highest at 12 h, which were concomitant with the elevation of IP 3 RI protein expression in the kidney[ 42 , 43 ]. By treating the animals with D-GalN or LPS alone, we excluded the effect of these drugs on IP 3 RI protein expression.…”

Protective Effects of the Third Generation Vasodilatory Βeta - Blocker Nebivolol against D-Galactosamine - Induced Hepatorenal Syndrome in Rats

“…In the current study, there was a significant histopathological alteration in the Gal- treated rats. The livers extensively displayed diffuse coagulative necrosis [ 35 , 71 ]. In the same line, the kidneys revealed congestion in the blood vessels, glomeruli associated with perivascular oedema, inflammatory cells infiltration, degeneration in the lining epithelium of the tubules and focal haemorrhage in the corticomedullary portion due to the elevated level of ROS and the upshot of pro-inflammatory cytokines [ 42 ].…”

Interfering RNA against PKC-α inhibits TNF-α-induced IP3R1 expression and improves glomerular filtration rate in rats with fulminant hepatic failure

“…Induction of FHF and treatments in different groups. FHF was induced in rats using a combination of GalN (400 mg/kg) plus LPS (32 g/kg) in saline, administrated through tail vein at a volume of 2 ml/kg 2 wk after lentiviral injection and 7 days after intraperitoneal implantation of micro-osmotic pumps (29). Rats with the implantation of 2 micro-osmotic pumps were randomly divided into four groups 1) N.S.…”

“…At the same time, these rats exhibited a similar trend of increased plasma TNF-␣ and ET-1 levels. Pretreatment with anti-TNF-␣ antibody significantly improved renal function and GFR (29). TNF-␣ treatment led to an increase in IP 3 R1 expression; in turn, enhanced IP 3 R1 expression amplified the sensitivity of GMCs and VSMCs in response to a variety of vasoconstrictors, thus leading to contraction of these two cell types and resulting in reduced GFR.…”