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

Jing Bo Wang, Dong Lei Wang, Hai Tao Wang, Zhao Han Wang, Ying Wen, Cui Ming Sun, Yi Tong Zhao, Jian Wu, Pei Liu

Research output: Contribution to journalArticle

5 Scopus citations

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-α and ET-1 levels as well as significantly upregulated renal type 1 inositol 1,4,5-trisphosphate receptor (IP 3R1) expression. The upregulated IP3R1 expression was abrogated by the treatment of anti-TNF-α antibodies, but not by 2-aminoethoxydiphenylborate (2-APB), which blocks the inositol 1,4,5-trisphosphate signaling pathway. Treatments with either TNF-α 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-α antibodies than by 2-APB. Liver histology further confirmed that anti-TNF-α antibodies conferred better protection than 2-APB in GalN/LPS-exposed rats. LPS-elicited TNF-α over-production is responsible for decreased GFR through IP 3R1 overexpression, and the compromised GFR resulted in the development of acute renal failure in rats with FHF.

Original languageEnglish (US)
Pages (from-to)740-751
Number of pages12
JournalLaboratory Investigation
Volume94
Issue number7
DOIs
StatePublished - 2014

Keywords

  • acute renal failure
  • fulminant hepatic failure
  • glomerular calcium content
  • glomerular filtration rate
  • tumor necrosis factor-alpha
  • type 1 inositol 1,4,5-trisphosphate receptor

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology

Fingerprint Dive into the research topics of 'Tumor necrosis factor-alpha-induced reduction of glomerular filtration rate in rats with fulminant hepatic failure'. Together they form a unique fingerprint.

  • Cite this

    Wang, J. B., Wang, D. L., Wang, H. T., Wang, Z. H., Wen, Y., Sun, C. M., Zhao, Y. T., Wu, J., & Liu, P. (2014). Tumor necrosis factor-alpha-induced reduction of glomerular filtration rate in rats with fulminant hepatic failure. Laboratory Investigation, 94(7), 740-751. https://doi.org/10.1038/labinvest.2014.71