Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression

N. Shah, D. Dhar, F. El Zahraa Mohammed, A. Habtesion, N.A. Davies, M. Jover-Cobos, J. Macnaughtan, V. Sharma, S. Olde Damink, R. P. Mookerjee, R.A. Jalan

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Abstract

BACKGROUND & AIMS: Superimposed infection and/or inflammation precipitate renal failure in cirrhosis. This study aimed at testing the hypothesis that increased gut bacterial translocation in cirrhosis primes the kidney to the effect of superimposed inflammation by upregulating expression of Toll-like receptor 4 (TLR4), NFkappaB, and cytokines. A well-characterized bile-duct ligated (BDL) model of cirrhosis, which develops renal failure following superimposed inflammatory insult with lipopolysaccharide (LPS), was used and selective gut decontamination was performed using norfloxacin. METHODS: Sprague-Dawley rats were studied: Sham, Sham+LPS; BDL, BDL+LPS; an additional BDL and BDL+LPS groups were selectively decontaminated with norfloxacin. Plasma biochemistry, plasma renin activity (PRA) and cytokines and, protein expression of TLR4, NFkappaB, and cytokines were measured in the kidney homogenate. The kidneys were stained for TLR4, TLR2, and caspase-3. Endotoxemia was measured using neutrophil burst and Limulus amoebocyte lysate (LAL) assays. RESULTS: The groups treated with norfloxacin showed significant attenuation of the increase in plasma creatinine, plasma and renal TNF-alpha and renal tubular injury on histology. The increased renal protein expression of TLR4, NFkappaB, and caspase-3 in the untreated animals was significantly attenuated in the norfloxacin treated animals. PRA was reduced in the treated animals and severity of endotoxemia was also reduced. CONCLUSIONS: The results show for the first time that kidneys in cirrhosis show an increased expression of TLR4, NFkappaB, and the pro-inflammatory cytokine TNF-alpha, which makes them susceptible to a further inflammatory insult. This increased susceptibility to LPS can be prevented with selective decontamination, providing novel insights into the pathophysiology of renal failure in cirrhosis.
Original languageEnglish
Pages (from-to)1047-1053
Number of pages7
JournalJournal of Hepatology
Volume56
Issue number5
DOIs
Publication statusPublished - 1 Jan 2012

Keywords

  • Acute kidney injury
  • Hepatorenal syndrome
  • Toll-like receptor 4
  • Liver failure
  • TOLL-LIKE RECEPTOR-2
  • DUCT LIGATED RATS
  • NF-KAPPA-B
  • HEPATORENAL-SYNDROME
  • LIVER-DISEASE
  • ALCOHOLIC HEPATITIS
  • ESCHERICHIA-COLI
  • NEUTROPHIL DYSFUNCTION
  • FAILURE
  • LIPOPOLYSACCHARIDE

Cite this

Shah, N., Dhar, D., El Zahraa Mohammed, F., Habtesion, A., Davies, N. A., Jover-Cobos, M., Macnaughtan, J., Sharma, V., Olde Damink, S., Mookerjee, R. P., & Jalan, R. A. (2012). Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression. Journal of Hepatology, 56(5), 1047-1053. https://doi.org/10.1016/j.jhep.2011.11.024