title: Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression.
abstract: OBJECTIVE
  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), NFκB, 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, NFκB, 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-α and renal tubular injury on histology. The increased renal protein expression of TLR4, NFκB, 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, NFκB, and the pro-inflammatory cytokine TNF-α, 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.
authors.affiliation: UCL Institute of Hepatology, Upper Third Floor, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Naina
authors.initials: N
authors.lastname: Shah
authors.affiliation: UCL Institute of Hepatology, Upper Third Floor, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Dipok
authors.initials: D
authors.lastname: Dhar
authors.affiliation: UCL Institute of Hepatology, Upper Third Floor, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK; Pathology Department, Minia University, Egypt.
authors.forename: Fatma
authors.initials: F
authors.lastname: El Zahraa Mohammed
authors.affiliation: UCL Institute of Hepatology, Upper Third Floor, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Abeba
authors.initials: A
authors.lastname: Habtesion
authors.affiliation: UCL Institute of Hepatology, Upper Third Floor, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Davies
authors.affiliation: UCL Institute of Hepatology, Upper Third Floor, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Jover-Cobos
authors.affiliation: UCL Institute of Hepatology, Upper Third Floor, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Macnaughtan
authors.affiliation: UCL Institute of Hepatology, Upper Third Floor, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Vikram
authors.initials: V
authors.lastname: Sharma
authors.affiliation: UCL Institute of Hepatology, Upper Third Floor, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK; Department of Surgery, Maastricht University Medical Centre, and Nutrition and Toxicology Research Institute (NUTRIM), Maastricht University, Maastricht, The Netherlands.
authors.forename: Steven W M
authors.initials: SWM
authors.lastname: Olde Damink
authors.affiliation: UCL Institute of Hepatology, Upper Third Floor, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Rajeshwar P
authors.initials: RP
authors.lastname: Mookerjee
authors.affiliation: UCL Institute of Hepatology, Upper Third Floor, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK. Electronic address: r.jalan@ucl.ac.uk.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Jalan
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000382:microbiology*; D007668:Kidney / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D008103:Liver Cirrhosis / Q000150:complications* / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009643:Norfloxacin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D012083:Renin; D009643:Norfloxacin