title: Liver proteomics for therapeutic drug discovery: inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure.
abstract: OBJECTIVE
  Sepsis-induced multi-organ failure continues to have a high mortality. The liver is an organ central to the disease pathogenesis. The objective of this study was to identify the liver proteins that change in abundance with sepsis and subsequently identify new drug targets.
  
  
  METHODS
  Proteomic discovery study and drug target validation. For the proteomics study, three biological replicate mice were used per group.
  
  
  METHODS
  Research institute laboratory.
  
  
  METHODS
  Three-month-old C57BL/6 mice.
  
  
  METHODS
  We used a mouse model of sepsis based on cecal ligation and puncture, but with fluid and antibiotic resuscitation. Liver proteins that changed in abundance were identified by difference in gel electrophoresis. We compared liver proteins from 6-hr post-cecal ligation and puncture to sham-operated mice ("early proteins") and 24-hr post-cecal ligation and puncture with 6-hr post-cecal ligation and puncture ("late proteins"). Proteins that changed in abundance were identified by tandem mass spectrometry. We then inhibited the receptor for one protein and determined the effect on sepsis-induced organ dysfunction.
  
  
  RESULTS
  The liver proteins that changed in abundance after sepsis had a range of functions such as acute phase response, coagulation, endoplasmic reticulum stress, oxidative stress, apoptosis, mitochondrial electron transfer proteins, and nitric oxide metabolism. We found that cyclophilin increased in abundance after cecal ligation and puncture. When the receptor for this protein, CD147, was inhibited, sepsis-induced renal dysfunction was reduced. There was also a significant reduction in serum cytokine production when CD147 was inhibited.
  
  
  CONCLUSIONS
  By applying proteomics to a clinically relevant mouse model of sepsis, we identified a number of novel proteins that changed in abundance. The inhibition of the receptor for one of these proteins, cyclophilin, attenuated sepsis-induced acute renal failure. The application of proteomics to sepsis research can facilitate the discovery of new therapeutic targets.
authors.affiliation: Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Dear
authors.forename: Asada
authors.initials: A
authors.lastname: Leelahavanichkul
authors.forename: Angel
authors.initials: A
authors.lastname: Aponte
authors.forename: Xuzhen
authors.initials: X
authors.lastname: Hu
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Constant
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.forename: Peter S T
authors.initials: PS
authors.lastname: Yuen
authors.forename: Robert A
authors.initials: RA
authors.lastname: Star
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology*; D000818:Animals; D051926:Basigin; D021983:Cyclophilins / Q000037:antagonists & inhibitors*; D008099:Liver; D051379:Mice; D008810:Mice, Inbred C57BL; D040901:Proteomics; D018805:Sepsis / Q000150:complications*
chemical_list: D051926:Basigin; D021983:Cyclophilins