Liver proteomics for therapeutic drug discovery: inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure.
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.
Dear
James W
JW
Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Leelahavanichkul
Asada
A
Aponte
Angel
A
Hu
Xuzhen
X
Constant
Stephanie L
SL
Hewitt
Stephen M
SM
Yuen
Peter S T
PS
Star
Robert A
RA
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*
D051926:Basigin; D021983:Cyclophilins