title: Role of protein C in renal dysfunction after polymicrobial sepsis.
abstract: Protein C (PC) plays an important role in vascular function, and acquired deficiency during sepsis is associated with increased mortality in both animal models and in clinical studies. This study explored the consequences of PC suppression on the kidney in a cecal ligation and puncture model of polymicrobial sepsis. This study shows that a rapid drop in PC after sepsis is strongly associated with an increase in blood urea nitrogen, renal pathology, and expression of known markers of renal injury, including neutrophil gelatinase-associated lipocalin, CXCL1, and CXCL2. The endothelial PC receptor, which is required for the anti-inflammatory and antiapoptotic activity of activated PC (APC), was significantly increased after cecal ligation and puncture as well as in the microvasculature of human kidneys after injury. Treatment of septic animals with APC reduced blood urea nitrogen, renal pathology, and chemokine expression and dramatically reduced the induction of inducible nitric oxide synthase and caspase-3 activation in the kidney. The data demonstrate a clear link between acquired PC deficiency and renal dysfunction in sepsis and suggest a compensatory upregulation of the signaling receptor. Moreover, these data suggest that APC treatment may be effective in reducing inflammatory and apoptotic insult during sepsis-induced acute renal failure.
authors.affiliation: Biotechnology Discovery Research, Eli-Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, DC# 0434, Lilly & Company, Indianapolis, Indiana 462225, USA.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Gupta
authors.forename: David T
authors.initials: DT
authors.lastname: Berg
authors.forename: Bruce
authors.initials: B
authors.lastname: Gerlitz
authors.forename: Ganesh R
authors.initials: GR
authors.lastname: Sharma
authors.forename: Samreen
authors.initials: S
authors.lastname: Syed
authors.forename: Mark A
authors.initials: MA
authors.lastname: Richardson
authors.forename: George
authors.initials: G
authors.lastname: Sandusky
authors.forename: Josef G
authors.initials: JG
authors.lastname: Heuer
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Galbreath
authors.forename: Brian W
authors.initials: BW
authors.lastname: Grinnell
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology*; D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002432:Cecum / Q000601:surgery; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000378:metabolism; D004195:Disease Models, Animal; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D000071068:Lipocalin-2; D054834:Lipocalins; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011486:Protein C / Q000378:metabolism*; D020151:Protein C Deficiency / Q000150:complications; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; C513296:Cxcl2 protein, rat; C097278:Lcn2 protein, rat; D000071068:Lipocalin-2; D054834:Lipocalins; D011486:Protein C; D011518:Proto-Oncogene Proteins; D019001:Nitric Oxide Synthase; D053148:Caspase 3