Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice.
BACKGROUND
Sepsis is a common cause of acute renal failure (ARF). The incidence of sepsis increases dramatically after 50 years of age; however, most ARF studies are performed in young mice.


METHODS
We performed two common sepsis models, lipopolysaccharide (LPS) administration and cecal ligation puncture (CLP) in aged mice. We developed a fully treated CLP model in aged mice by treating mice with fluid resuscitation and antibiotics.


RESULTS
LPS induced renal injury in aged but not young mice. However, volume resuscitation starting within 6 hours decreased renal injury. We then used this fluid resuscitation scheme, along with antibiotics, to develop a fully treated CLP model in aged mice. Mice subjected to CLP developed functional and histologic ARF and multiple organ damage. Treatment with ethyl pyruvate, even when started 12 hours after surgery, decreased serum creatinine, tubular damage, and multiple organ injury at 24 hours. Ethyl pyruvate decreased plasma tumor necrosis factor-alpha (TNF-alpha), and kidney mRNA for TNF alpha, tissue factor, and plasminogen activator inhibitor-1 (PAI-1), and increased mRNA for urokinase-like plasminogen activator.


CONCLUSIONS
CLP in aged mice causes functional and histologic changes consistent with human ARF. A single dose of ethyl pyruvate inhibits renal and multiple organ damage, and is still effective when given 12 hours after surgery.
Miyaji
Takehiko
T
Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
Hu
Xuzhen
X
Yuen
Peter S T
PS
Muramatsu
Yasunari
Y
Iyer
Swarnalatha
S
Hewitt
Stephen M
SM
Star
Robert A
RA
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D000375:Aging; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D002432:Cecum; D055515:Cysteine-Rich Protein 61; D004195:Disease Models, Animal; D005342:Fibrinolysis / Q000187:drug effects; D005440:Fluid Therapy; D015870:Gene Expression / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007684:Kidney Tubules / Q000473:pathology; D008026:Ligation; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D011773:Pyruvates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D018805:Sepsis / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014951:Wounds, Stab
D000900:Anti-Bacterial Agents; C501848:CCN1 protein, human; C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D011773:Pyruvates; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C046522:ethyl pyruvate