Hormones – Cytokines – Signaling
Kidney International (2003) 64, 1620–1631; doi:10.1046/j.1523-1755.2003.00268.x
Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice
Takehiko Miyaji, Xuzhen Hu, Peter ST Yuen, Yasunari Muramatsu, Swarnalatha Iyer, Stephen M Hewitt and Robert A Star
Renal Diagnostics and Therapeutics Unit, NIDDK; Laboratory of Pathology, CCR, NCI, National Institutes of Health, Bethesda, Maryland
Correspondence: Robert A. Star, M.D., National Institutes of Health, Building 10, Room 3N108, 10 Center Drive MSC 1268, Bethesda, MD 20892-1268. E-mail: Robert_Star@nih.gov
Received 21 April 2003; Revised 5 June 2003; Accepted 23 June 2003.
Abstract
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-
(TNF-), and kidney mRNA for TNF, tissue factor, and plasminogen activator inhibitor-1 (PAI-1), and increased mRNA for urokinase-like plasminogen activator.
Conclusion
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.
Keywords:
acute renal failure, inflammation, TNF-, coagulation, lipopolysaccharide
