Acute renal failure has a high morbidity and mortality. We have finished developing a set of new model of sepsis-induced ARF that employ cecal ligation puncture in elderly mice treated with fluids and antibiotics. We get increases in creatinine and modest changes in renal histology - similar to human ARF - along with clear evidence of injury in other organs (lung, liver, muscle, etc). These models are very exciting because the mice are treated with fluids and antibiotics, as occurs to humans with sepsis. We are now studying the pathophysiology of injury, screening drugs, and studying their mechanisms of action. We have used the model to screen for drugs that inhibit renal and multiorgan damage. We have found three drugs (Ethyl pyurvate, Pirfenidone, RDT2, and RDT3) that inhibit renal injury, even when first started 8-12 hours after induction of sepsis. We found that blocking TNFa or TRL2 receptors has no effect on ARF. However, we can block renal injury, without altering sepsis using a knock-out system. We have also performed microarray experiments to search for new drug targets and biomarkers, and additional studies that investigate the mechanism of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Intramural Research (Z01)
Project #
1Z01DK043403-05
Application #
6983890
Study Section
(MDB)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2004
Total Cost
Indirect Cost
Name
U.S. National Inst Diabetes/Digst/Kidney
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Doi, Kent; Leelahavanichkul, Asada; Hu, Xuzhen et al. (2008) Pre-existing renal disease promotes sepsis-induced acute kidney injury and worsens outcome. Kidney Int 74:1017-25
Yasuda, Hideo; Leelahavanichkul, Asada; Tsunoda, Shinichiro et al. (2008) Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury. Am J Physiol Renal Physiol 294:F1050-8
Doi, K; Hu, X; Yuen, P S T et al. (2008) AP214, an analogue of alpha-melanocyte-stimulating hormone, ameliorates sepsis-induced acute kidney injury and mortality. Kidney Int 73:1266-74
Dear, James W; Leelahavanichkul, Asada; Aponte, Angel et al. (2007) Liver proteomics for therapeutic drug discovery: inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure. Crit Care Med 35:2319-28
Holly, M K; Dear, J W; Hu, X et al. (2006) Biomarker and drug-target discovery using proteomics in a new rat model of sepsis-induced acute renal failure. Kidney Int 70:496-506
Yasuda, H; Yuen, P S T; Hu, X et al. (2006) Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects. Kidney Int 69:1535-42
Dear, J W; Yasuda, H; Hu, X et al. (2006) Sepsis-induced organ failure is mediated by different pathways in the kidney and liver: acute renal failure is dependent on MyD88 but not renal cell apoptosis. Kidney Int 69:832-6
Jo, Sang-Kyung; Hu, Xuzhen; Yuen, Peter S T et al. (2004) Delayed DMSO administration protects the kidney from mercuric chloride-induced injury. J Am Soc Nephrol 15:2648-54
Deng, Jiangping; Hu, Xuzhen; Yuen, Peter S T et al. (2004) Alpha-melanocyte-stimulating hormone inhibits lung injury after renal ischemia/reperfusion. Am J Respir Crit Care Med 169:749-56
Morimoto, Motoko; Morimoto, Masahiro; Whitmire, Jeannette et al. (2004) Peripheral CD4 T cells rapidly accumulate at the host: parasite interface during an inflammatory Th2 memory response. J Immunol 172:2424-30

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