Acute kidney injury (also known as acute renal failure) has a high morbidity and mortality. After developing a novel model of sepsis-induced AKI that employs cecal ligation puncture in elderly mice treated with fluids and antibiotics, we are using the model to study the pathophysiology of injury, to screen drugs, and to study their mechanisms of action. ? ? 1) We have found that renal injury from sepsis can be dramatically reduced in MyD88-deficient mice, suggesting a significant role for innate immunity. Further, a lack of MyD88 inhibited sepsis-induced apoptosis in the spleen, but not the kidney, opening the possibility of communication and/or disease progression from one organ to another.? ? 2) As a result of our proteomic screens of kidney-derived urine proteins during sepsis-induced AKI, we identified a potential drug target, meprin-alpha. When we used actinonin, an inhibitor of meprin-alpha, we found significant protection from AKI.? ? 3) Statin drugs are commonly used for cholesterol management, but they also have antiinflammatory effects. We tested simvastatin in our mouse sepsis model, and found substantial protection from AKI and mortality. Simvastatin improved sepsis-induced vascular leakage in kidney, as well as sepsis-induced kidney tubule hypoxia.
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