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) As a result of a liver biomarker study, we tested whether cyclophilin A, which is found in the circulation during sepsis-AKI, we tested whether it affected the severity of AKI, indirectly, by using an antibody against its putative receptor CD147, and the antibody was demonstrated to be partially effective to treat sepsis-AKI.? ? 2) alpha-Melanocyte Stimulating Hormone (alphaMSH) has been shown by this laboratory to be effective against AKI in ischemia/reperfusion and cisplatin AKI models. Its use clinically is hampered, in part, by unfavorable pharmacokinetics, and this limitation has been overcome by an alphaMSH analog, AP214. In our sepsis AKI model, AP214 was effective in improving the severity of AKI as well as mortality. AP214 was still effective with delayed treatment, making it a promising candidate for treating patients with established sepsis-AKI.? ? 3) Following up our studies on innate immunity, where we showed that Toll-like receptors had an important role in sepsis-AKI, we were able to demonstrate that chloroquine, an inhibitor of the endosomal subset of TLRs was effective in treating sepsis-AKI, even with delayed administration. Because it is well-tolerated clinically, it is a prime candidate for further therapeutic development. In addition to chloroquine, TLR9 was shown to account for most of the beneficial effect, by TLR9-deficient mice and by a TLR9-selective antagonist.? ? 4) Our previous studies showed that ethyl pyruvate was effective in treating sepsis-AKI, but the instability of this agent makes it an unlikely candidate to develop for clinical use. A more stable analog of ethyl pyruvate, methyl 2-acetamidoacrylate (M2AA), was also effective in treating sepsis AKI. Mechanistically it is distinct from chloroquine, and the combination of M2AA and chloroquine was more effective than either agent alone.
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