Acute kidney injury (previously 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, including conscious blood pressure by telemetry. We adjusted our mouse model by using outbred mice, which develop AKI at a younger age, allowing us to explore another comorbidity, namely pre-existing renal dysfunction, which is thought to increase susceptibility to AKI in patients.? ? 1) 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.? ? 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. We further showed that AP214 alleviated some of the sepsis-induced hypotension and most of the sepsis-induced bradycardia. Finally, we established our model in an outbred strain of mice which has genetic variability, without needing to use older mice.? ? 3) A consensus is emerging that patients with chronic kidney disease are more susceptible to AKI. To study this 'acute-on-chronic' phenomenon, we developed a model using folic acid, a nephrotoxin, to simulate chronic kidney disease, followed by cecal ligation puncture to induce sepsis-AKI. We demonstrated increased vascular permeability and vasular endothelial growth factor (VEGF), and used sFLT-1, a VEGF antagonist, to reduce AKI. Chloroquine, used in combination with sFLT-1, was synergistic, demonstrating clinical potential for this combination. The two agents are complementary in mechanism, for example, chloroquine was ineffective for sepsis-induced bradycardia, whereas sFLT-1 could relieve most of the defect.
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