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, and we established another model using comorbidity, namely pre-existing renal dysfunction, which is thought to increase susceptibility to AKI in patients. This acute-on-chronic syndrome has not been studied in animals, and the nephrology field is trying to gain more information about how this is manifest in patients. Because the model we used for pre-existing renal dysfunction is reversible, unlike the progression seen in CKD patients, we started with a partial renal ablation (5/6 nephrectomy) procedure, a classic rat CKD model, then adapted it to the mouse. We have characterized our model, and it has several hallmarks of progressive CKD, including hypertension, proteinuria, glomerulosclerosis, interstitial renal tubular fibrosis, anemia, and cardiac fibrosis. In order to make our CKD mouse model compatible with our sepsis AKI models, we tested three mouse strains, which had differential susceptibility to CKD. In the most susceptible strain, all aspects of CKD could be lowered by an angiotensin receptor blocker (olmesartan). Conversely, angiotensin II could convert a resistant strain to a susceptible strain. However, this effect is largely independent of blood pressure. 1) We previously showed that lipid scavenger receptors SR-BI/II and CD36 was important in polymicrobial sepsis and sepsis-AKI. In a follow-up study CD36 knockout mice had decreased progression of CKD in our 5/6 nephrectomy model, but the mechanism is unknown. We have demonstrated that this benefit is independent of blood pressure, and that CD36 mRNA and protein can be detected in proximal tubule cells, a possible site of action. 2) In a related study, we used transgenic mice to overexpress SR-BI and SR-BII in liver and kidney to study their role in systemic and local inflammation that was induced by lipopolysaccharide (endotoxin). We found that SR-BII had a more pronounced effect in mediating lipopolysaccharide-induced injury that was targeted to both liver and kidney. 3) High mobility group B1 (HMGB1) is a protein that is released during cell stress, as an alarmin that can amplify sterile inflammation. We previously showed that HMGB1 plays a key role in acute-on-chronic kidney disease, but there are several downstream receptors/targets for HMGB1. One receptor for HMGB1 is Toll-like receptor 4 (TLR4), and we found that mice with genetic TLR4 deficiency are completely protected from CKD progression in our 5/6 nephrectomy model. We are continuing mechanistic studies to determine whether we can identify the important target cell where TLR4 is contributing to CKD progression. 4) In collaboration with John Coligan, we found that CD300b, which interacts with TLR4, contributes to sepsis-induced mortality in mice, as the mice null for the CD300b gene had less inflammation, organ damage, and a lower death rate. Therefore, CD300b contributes to the pathogenesis of septic peritonitis. We continue to explore potential mechanisms and treatments for sepsis-AKI, CKD, and acute-on-chronic kidney disease.
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