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) In collaboration with Tom Eggerman, 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 serum amyloid A (SAA). We found that SR-BII had a more pronounced effect in mediating SAA-induced injury that was targeted to both liver and kidney. 2) Using a novel method to measure glomerular filtration rate (GFR), where we can monitor conscious, freely moving mice non-invasively, we determined that early drop in GFR precedes drop in blood pressure in sepsis, ruling out a purely hemodynamic effect. We also examined whether tubuloglomerular feedback (TGF) mediated and/or counteracted this drop in GFR by using adenosine A1a receptor knockout mice. We found that there is an important role for TGF to maintain GFR in the immediate aftermath of sepsis, but lasting only for an hour, with an opposite effect from 1-4 hours, with no net long-term effect on sepsis outcomes. We continue to explore potential mechanisms and treatments for sepsis-AKI, CKD, and acute-on-chronic kidney disease. We also continue to develop models for acute and chronic kidney disease.
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