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) In collaboration with Mariana Kaplan, we contributed to the findings that CD11b in macrophages reduces TLR-dependent activation of interferon signaling within the setting of lupus mouse model and that the CD11b inhibitor LA1 may be a new treatment for lupus. 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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18
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2017
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U.S. National Inst Diabetes/Digst/Kidney
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Street, Jonathan M; Koritzinsky, Erik H; Bellomo, Tiffany R et al. (2018) The role of adenosine 1a receptor signaling on GFR early after the induction of sepsis. Am J Physiol Renal Physiol 314:F788-F797
Faridi, Mohd Hafeez; Khan, Samia Q; Zhao, Wenpu et al. (2017) CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus. J Clin Invest 127:1271-1283
Baranova, Irina N; Souza, Ana C P; Bocharov, Alexander V et al. (2017) Human SR-BII mediates SAA uptake and contributes to SAA pro-inflammatory signaling in vitro and in vivo. PLoS One 12:e0175824
Voss, Oliver H; Murakami, Yousuke; Pena, Mirna Y et al. (2016) Lipopolysaccharide-Induced CD300b Receptor Binding to Toll-like Receptor 4 Alters Signaling to Drive Cytokine Responses that Enhance Septic Shock. Immunity 44:1365-78
Bavendam, Tamara G; Norton, Jenna M; Kirkali, Ziya et al. (2016) Advancing a Comprehensive Approach to the Study of Lower Urinary Tract Symptoms. J Urol 196:1342-1349
Baranova, Irina N; Souza, Ana C P; Bocharov, Alexander V et al. (2016) Human SR-BI and SR-BII Potentiate Lipopolysaccharide-Induced Inflammation and Acute Liver and Kidney Injury in Mice. J Immunol 196:3135-47
Askenazi, David J; Morgan, Catherine; Goldstein, Stuart L et al. (2016) Strategies to improve the understanding of long-term renal consequences after neonatal acute kidney injury. Pediatr Res 79:502-8
Souza, Ana Carolina P; Bocharov, Alexander V; Baranova, Irina N et al. (2016) Antagonism of scavenger receptor CD36 by 5A peptide prevents chronic kidney disease progression in mice independent of blood pressure regulation. Kidney Int 89:809-22
Burks, Scott R; Nguyen, Ben A; Tebebi, Pamela A et al. (2015) Pulsed focused ultrasound pretreatment improves mesenchymal stromal cell efficacy in preventing and rescuing established acute kidney injury in mice. Stem Cells 33:1241-53
Souza, Ana Carolina P; Yuen, Peter S T; Star, Robert A (2015) Microparticles: markers and mediators of sepsis-induced microvascular dysfunction, immunosuppression, and AKI. Kidney Int 87:1100-8

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