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 are continuing mechanistic studies to determine whether we can identify the important target cell where CD36 is contributing to CKD progression. 2) 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. We continue to explore potential mechanisms and treatments for sepsis-AKI, CKD, and acute-on-chronic kidney disease.

Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2013
Total Cost
$549,980
Indirect Cost
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State
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Zip Code
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
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
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
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
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; 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
Souza, Ana C P; Tsuji, Takayuki; Baranova, Irina N et al. (2015) TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression. Physiol Rep 3:
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
Wiggins, Roger C; Alpers, Charles E; Holzman, Lawrence B et al. (2014) Glomerular disease: looking beyond pathology. Clin J Am Soc Nephrol 9:1138-40
Kaskel, Frederick; Batlle, Daniel; Beddhu, Srinivasan et al. (2014) Improving CKD therapies and care: a National Dialogue. Clin J Am Soc Nephrol 9:815-7

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