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
Fiscal Year
Total Cost
Indirect Cost
Zip Code
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
Tuot, Delphine S; Diamantidis, Clarissa Jonas; Corbett, Cynthia F et al. (2014) The last mile: translational research to improve CKD outcomes. Clin J Am Soc Nephrol 9:1802-5
Chawla, Lakhmir S; Eggers, Paul W; Star, Robert A et al. (2014) Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med 371:58-66
Nemeth, Krisztian; Leelahavanichkul, Asada; Yuen, Peter S T et al. (2009) Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 15:42-9
Gonzales, Denise A; Star, Robert A; Kern, Steven J et al. (2008) Is there enough evidence to support use of N-acetylcysteine in contrast-induced nephropathy? Ann Intern Med 149:213-4;author reply 215-6
Knepper, Mark A; Star, Robert A (2008) Vasopressin: friend or foe? Nat Med 14:14-6
VA/NIH Acute Renal Failure Trial Network; Palevsky, Paul M; Zhang, Jane Hongyuan et al. (2008) Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med 359:7-20
Leelahavanichkul, Asada; Yasuda, Hideo; Doi, Kent et al. (2008) Methyl-2-acetamidoacrylate, an ethyl pyruvate analog, decreases sepsis-induced acute kidney injury in mice. Am J Physiol Renal Physiol 295:F1825-35