There are no FDA approved drugs for the prevention and treatment of acute kidney injury (AKI). Thus, mortality remains high and survivors of AKI suffer from significant morbidity;many develop chronic kidney disease and end stage renal disease. A precise understanding of early mechanisms of AKI is critically needed to guide development of novel therapies. Over the past two grant cycles, we identified novel therapeutic targets for the prevention and treatment of AKI. Among these, tissue resident dendritic cells (DCs) play disparate roles in tissue homeostasis - assuming a central role in the early pathogenesis of AKI, yet also playing a tolerogenic role - and in different forms of AKI, where they promote injury in ischemia-reperfusion injury (IRI) and are protective in cisplatin nephrotoxicity (CN). During the current funding cycle new information has shown that DCs can initiate immune responses following kidney IRI by activating natural killer T cells via the IL23/IL17 pathway. Abrogating this process, e.g. by adenosine 2a receptor (A2aR) agonist administration, attenuates injury. DCs express A2aRs;we demonstrate that DCs are tolerized by exposure to A2aR agonists. We propose studies to better understand the role of DC function in AKI and the role of adenosine signaling through endogenous DC A2aRs in two models of AKI (IRI and CN). These fundamental findings form the basis of a cell-based therapeutic approach, modeled after current clinical trials in cancer, autoimmune diseases, and transplantation, to tolerize DCs ex vivo with A2aR agonists for the prevention and treatment of AKI. Our preliminary data demonstrate that endogenous DC A2aRs critically control the extent of IRI, administration of A2a-tolDCs (up to 7 days before or 6 hrs after injury) protects kidneys from IRI, A2a agonists block CN, and allogenic A2a-tolDCs block IRI. Our studies will define the mechanism by which A2a agonists tolerize both murine and human DCs and the mechanism by which they prevent kidney AKI in vivo. The significance of this approach is that cell-based therapy using A2a-tolDC promotes superior tissue protection with a broad therapeutic window, avoids systemic administration of a drug (or other drugs) that could potentially have adverse side effects such as platelet dysfunction, hypotension and systemic immunosuppression, serves as a proof of concept model that tolerized DCs (from any treatment modality) may be useful in future strategies for the treatment of AKI, and promotes prolonged protection due to a lasting memory effect of A2a agonists on DCs. Using transgenic mice, selective pharmacological reagents, and novel reagents, we will test the hypotheses that (Aim 1) endogenous DC A2aRs control the extent of IRI and CN, (Aim 2) A2a-tolerized DCs are effective in prevention of AKI and treatment of established AKI, and (Aim 3) A2a-tolDCs protect kidneys by enhancing IL-10 signaling and regulatory T cells. These studies will form the basis of therapy for prevention of AKI and more broadly for transplantation and other autoimmune diseases.

Public Health Relevance

Kidney disease and, in particular, acute kidney injury (AKI), is a major economic and public health burden in the United States and worldwide with ever increasing rates of hospitalization and unacceptably high mortality (40-60%) in critically ill patients. Furthermore, AKI may predispose patients to progression to chronic kidney disease and end stage renal disease and, ultimately, shortened lifespan. The development of effective treatments for AKI is urgently needed and depends on a precise understanding of the molecular, cellular and immunological basis of AKI. The major goal of the current proposal is to further investigate the role of the immune system in the inflammatory process that occurs in kidney injury and to explore mechanisms, such as immune suppression with adenosine 2A receptor agonists, which might be manipulated advantageously with new drugs to control the disease process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK062324-10A1
Application #
8439588
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Kimmel, Paul
Project Start
2002-07-01
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
10
Fiscal Year
2013
Total Cost
$343,650
Indirect Cost
$126,150
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Okusa, Mark D; Rosner, Mitchell H; Kellum, John A et al. (2016) Therapeutic Targets of Human AKI: Harmonizing Human and Animal AKI. J Am Soc Nephrol 27:44-8
Perry, Heather M; Huang, Liping; Ye, Hong et al. (2016) Endothelial Sphingosine 1‑Phosphate Receptor‑1 Mediates Protection and Recovery from Acute Kidney Injury. J Am Soc Nephrol 27:3383-3393
Inoue, Tsuyoshi; Abe, Chikara; Sung, Sun-Sang J et al. (2016) Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes. J Clin Invest 126:1939-52
Bajwa, Amandeep; Huang, Liping; Kurmaeva, Elvira et al. (2016) Sphingosine 1-Phosphate Receptor 3-Deficient Dendritic Cells Modulate Splenic Responses to Ischemia-Reperfusion Injury. J Am Soc Nephrol 27:1076-90
Perry, Heather M; Okusa, Mark D (2016) Endothelial Dysfunction in Renal Interstitial Fibrosis. Nephron 134:167-171
Cerdá, Jorge; Liu, Kathleen D; Cruz, Dinna N et al. (2015) Promoting Kidney Function Recovery in Patients with AKI Requiring RRT. Clin J Am Soc Nephrol 10:1859-67
Vincent, I S; Okusa, M D (2015) Adenosine 2A receptors in acute kidney injury. Acta Physiol (Oxf) 214:303-10
Bajwa, Amandeep; Rosin, Diane L; Chroscicki, Piotr et al. (2015) Sphingosine 1-phosphate receptor-1 enhances mitochondrial function and reduces cisplatin-induced tubule injury. J Am Soc Nephrol 26:908-25
Abdel-Rahman, Emaad M; Okusa, Mark D (2015) Recovery from acute kidney injury: predicting outcomes. Am J Kidney Dis 65:528-9
Inoue, Tsuyoshi; Okusa, Mark D (2015) Neuroimmune Control of Acute Kidney Injury and Inflammation. Nephron 131:97-101

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