Dendritic cells (DCs) contribute fundamentally to innate immunity in part through the activation of natural killer T (NKT) cells to induce tissue injury. DCs produce IL-12 and IL-23, a new member of the IL-12 family, and contribute to autoimmunity and host defense through IL-12/Th1/IFN-3 and/or IL-23/Th17/IL-17 dependent pathways, respectively. Our short term goal is to harness current immunological concepts to: 1) to understand the role of DCs in the pathogenesis of kidney ischemia-reperfusion injury (IRI) and 2) to determine how adenosine 2A receptor (A2AR) agonists block activation of this pathway leading to tissue protection from kidney IR. A2ARs are members of a family of G protein coupled receptors that are expressed on hematopoietic cells. Over the past funding cycle we have found that an important target for A2AR agonists in attenuating renal IRI resides with CD4+NKT cells, and with additional support from our preliminary findings, we now suggest that A2ARs are uniquely suited to interrupt the DC-NKT pathway. Thus the proposed studies will investigate the role of DC production of IL- 12/Th1 and IL-23/TH17 in the activation of NKT cells and neutrophil (PMN) accumulation in kidney IRI. We will also determine the mechanism by which A2AR agonists interrupt this pathway leading to kidney protection from IRI. Therefore, we hypothesize that 1) kidney resident dendritic cells activates innate immunity through NKT cells and 2) A2A agonists block this pathway through effects mediated by A2ARs expressed on DCs and/or NKT cells.
Aim 1. Our hypothesis predicts that kidney IRI activates resident DCs to initiate early reperfusion injury.
Aim 2. Our hypothesis predicts that IL-12 secreted by DCs and antigen presentation by CD1d molecules are required for NKT cell IFN-3 production.
Aim 3. Our hypothesis predicts that DCs produce IL-23, which drives the production of IL-17 to promote kidney IRI.
Aim 4. Our hypothesis predicts that A2AR stimulated inhibition of DC-NKT cell interaction mediates the ability of A2AR agonists to block IRI. The long-term goal is to provide a precise understanding of the innate and adaptive immunity and their role in early injury and late repair of acute kidney IRI. Project Narrative The incidence and prevalence of acute kidney injury (AKI) and its contribution to end- stage renal disease is increasing with mortality reaching as high as 50 - 80% in some cases. Current treatments have failed in part due to the absence of a complete understanding of the pathophysiology. These studies will identify novel immune pathways that participate in early injury associated with AKI and new targets for therapeutic intervention using novel compounds including adenosine 2A agonists.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062324-09
Application #
8021844
Study Section
Special Emphasis Panel (ZRG1-RUS-B (12))
Program Officer
Kimmel, Paul
Project Start
2002-07-01
Project End
2012-07-31
Budget Start
2011-02-01
Budget End
2012-07-31
Support Year
9
Fiscal Year
2011
Total Cost
$315,531
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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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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