Leukocyte Trafficking in Acute Renal Failure

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DESCRIPTION (provided by applicant): Project Summary/Abstract 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.