Acute kidney injury (AKI) is a common and often fatal event. Inflammation plays a key role in the pathogenesis of AKI. Relatively little is known regarding the endogenous pathways which limit inflammation and reduce the incidence and/or severity of AKI. We recently determined that resident dendritic cells (DCs) and endogenous IL-10 are anti-inflammatory and reduce the severity of AKI. Moreover, the protective actions of dendritic cells are partially dependent upon their production of IL-10. The objective of this application is to delineate the mechanisms by which dendritic cells and endogenous IL-10 interact to reduce the severity of AKI. The central hypothesis is that a network of renal epithelial cells, dendritic cells and Treg cells, interacting through TLR receptors and IL-10, form a potent defense against acute kidney injury. In order to preserve the important contextual cues provided by the local cellular environment, our approach will emphasize in vivo models in pursuing an integrated analysis of anti-inflammatory mechanisms active in AKI through three aims. 1. Determine the mechanisms of regulation of dendritic cell (DC) IL-10 production and protection in AKI. We hypothesize that renal dendritic cells produce IL-10 and exert their anti-inflammatory and protective effects in AKI in a TLR4 and HO-1-dependent manner. 2. Determine the role of T cells in DC and IL-10 mediated protection against ARF. We hypothesize that resident dendritic cell protection in AKI is mediated through their ability to suppress antigen-specific activation of T cells and enhance IL- 10 production by Treg cells. 3. Determine the targets of IL-10 which mediate protection against AKI. We hypothesize that IL-10 reduces AKI by activating cell survival pathways in renal epithelial cells and reducing inflammatory cytokine production in both leukocytes and epithelial cells. These studies are unique as they integrate in vitro and in vivo approaches permitting detailed effector mechanisms to be defined and the pathophysiological relevance of the observations to be confirmed. These studies will provide new insights into this critical regulatory system. They will lead not only to a more complete understanding of cisplatin nephrotoxicity but also of other forms of AKI. The proposed studies have a translational underpinning in that they will stimulate the development of novel clinical interventions designed to abrogate the consequences of AKI.
The proposed studies will elucidate the key role of kidney dendritic cells and IL-10 as endogenous protectors against acute kidney injury. These results will be relevant because they are expected to lead to clinical trials to test the efficacy of immunomodulatory strategies for the prevention or treatment of acute renal injury.
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