Anti-inflammatory actions of exosomes in the postischemic kidney

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Ischemic renal injury is common, causes acute kidney injury (AKI), contributes to the epidemic of chronic kidney disease (CKD) and progression of CKD of other etiologies to end stage renal disease and to transplant dysfunction. AKI occurs in up to two thirds of intensive care patients and 1 in 5 hospitalized adults worldwide, yet there is currently no effective therapy. Unfortunately, mortality has not improved significantly in decades. Thus, new approaches are needed. Despite large advances in understanding pathophysiology, and in renal replacement therapy, AKI is associated with unacceptably high mortality. We and others have documented the role of inflammatory responses in injury following renal ischemia. In addition, we have found that exosomes can improve renal function, structure, inflammation and oxidative stress, even when given after renal failure is established. The mechanisms of renal inflammation and benefit with exosomes, however, are not well understood. This proposal aims to fill those gaps by examining the effects of exosomes from different sources on inflammation and oxidative stress in the postischemic kidney. Our long-term goal is the development of effective therapies to improve outcomes in acute kidney injury. The objective of this application is defining the mechanisms by which renal exosomes decrease inflammation and oxidative stress following ischemia/reperfusion injury. Our central hypothesis is that renal exosomes provide a multi-faceted therapy for renal ischemic injury, increasing renal superoxide and catalase and anti-inflammatory cytokines. Furthermore, we posit that skin and platelet exosomes are not protective, allowing us to define specific beneficial exosomal cargo. Based on our preliminary data, we propose the following aims, employing out well established model: 1. To define the efficacy of exosomes from different sources on postischemic, renal function, inflammation and oxidative stress. 2. To determine the effect of exosomes on the proinflammatory transformation of hypoxic kidney tubular and endothelial cells in a system in which many factors can be controlled. 3. To compare cargo and the anti-inflammatory and anti-oxidation effects of protective and ineffective exosomes, including renal, skin, platelet and mesenchymal stem cell exosomes. At the conclusion of this work, we expect to have defined the key inflammatory and oxidative stress mediators of ischemic renal injury and the exosomal cargo that improve function. The results are expected to have a significant positive impact in that they will provide the strong evidence-based proof of principle for further development of potential therapies to improve outcomes in AKI.