Acute kidney injury (AKI) is a common and serious complication of medical and surgical diseases that has significant attributable morbidity and mortality in critically ill Veterans. Analysis of Veterans Health Administrative data reported that Veterans who develop AKI during a hospitalization are at substantial risk for the development of chronic kidney disease (CKD) within 1 year. Numerous therapeutic interventions have been evaluated in clinical trials to overcome this significant clinical challenge, with none proven successful. The overall goal of this proposal is to fill this gap in knowledge by discovering new targets that could be exploited for therapeutic interventions in AKI. The lymphatic system is crucial for maintaining fluid balance, transporting lipids, and aiding in immune function. During pathological conditions that involve inflammation such as would occur in AKI and the AKI to CKD transition, these functions of the lymphatic system are further accentuated. Inflammation induces lymphangiogenesis through expression of vascular endothelial growth factors (VEGFs), particularly VEGF-C, VEGF-D, and their receptor VEGF-R3. New lymphatic vessels can then aid in transition of inflammatory cells, removing the cellular debris from the microenvironment of inflammation-induced injury, draining the excess fluid and ultimately facilitating tissue repair. While recent studies have shown lymphangiogenesis to be an active participant in a number of inflammatory diseases, very little is known about the role of the lymphatic system and more importantly, lymphangiogenesis, in the pathogenesis of AKI and the AKI to CKD transition. Our preliminary data demonstrate a significant upregulation of lymphangiogenic markers along with increased lymphatic vessel density during AKI. Our central hypothesis is that inflammation associated lymphangiogenesis (IAL), regulated by VEGF-C expression in myeloid and proximal tubule cells, is involved in the resolution of inflammation following AKI and the AKI to CKD transition. The aims of this proposal are designed to 1) determine how lymphangiogenesis modulates AKI; 2) determine how lymphangiogenesis affects the AKI to CKD transition; and 3) determine the cross-talk between the proximal tubule and myeloid cells in regulating lymphangiogenesis, inflammation, and AKI. Successful completion of the aims of this project will help elucidate the underlying mechanisms involved in the pathogenesis of AKI during both injury and the recovery phases and have the potential to provide new avenues for therapeutic interventions in AKI.