Project Summary 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. AKI is also a major complication of hospitalized COVID-19 patients and almost half of these patients who develop AKI do not recover to baseline kidney function. 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 focus of this project on the lymphatic system, specifically lymphangiogenesis in the kidney, will build upon the progress made during the previous funding cycle. Lymphatics aid in transport of inflammatory cells, removal of cellular debris from the microenvironment of inflammation-induced injury, drainage of excess fluid and ultimately facilitate tissue repair. While studies have highlighted the key role for lymphangiogenesis in the heart, the role of the lymphatic system in the kidney in the pathogenesis of AKI and the AKI to CKD transition is only now being recognized. Our recently work demonstrated that VEGF-C and VEGF-D, the major ligands in lymphangiogenesis, are abundantly present in renal tubules at baseline and are secreted following injury. Lymphatic vessel formation is robustly induced following kidney injury in multiple models of AKI. Our central hypothesis is that inflammation associated lymphangiogenesis is beneficial in the pathogenesis of AKI and the transition of AKI to CKD. We will test this overall hypothesis in three aims. In Aim 1, we will test the hypothesis that inflammation associated lymphangiogenesis originates from preexisting lymphatic endothelial cells in the kidney after AKI. In Aim 2, we will test the hypothesis that an intact lymphatic network maintained by myeloid lineage cells is required for preserving renal structure and function after AKI. In Aim 3, we will test the hypothesis that LA is dependent on NF-κB expression in lymphatic endothelial cells following AKI and during the AKI to CKD transition. These studies will have a significant impact both in uncovering mechanisms of lymphangiogenesis and providing new insights into the dynamic function of lymphatics in the pathobiology of AKI. Upon successful completion of the proposed aims, we will have comprehensively examined the role of lymphangiogenesis in AKI and the AKI to CKD transition, and will also provide a novel platform that will facilitate translational therapeutic efforts in the field.