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Principal Investigator: ANUPAM AGARWAL
Organization: BIRMINGHAM VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
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.
Terms: <3-D><3-Dimensional><3D><Abscission><Acute><Acute Renal Failure with Renal Papillary Necrosis><Bilateral><Blood monocyte><Body Tissues><CDDP><COVID infected patient><COVID patient><COVID positive patient><COVID-19 infected patient><COVID-19 patient><COVID-19 positive patient><COVID19 patient><COVID19 positive patient><Cell Body><Cell Communication and Signaling><Cell Isolation><Cell Lineage><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cells><Cellular Immune Function><Chronic><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Clinical><Clinical Trials><Collaborations><Complication><Corynebacterium Diphtheriae Toxin><Critical Illness><Critically Ill><Cysplatyna><Cytometry><DTR Protein><Data Reporting><Development><Dialysis><Dialysis procedure><Dichlorodiammineplatinum><Diphtheria Toxin><Diphtheria Toxin Sensitivity><Disease><Disorder><Drainage><Drainage procedure><Excision><Exclusion><Exhibits><Exposure to><Extirpation><FIGF protein><FLT4><FLT4 Ligand><FLT4 Protein><FLT4 gene><FLT4-L><FMS-Related Tyrosine Kinase 4><Flt-4><Fluid Balance><Fluid Homeostasis><Funding><Goals><HB-EGF precursor><Health><Heart><Hospital Admission><Hospitalization><Human><Hypoxia><Hypoxic><Image><Immunoglobulin Enhancer-Binding Protein><Impairment><In Vitro><Indiana><Inflammation><Inflammatory><Injury><Injury to Kidney><Intensive Care Units><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Ischemia-Reperfusion Injury><Kidney><Kidney Tubules><Kidney Urinary System><Knowledge><Ligands><Lipid Trafficking><Liquid substance><Lymph System><Lymphangiogeneses><Lymphangiogenesis><Lymphatic><Lymphatic Endothelial Cells><Lymphatic Network><Lymphatic Research><Lymphatic System><Lymphatic System Reticuloendothelial System><Lymphatic function><Macrophage><Maps><Marrow monocyte><Mediating><Mice><Mice Mammals><Modality><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Mφ><NF-kB><NF-kappa B><NF-kappaB><NFKB><Nephrotoxic><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Operative Procedures><Operative Surgical Procedures><Oxygen Deficiency><Pathogenesis><Pathologic><Patients><Peyrone's Chloride><Peyrone's Salt><Phase><Platinum Diamminodichloride><Publishing><Receptor Protein><Recovery><Removal><Renal function><Renal tubule structure><Reperfusion Damage><Reperfusion Injury><Reporter><Risk><Role><SARS-CoV-2 infected patient><SARS-CoV-2 patient><SARS-CoV-2 positive patient><Signal Transduction><Signal Transduction Systems><Signaling><Source><Structure><Supportive Therapy><Supportive care><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Techniques><Testing><Therapeutic Intervention><Time><Tissues><Transcription Factor NF-kB><Transgenic Mice><Tube><Tyrosine-Protein Kinase Receptor FLT4><Universities><Up-Regulation><Upregulation><VEGF><VEGF-C><VEGF-D><VEGFR-3><VEGFR3><VEGFs><VGR3><Vascular Endothelial Growth Factor C><Vascular Endothelial Growth Factor D><Vascular Endothelial Growth Factor Receptor-3><Vascular Endothelial Growth Factor Related Protein><Vascular Endothelial Growth Factors><Veterans><Work><acute kidney injury><biological signal transduction><c-fos-induced growth factor><cell sorting><chronic kidney disease><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><coronavirus disease 2019 infected patient><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19 patient><coronavirus patient><data representation><data representations><developmental><dialysis therapy><diphtheria toxin receptor><diptheria toxin receptor><fluid><imaging><immune function><in vitro Assay><in vivo><injuries><injury and repair><injury recovery><insight><intervention therapy><interventional strategy><kappa B Enhancer Binding Protein><kidney function><kidney injury><kidney toxicity><lipid transport><liquid><lymph channel><lymph vessel><lymphatic channel><lymphatic vessel><medical complication><monocyte><mortality><nephrotoxicity><novel><nuclear factor kappa beta><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><preservation><receptor><recovery after injury><recovery following injury><recovery post injury><renal><renal injury><renal tubule><resection><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><social role><surgery><three dimensional><tissue repair><transcriptomics><translational therapeutics><translational therapy>