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Principal Investigator: Roderick Jason Tan
Organization: VETERANS HEALTH ADMINISTRATION
Fiscal Year: 2024
Funding agency: Veterans Affairs
Chronic kidney disease (CKD) affects over 35 million Americans, and veterans have a higher
prevalence of CKD compared to the general population. Progressive CKD leads to end-stage
renal disease (ESRD), a state of complete kidney failure requiring dialysis or renal
transplantation for survival. Glomerular diseases are the leading cause of CKD and are caused
by diseases such as diabetic nephropathy, Alport syndrome, and focal segmental
glomerulosclerosis. All of these diseases are characterized by abnormal urinary protein
excretion (proteinuria). This is caused by the dysfunction of the glomerular filtration barrier
which is comprised of endothelial cells, podocytes, and their shared basement membrane.
Treatments for proteinuric CKD are extremely limited, with most slowing progression of disease
rather than curing it. Thus, the unmet need for proteinuric CKD is to improve therapeutics
through a better understanding of glomerular biology. Nuclear factor erythroid 2 related 2 (Nrf2)
is a transcription factor that upregulates cytoprotective antioxidant and detoxification genes.
Although primed to activate quickly during cellular stress, it is restrained by its inhibitor Kelch-
like ECH-associated protein 1 (Keap1) under normal conditions. Nrf2 can be pharmacologically
activated with compounds such as bardoxolone methyl (CDDO-Me) and its analog CDDO-Im.
Recently completed and ongoing human clinical trials utilize bardoxolone methyl to treat
proteinuric CKD. These trials have consistently demonstrated an increase in glomerular
filtration rates (eGFR), but whether this effect leads to an overall benefit in patients is
controversial. Furthermore, bardoxolone methyl caused a worsening of proteinuria in diabetic
kidney disease, but not in Alport syndrome. In our preliminary work, we find that genetic and
pharmacologic Nrf2 enhancement worsened podocyte injury and proteinuria in several
experimental models of CKD in mice. Our proposal will focus on the pros and cons of Nrf2 in
proteinuric CKD to better understand its role in disease. In Specific Aim 1, we will examine
whether Nrf2 plays differential roles in diabetic kidney disease and Alport syndrome. In Specific
Aim 2, we will test the effects of Nrf2 in different kidney cells using conditional knockout mice.
In Specific Aim 3, we will evaluate how dose or timing of Nrf2 affects the overall course of
disease. Surprisingly, there are few preclinical studies to support the use of Nrf2 enhancers in
CKD. A systematic and comprehensive assessment of Nrf2 in animal models is required to
guide the rational use of Nrf2 enhancers in the clinic. Our proposal will provide this critical data
with the goal of improving the lives of our veterans and of all patients with CKD.
Terms: <Active Oxygen><Adriablastin><Adriablastine><Adriacin><Adriamycin PFS><Adriamycin RDS><Adriblastin><Adriblastina><Adriblastine><Adrimedac><Affect><Albuminuria><Alport syndrome><Alport syndrome (AS, ATS)><Alport syndrome-like hereditary nephritis><Alport syndrome-like hereditary nephritis (ASLHN, ASLN)><Alport's Syndrome><American><AngII><Angiotensin II><Animal Model><Animal Models and Related Studies><Animals><Antioxidants><Basal Transcription Factor><Basal transcription factor genes><Basement membrane><Biologic Models><Biological Models><Biology><Cancers><Cardiovascular Diseases><Causality><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Protection><Cells><Cellular Proliferation><Cellular Stress><Cellular Stress Response><Chronic><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinic><Clinical Trials><Consumption><Cytoprotection><DOXO-CELL><Data><Diabetes Mellitus><Diabetic Kidney Disease><Diabetic Nephropathy><Dialysis><Dialysis procedure><Dickinson syndrome><Disease><Disease Progression><Disorder><Dose><Doxolem><Doxorubin><Drug Metabolic Detoxication><Drug Metabolic Detoxification><Dysfunction><ERYF1><ESRD><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Endothelial Cells><Endothelium><Enhancers><Etiology><Excretory function><Experimental Models><Exposure to><FSGS><Familial Nephritis><Farmiblastina><Fibrosis><Focal and Segmental Glomerulosclerosis><Focal segmental glomerular sclerosis><Foot Process><Functional disorder><GATA Binding Protein 1><GATA-1><GATA1><GATA1 gene><GATA1 protein><GATA1 transcription factor><GF-1 protein><General Population><General Public><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Glomerular Filtration Rate><Glomerular disease><Goals><Health><Health Care Costs><Health Costs><Healthcare Costs><Hereditary nephritis><High Prevalence><Human><Individual><Injury><Injury to Kidney><KO mice><Kidney><Kidney Failure><Kidney Grafting><Kidney Insufficiency><Kidney Transplantation><Kidney Transplants><Kidney Urinary System><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Liposomal Adriamycin><Malignant Neoplasms><Malignant Tumor><Mediator><Metabolic Drug Detoxications><Metabolism of Toxic Agents><Mice><Mice Mammals><Model System><Modeling><Modern Man><Murine><Mus><NF-E1 erythroid-specific transcription factor><NF-E2 protein><NF-E2 transcription factor><NFE1 protein><NFE2 protein><Nuclear Translocation><Null Mouse><Oxygen Radicals><Pathologic><Pathway interactions><Patients><Pedicel><Physiopathology><Play><Population><Prevalence><Pro-Oxidants><Proteins><Proteinuria><Reactive Oxygen Species><Renal Cell><Renal Failure><Renal Glomerular Diseases and Syndromes><Renal Grafting><Renal Insufficiency><Renal Transplantation><Renal Transplants><Renal dialysis><Renal glomerular disease><Renal glomerular disease or syndrome><Renal glomerular disorder><Renal glomerular syndrome><Repression><Risk><Role><Rubex><Single-Nucleus Sequencing><Testing><Therapeutic><Time><Transcription Factor GATA1><Transcription Factor Proto-Oncogene><Transcription factor genes><Tubular><Tubular formation><United States Department of Veterans Affairs><United States Veterans Administration><Up-Regulation><Upregulation><Urine><Veterans><Veterans Administration><Veterans Affairs><Visceral Epithelial Cell><Wild Type Mouse><Work><adriamycin><adverse consequence><adverse outcome><analog><cardiovascular disorder><causation><cell stress><cell type><cellular differentiation><chronic kidney disease><clinical relevance><clinically relevant><conditional knock-out><conditional knockout><congenital hereditary hematuria><cytoprotective><deafness-nephritis syndrome><detoxification><diabetes><dialysis therapy><disease causation><effective therapy><effective treatment><excretion><globin transcription factor 1><glomerular filtration><glomerular sclerosis><glomerular visceral epithelial cell><glomerulosclerosis><hearing loss-nephritis syndrome><hematuria-nephropathy-deafness syndrome><hematuric familial nephropathy><hematuric hereditary nephritis><hemorrhagic familial nephritis><hemorrhagic hereditary nephritis><hereditary familial congenital hemorrhagic nephritis><hereditary hematuria syndrome><hereditary interstitial pyelonephritis><hereditary nephritis-deafness syndrome><hereditary nephritis-deafness-abnormal thrombogenesis syndrome><human disease><improved><inhibitor><injuries><interstitial><kidney cell><kidney dialysis><kidney injury><kidney tx><malignancy><military veteran><model of animal><mouse model><murine model><neoplasm/cancer><nuclear factor-erythroid 1><nuclear factor-erythroid 2><pathophysiology><pathway><pharmacologic><podocyte><pre-clinical study><preclinical study><renal><renal injury><restraint><sNuc-Seq><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><social role><transcription factor><transcription factor NFE-1><trigonelline><urinary><veteran population><wildtype mouse>