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.