Pros and Cons of Nrf2 in FSGS Pathogenesis
Abstract
Focal segmental glomerulosclerosis (FSGS) is a kidney disease characterized by the abnormal leak of protein into the urine (proteinuria)and eventual kidney failure. Nuclear factor 2 erythroid 2 (Nrf2) is a transcription factor that may play a role in FSGS. Nrf2 is classically thought to protect cells from injury, but clinical trials using Nrf2 enhancers actually worsened proteinuria. Our own studies in animal models of FSGS also show increased proteinuria and kidney injury when Nrf2 activity is increased. We hypothesize that increasing Nrf2activity actually increases injury during FSGS. In specific aim 1, we will perform animal experiments that will tell us how Nrf2 affects the different types of cells in the kidney during FSGS disease. To do this, we will conditionally knockout or activate Nrf2 in specific kidney cell types in vivo (tubules or endothelium) and examine progression of FSGS. We will also perform single cell/nucleus RNA sequencing in mouse kidneys to provide comprehensive cell-specific transcriptomes in response FSGS and to Nrf2 activation or deletion.In specific aim 2, we will comprehensively and definitively test whether drugs that increase or inhibit Nrf2 activity will be beneficial in FSGS. In this reporting period we successfully generated tubule-specific Keap1 knockout mice and exposed them to disease. These mice did not exhibit differences in FSGS disease but require additional study. If confirmed, these findings suggest that tubular Nrf2 may not play a role in FSGS pathogenesis and we will focus on endothelial-specific knockouts instead.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2023
- Accession Number
- AD1217433
Entities
People
- Roderick J Tan
Organizations
- University of Pittsburgh