Pros and Cons of Nrf2 in FSGS Pathogenesis
Abstract
Focal segmental glomerulosclerosis (FSGS) is a debilitating kidney disease characterized by the abnormal leak of blood proteins into the urine (proteinuria). When severe, FSGS causes fluid accumulation and swelling, high blood pressure, and high cholesterol. Patients with FSGS can also develop complete kidney failure, which requires dialysis or kidney transplantation in order to survive. FSGS is much more common in populations that are highly represented among military personnel and Veterans, including individuals with African ancestry. There are very few treatment options for FSGS, and existing treatments have a high rate of failure or can lead to severe side effects. Even kidney transplantation is flawed as there is a 30%-40% recurrence of FSGS disease in the transplanted organ. Thus, there is an urgent clinical need to develop better treatments for FSGS. Nuclear factor 2 erythroid 2 (Nrf2) is a small protein present in kidney cells that may play a role in FSGS disease. Nrf2 is known to protect cells from injury, but clinical trials using drugs to increase Nrf2 activity have not been shown to improve kidney disease convincingly. In fact, some trials show worsening of the proteinuria. Very few FSGS patients have been enrolled in such studies, so effects in this disease are not well known. However, our own studies in animal models of FSGS also show increased proteinuria and kidney injury when Nrf2 activity is increased. Therefore, the role of Nrf2 in FSGS is unclear. In this context, this proposal will determine how Nrf2 affects FSGS disease progression and whether targeting Nrf2 is a potential treatment. We hypothesize that increasing Nrf2 activity 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. We will induce FSGS disease in mice that carry a mutation affecting Nrf2 activity only in specific kidney cell types. In this way, we can understand whether the presence of Nrf2 in a specific type of kidney cell has therapeutic or harmful effects during disease. This knowledge can aid in the future development of therapeutic drugs, which can then be targeted to specific kidney cells for maximal benefit. In Specific Aim 2, we will comprehensively and definitively test whether drugs that increase or inhibit Nrf2 activity will be beneficial in FSGS in our mice. Filling this gap in knowledge will help to design future clinical trials in humans. The role of Nrf2 in kidney diseases, particularly FSGS, is unclear. In the short term, this proposal aims to provide much-needed animal data to better understand Nrf2 effects in FSGS. The long-term goal is to guide the rational use of Nrf2-targeted therapies in clinical trials to improve the health of our Veterans and civilians with FSGS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210845
Entities
People
- Roderick J Tan
Organizations
- United States Army
- University of Pittsburgh