# The Role of Nrf2 in Proteinuric Chronic Kidney Disease

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 10874499
- **Project number:** 5I01BX005680-03
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Roderick Jason Tan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874499

## Citation

> US National Institutes of Health, RePORTER application 10874499, The Role of Nrf2 in Proteinuric Chronic Kidney Disease (5I01BX005680-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10874499. Licensed CC0.

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