# Role of Fumarate and Nrf2 response in the pathogenesis of Autosomal Dominant Polycystic Kidney Disease

> **NIH NIH R21** · MAYO CLINIC ROCHESTER · 2020 · $198,750

## Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a multisystem devastating disease,
characterized by multiple bilateral renal cysts, renal complications, and progression to end-stage renal disease.
Abnormal epithelial cell proliferation, a distinctive feature in PKD, underlies cyst formation and enlargement.
Therefore, identifying dysregulations in the cellular mechanisms known to promote cell proliferation represents
a major opportunity for therapeutic interventions. The Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a
transcription factor that regulates cellular protection against stress and survival by modulating the expression
of antioxidant proteins. Phenolic compounds like nordihydroguaiaretic acid (NDGA) interfere with Nrf2
ubiquitination, favoring its transcriptional activation. NDGA is known to cause cystogenesis in non-PKD rats.
Fumarate is a citric acid cycle (TCA) and urea cycle intermediate that can also modulate Nrf2 ubiquitination.
Increased fumarate has been associated with cystogenesis and renal cell cancer in fumarate hydratase (FH)
deficiency. In preliminary studies we have discovered an increase in fumarate levels in PKD deficient cells.
What is more, our studies in early stage PKD rats (PCK) discovered increased urinary and renal tissue
fumarate compared to wild-type (WT) rats. In addition, urinary and renal tissue fumarate levels were higher in
Pkd1RC/RC mice compared to controls, and positively correlated with disease severity (cystic index and fibrosis).
Notably, renal expression of nuclear Nrf2 was higher in Pkd1RC/RC mice compared to controls. Finally, urine
from young patients with ADPKD had increased levels of fumarate compared to normal volunteers. However,
whether increased fumarate levels in the context of PKD contribute to a dysregulation in the Nrf2 response,
ultimately promoting cystogenesis has never been explored. The hypothesis underlying this proposal is that
ADPKD results in increased levels of fumarate and that this increase results in upregulation of Nrf2 signaling
leading to cellular proliferation and contributing to cystogenesis. Hence, determining the origin of the increase
in fumarate would uncover metabolic pathways altered in ADPKD that could help identifying novel disease
biomarkers and developing targeted therapeutic interventions. To test this hypothesis we will take advantage of
genetically engineered rodent models, our previously developed imaging classification of ADPKD, and state of
the art spectroscopic techniques as well as unique stable isotope metabolomics and spectroscopic imaging
techniques. Three specific aims will be pursued: Specific Aim 1 will test the hypothesis that cystogenesis in
orthologous models of ADPKD is accompanied by altered metabolomics and increased levels of fumarate that
leads to up regulation of Nrf2 signaling and cystogenesis. Specific Aim 2 will test the hypothesis that fumarate
levels and Nrf2 response are increased in patients with ADPKD and correla...

## Key facts

- **NIH application ID:** 9987595
- **Project number:** 5R21DK118391-03
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Maria V Irazabal
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $198,750
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987595

## Citation

> US National Institutes of Health, RePORTER application 9987595, Role of Fumarate and Nrf2 response in the pathogenesis of Autosomal Dominant Polycystic Kidney Disease (5R21DK118391-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9987595. Licensed CC0.

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