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

Project: Research project

Project Details

Description

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 correlate with disease severity. Specific Aim 3 will test the hypothesis that the increased levels of fumarate in kidneys and urines of patients and rodent models of ADPKD result from dysregulation of TCA cycle, glutamine metabolism, or the urea cycle and fumarate hydratase activity. Successful studies will have important clinical implications by advancing understanding of the pathophysiology of the disease, identifying novel early biomarkers, and highlighting additional metabolic pathways that could be targeted for therapeutic intervention in a disease with no specific treatment available.
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