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Kidney Week

Abstract: PO1555

Characterization of the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Response in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Lutsic, Jared J., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
  • Alsawaf, Yahya, Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
  • Harris, Peter C., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
  • Torres, Vicente E., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
  • Irazabal, Maria V., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
Background

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive development and enlargement of bilateral renal cysts. Abnormal epithelial cell proliferation, along with the inability to maintain planar cell polarity, underlies cyst formation and enlargement. Therefore, processes that stimulate renal cell proliferation have the potential to generate the cystic phenotype. Interestingly, an increased nuclear factor erythroid 2-related factor 2 (Nrf2) response has been shown to direct cancer cells into an anabolic mode that favors cellular proliferation, and has been associated with renal cyst formation in experimental and human fumarate hydratase deficiency. However, the Nrf2 response has not been described in ADPKD. We hypothesized that early ADPKD presents with an elevation in the Nrf2 response that favors cellular proliferation and contributes to cystogenesis.

Methods

We sought to longitudinally characterize the Nrf2 response and association with cystogenesis and fibrosis in a slow progressive mouse model of ADPKD (Pkd1RC/RC) and its wildtype controls (n=6 males, 6 females per group). Urine and plasma samples were collected at 30, 60, 120, and 180 days for chemistries and metabolic profiles, and cystic index (CI), and total kidney volume (TKV) were determined from abdominal MRI. Nrf2 levels and related response enzymes, as well as cell proliferation and fibrosis were analyzed using western-blots, immunofluorescence, and assay kits.

Results

At 30 days, Pkd1RC/RC mice presented increased CI and TKV/BW. However, serum creatinine and fibrotic markers were not different compared to controls. Pkd1RC/RC mice exhibited elevated Nrf2 expression and immunoreactivity early on that declined as ADPKD progressed from 30 to 180 days and correlated directly with cell proliferation (R2=0.693, p<0.05) and inversely with fibrotic markers (R2=0.672, p<0.05).

Conclusion

Our study shows longitudinal changes in the Nrf2 response in Pkd1RC/RC mice that are associated with cystogenesis early on and renal fibrosis at later stages of the disease. These findings have significant implications for the treatment of human ADPKD, and suggest that Nrf2 modulators might represent an advantageous intervention for the disease.

Funding

  • NIDDK Support