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Kidney Week

Abstract: TH-PO586

Possible Role of Nox4 in Cystogenesis through Its Effects on Fumarate Hydratase in Experimental PKD

Session Information

Category: Genetic Diseases of the Kidney

  • 801 Cystic Kidney Diseases

Authors

  • Vuckovic, Ivan, Mayo Clinic, Rochester, Minnesota, United States
  • Arroyo, Jennifer, Mayo Clinic, Rochester, Minnesota, United States
  • Chebib, Fouad T., Mayo Clinic, Rochester, Minnesota, United States
  • Harris, Peter C., Mayo Clinic, Rochester, Minnesota, United States
  • Macura, Slobodan, Mayo Clinic, Rochester, Minnesota, United States
  • Torres, Vicente E., Mayo Clinic, Rochester, Minnesota, United States
  • Irazabal, Maria V., Mayo Clinic, Rochester, Minnesota, United States
Background

Autosomal Dominant Polycystic Kidney Disease (PKD) is the most frequent hereditary renal disease, but the exact mechanisms of cystogenesis remain to be elucidated. Deficiency in fumarate hydratase (FH) is accompanied by increases in fumarate and is associated with the development of kidney cysts. Studies in diabetic nephropathy showed that NADPH oxidase (NOX)-4 (Nox4) can inhibit FH leading to accumulation of fumarate. No studies have explored the role of Nox4 in PKD.

Methods

Metabolomics analysis of cell extracts, urine, plasma & kidney of PCK (n=32) and wildtype (WT; n=24) rats, and human samples (ADPKD n=10; ctrl n=10) was performed by HNMR & confirmed by MS. Immunoreactivity and protein expression of FH & Nox4 were assessed by staining & western blotting, FH activity by a colorimetric method and mitochondria by electron microscopy.

Results

Fumarate was consistently increased in PKD-deficient cells, PCK rats & human samples (Fig1A-D). Mitochondrial FH activity was significantly lower in PCK rats (2A), but protein expression and immunoreactivity did not differ (fig2B-C). Furthermore, FH activity highly correlated with tissue fumarate (fig2D). Decreased FH activity was associated with significantly increased protein expression and immunoreactivity of Nox4 in PCK compared to WT rats (fig3). These findings were associated with disruption of mitochondria cristae, swelling, and decreased matrix density exclusively in tubular cells from CD lining microcysts in PCK rats (fig4).

Conclusion

Metabolomic analysis identified fumarate as a potential mediator of cystogenesis in PKD. Accumulation of fumarate in PKD may be due to FH inhibition through upregulation of Nox4. Further experiments are needed to investigate the role of Nox4, FH and fumarate in PKD.