ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO1561

Glucosylceramide Synthase Inhibition Preserves Mitochondrial Function and Reduces Reactive Oxygen Damage in the Jck Mouse Model of Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Picariello, Tyler, Rare and Neurological Disease Research, Framingham, Massachusetts, United States
  • Rogers, Kelly A., Rare and Neurological Disease Research, Framingham, Massachusetts, United States
  • Smith, Laurie A., Rare and Neurological Disease Research, Framingham, Massachusetts, United States
  • Bracken, Christina M., Rare and Neurological Disease Research, Framingham, Massachusetts, United States
  • Bukanov, Nikolay O., Rare and Neurological Disease Research, Framingham, Massachusetts, United States
  • Beskrovnaya, Oxana, Rare and Neurological Disease Research, Framingham, Massachusetts, United States
  • Natoli, Thomas A., Rare and Neurological Disease Research, Framingham, Massachusetts, United States
Background

Glucosylceramide synthase inhibitor (GCSi) treatment blocks disease progression in PKD mouse models. Defective mitochondrial morphology and function are observed in kidneys of ADPKD patients and murine models. We assessed the impact of GCSi treatment on mitochondrial function in the jck mouse model of PKD and jck derived kidney epithelial cells.

Methods

Twenty-six-day old WT or jck mice were treated with vehicle or 60 mg/kg GCSi (Genz667161) in feed for 38 days prior to tissue harvest. mRNA expression was measured using RT-PCR. protein levels were measured by western blot. Mitochondrial DNA content was measured using real-time PCR. Oxidized DNA was detected using anti-8OHdG antibodies. Oxidized proteins were measured using the Oxyblot system (Millipore).

Results

Reductions in electron transport chain and mitochondrial membrane proteins, as well as mitochondrial DNA were observed in control jck mouse and ADPKD patient samples. Decreased antioxidant gene expression was also observed in jck kidneys as were increased levels of oxidized DNA and protein; these changes were mirrored in ADPKD samples.
Reduced cystic burden following treatment of jck mice with GCSi was associated with increased levels of mitochondrial DNA, mitochondrial proteins, and induction of mitochondrial biogenesis pathways. GCSi treatment partially reversed antioxidant gene downregulation and normalized oxidized DNA and protein levels in jck tissues.
Jck cells exhibited decreased mitochondrial number, defective mitochondrial function, and increased protein oxidation consistent with in vivo and ADPKD patient data. GCSi treatment alleviates these defects. This suggests that reduced mitochondrial function and increased oxidative stress are primary cellular defects and not a result of cystogenesis.

Conclusion

Mitochondrial dysfunction and increased oxidative stress were observed in jck mouse tissues, jck cell lines, and ADPKD patient samples. GCSi treatment inhibited disease progression in jck mice, reducing oxidative stress and correcting mitochondrial dysfunction. Reduced kidney cyst growth following GCSi treatment correlates with preserved mitochondrial function.

Funding

  • Commercial Support