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Abstract: FR-PO728

Ciclopirox-Olamine Alters Ferritin Trafficking and Plays a Protective Role in Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Radadiya, Priyanka, University of Kansas, Lawrence, Kansas, United States
  • Subramaniam, Dharmalingam, Kansas University Medical Center, Kansas City, Kansas, United States
  • Weir, Scott J., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Calvet, James P., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Wallace, Darren P., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Sharma, Madhulika, University of Kansas Medical Center, Kansas City, Kansas, United States
Background

The search for safer and better drugs for Polycystic kidney disease (PKD) continue despite successful lauch of Tolvaptan.We have recently shown that the Notch3 signaling pathway is activated in renal cyst epithelial cells. To determine in vivo role of Notch inhibition, we used Ciclopirox-olamine (CPX). CPX can inhibit Notch and other pathways by its property to chelate iron and thus inhibit the activity of iron dependent enzymes such as gamma secretase (involved in Notch pathway activation).

Methods

We used primary normal human kidney (NHK) cells of collecting duct origin and primary cells from cysts of ADPKD patients (ADPKD cells). The effect of CPX on cell viability, ability to form cAMP dependent 3D cysts in vitro and cellular ferritin status was evaluated by both Western blotting and immunocytochemistry. CPX was also injected into a mouse model of PKD (PKD1RC/PC2) for 27 consecutive days and disease was analyzed and compared to the vehicle injected controls for Notch signaling and ferritin (another target of CPX).

Results

CPX (0.2micro molar) inhibited cyst formation in ADPKD cells and resulted in a 40% reduction in cyst area. In vivo use of CPX in an orthologous mouse model of PKD also resulted in amelioration of cyst progression. A significant reduction in cystic index and kidney to body weight ratio was observed. However, the disease rescue did not involve Notch3 inhibition. We then focused on iron metabolism, because CPX is an iron chelator. First, we found that ferritin levels were significantly elevated in the kidney lysates from PKD mice and CPX significantly down regulated that to the level of WT mice. Human ADPKD cells were highly enriched in ferritin and CPX reduced the ferritin levels in a dose dependent manner. Since ferritinophagy is one of the known mechanisms of ferritin degradation, consistent with that we found that an autophagy marker (LC3B) and ferritinophagy marker (NCO4) dose dependently increased in ADPKD cells upon CPX treatment.

Conclusion

Our data suggest that CPX confers protection against ADPKD pathology and increased ferritinophagy is one of the mechanisms. These data also indicate that CPX, a drug used to treat skin infections and currently in clinical trials for cancer, may have the potential to treat ADPKD.

Funding

  • NIDDK Support