JCI Insight (Apr 2021)

Ciclopirox olamine induces ferritinophagy and reduces cyst burden in polycystic kidney disease

  • Priyanka S. Radadiya,
  • Mackenzie M. Thornton,
  • Rajni V. Puri,
  • Sireesha Yerrathota,
  • Johnny Dinh-Phan,
  • Brenda Magenheimer,
  • Dharmalingam Subramaniam,
  • Pamela V. Tran,
  • Hao Zhu,
  • Subhashini Bolisetty,
  • James P. Calvet,
  • Darren P. Wallace,
  • Madhulika Sharma

Journal volume & issue
Vol. 6, no. 8

Abstract

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Despite the recent launch of tolvaptan, the search for safer polycystic kidney disease (PKD) drugs continues. Ciclopirox (CPX) or its olamine salt (CPX-O) is contained in a number of commercially available antifungal agents. CPX is also reported to possess anticancer activity. Several mechanisms of action have been proposed, including chelation of iron and inhibition of iron-dependent enzymes. Here, we show that CPX-O inhibited in vitro cystogenesis of primary human PKD cyst-lining epithelial cells cultured in a 3D collagen matrix. To assess the in vivo role of CPX-O, we treated PKD mice with CPX-O. CPX-O reduced the kidney-to-body weight ratios of PKD mice. The CPX-O treatment was also associated with decreased cell proliferation, decreased cystic area, and improved renal function. Ferritin levels were markedly elevated in cystic kidneys of PKD mice, and CPX-O treatment reduced renal ferritin levels. The reduction in ferritin was associated with increased ferritinophagy marker nuclear receptor coactivator 4, which reversed upon CPX-O treatment in PKD mice. Interestingly, these effects on ferritin appeared independent of iron. These data suggest that CPX-O can induce ferritin degradation via ferritinophagy, which is associated with decreased cyst growth progression in PKD mice. Most importantly these data indicate that CPX-O has the potential to treat autosomal dominant PKD.

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