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
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
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Research Article Nephrology

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

Abstract

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.

Authors

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

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Figure 4

CPX-O inhibits ferritin accumulation in the cystic and interstitial cells in ADPKD kidneys.

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CPX-O inhibits ferritin accumulation in the cystic and interstitial cell...
(A) IHC for ferritin in 7-week-old WT and PKD mouse sections treated with vehicle (Veh) or CPX-O. Note (arrowheads) accumulation of ferritin-positive cells near cystic areas in PKD mice. Ferritin-positive cells were reduced in kidneys of CPX-O–treated PKD mice. Scale bar: 100 μm. (B) Western blot (WB) of kidney lysates for ferritin (top) and quantification of ferritin expression relative to the Ponceau S expression (lower) in vehicle- and CPX-O–treated PKD mice in contrast to vehicle- and CPX-O–treated WT mice (n = 3 per group). (C) IHC was performed in NHK and ADPKD kidney for ferritin expression. Arrowheads indicate high ferritin in both cyst epithelium and interstitial cells. Original magnification, ×20. (D) WB for ferritin using lysates of primary cells from normal (n = 3) or ADPKD (n = 3). Quantification of ferritin expression normalized to Ponceau S is shown in the right panel. Data presented as relative fold change in ferritin ± SEM. (Unpaired Student’s 2-tailed t test, *P < 0.05.)