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 2

CPX-O ameliorates disease progression in a mouse model of ADPKD.

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CPX-O ameliorates disease progression in a mouse model of ADPKD. (A) Exp...
(A) Experimental timeline where 22-day-old PKD or WT mice were intraperitoneally injected with vehicle or CPX-O (10 mg/kg body weight) for 27 consecutive days until P49. At P50, mice were euthanized and samples were collected. (B) H&E staining of kidney sections. Representative images of each treatment group are shown. (C) Renal cystic index of vehicle-treated (n = 7) and CPX-O–treated (n = 8) PKD mice, presented as percentage cystic area ± SEM. (D) Kidney-to-body weight ratio from vehicle- or CPX-O–treated WT mice (n = 5 each) and from vehicle-treated (n = 7) or CPX-treated (n = 8) PKD mice. (E) Blood urea nitrogen values measured as mg/dL ± SEM from hemolysis-free serum samples of vehicle- and CPX-O–treated WT mice (n = 5 each) or from vehicle- and CPX-O–treated PKD mice (n = 5 and n = 8, respectively). Statistical significance was determined using unpaired Student’s 2-tailed t test (C) or 1-way ANOVA followed by Tukey’s HSD test (D and E) (*P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001). Scale bar: 1 mm.