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
View: Text | PDF
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

×

Figure 6

CPX-O induces ferritinophagy in primary cyst epithelial cells from patients with ADPKD.

Options: View larger image (or click on image) Download as PowerPoint
CPX-O induces ferritinophagy in primary cyst epithelial cells from patie...
(A) WBs for LC3B-II, and NCOA4, on kidney lysates of 7-week-old WT (n = 3) and PKD (n = 4) mice treated with vehicle (veh) or CPX-O. (B) Quantification of LC3B-II from A and expression normalized to Ponceau S and expressed as relative expression ± SEM. (C) Quantification of NCOA4 expression from A normalized to Ponceau S and expressed as relative expression ± SEM. (D) Total intracellular iron fold change in ADPKD primary cyst epithelial cells (n = 4) relative to NHK primary cells (n = 3) ± SEM. (E) Cyst-lining epithelial cells from a patient with ADPKD were grown to form cysts on a 3D system using collagen matrix in the presence of FSK and EGF for 5 days followed by treatment with vehicle, CPX-O (5 μM), holoferritin (50 μg/mL), apoferritin (50 μg/mL), holoferritin + CPX-O, and apoferritin + CPX-O for 6 additional days. Cysts were fixed, imaged, and measured. Cyst size is represented as surface area/cm2 (n = 6/treatment). One-way ANOVA followed by Tukey’s HSD test was used for statistical analyses of all graphs except D, where unpaired Student’s 2-tailed t test was used (*P < 0.05, **P < 0.01, ****P < 0.0001).