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

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

doi:10.1172/jci.insight.141299

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.

Highlights

Polycystic kidney disease (PKD) is a genetic disease characterized by multiple cysts in the kidneys, which enlarge over time and lead to end-stage renal disease
To first validate whether CPX-O may be a drug of choice for PKD in the clinic, and whether further mouse studies are required to validate it, we performed 3D cyst assays using primary autosomal dominant polycystic kidney disease (ADPKD) renal epithelial cells [33]
To determine whether decreased cystic area resulted from CPX-O toxicity, cell viability was determined with increasing concentrations of CPX in ADPKD cells as well as in cells obtained from normal human kidney (NHK) over 6 days in culture

Summary

Introduction

Polycystic kidney disease (PKD) is a genetic disease characterized by multiple cysts in the kidneys, which enlarge over time and lead to end-stage renal disease. About 85% of ADPKD cases have mutations in polycystin 1 (PC1) and the remaining 15% in polycystin 2 (PC2) (proteins encoded by PKD1 and PKD2, respectively) [1, 2]. Both PC1 and PC2 have been found to be localized to cilia. Decreased intracellular Ca2+ levels in ADPKD kidney cells in combination with activation of adenylate cyclase and accumulation of cAMP lead to increased proliferation and fluid secretion and contribute to enlargement of cysts [3,4,5,6]. Many signaling pathways have been shown to be deregulated in response to loss-offunction mutations in PKD [2, 3, 7, 8]

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Results

Conclusion