MP25-10 A CRITICAL ROLE FOR ZINC IN INITIATING URINARY STONE FORMATION IDENTIFIED IN A DROSOPHILA MELANOGASTER MODEL

Abstract

You have accessJournal of UrologyStone Disease: Basic Research II1 Apr 2014MP25-10 A CRITICAL ROLE FOR ZINC IN INITIATING URINARY STONE FORMATION IDENTIFIED IN A DROSOPHILA MELANOGASTER MODEL Thomas Chi, Man Su Kim, Tiffany Zee, Sven Lang, Gulinuer Muteliefu, Andrew Vinson, Sarah Blaschko, David Killilea, Katja Bruckner, Arnold Kahn, Pankaj Kapahi, and Marshall Stoller Thomas ChiThomas Chi More articles by this author , Man Su KimMan Su Kim More articles by this author , Tiffany ZeeTiffany Zee More articles by this author , Sven LangSven Lang More articles by this author , Gulinuer MuteliefuGulinuer Muteliefu More articles by this author , Andrew VinsonAndrew Vinson More articles by this author , Sarah BlaschkoSarah Blaschko More articles by this author , David KillileaDavid Killilea More articles by this author , Katja BrucknerKatja Bruckner More articles by this author , Arnold KahnArnold Kahn More articles by this author , Pankaj KapahiPankaj Kapahi More articles by this author , and Marshall StollerMarshall Stoller More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.312AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Calcium hydroxyapatite is thought to serve as a nidus for mineralized deposits leading to kidney stones; initiators of this process are poorly understood. A Drosophila model for urinary stone disease was used to identify novel targets for modulating urinary stone formation. Fly model findings were then confirmed with human tissue. This model revealed that zinc (Zn2+) is present in both Drosophila Malpighian tubule stones and human renal stones and plays a potential critical role in initiating urinary stones. METHODS A targeted double-knockdown screen to identify genes that mitigated stone formation was developed in a fly model. To confirm these genetic findings, targeted drug feeds were utilized to demonstrate inhibition of stone formation. Fly and human stone samples were then analyzed utilizing synchrotron radiation based techniques. RESULTS We found that upon xanthine dehydrogenase (Xdh) inhibition, flies fed a high protein diet formed 70% more stones compared to controls. The presence of hydroxyapatite in these stones was confirmed with a bisphosphonate dye stain, establishing that fly stones were similar on a structural level to human urinary stones. Xdh suppression provided a knockdown candidate with a strong, modifiable phenotype for further study. Targeted screening of 50 genes of interest was performed with concurrent inhibition of each gene with Xdh suppression. This identified 10 suppressors of stone formation. A renal zinc transporter in the ZnT family conferred the greatest rescue, increasing lifespan from 3 to 12 days (p < 0.05) and decreasing the percentage of tubule lumen occupied by stones from 36.0 ± 1.9 to 19.5 ± 2.8 (p < 0.001). This finding was replicated with zinc chelation drug feeds. To better understand the mechanism by which zinc exerted its influence, synchrotron radiation-based analysis was applied, demonstrating the presence of Zn2+ in both Drosophila and human stones. CONCLUSIONS Zn2+ plays an important, previously unrecognized structural role in the initiation of human kidney stones. This was supported with both genetic and pharmacologic modulation of zinc transport in our Drosophila model. Manipulation of Zn2+ could be leveraged as a therapeutic target for the treatment of nephrolithiasis. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e270 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Thomas Chi More articles by this author Man Su Kim More articles by this author Tiffany Zee More articles by this author Sven Lang More articles by this author Gulinuer Muteliefu More articles by this author Andrew Vinson More articles by this author Sarah Blaschko More articles by this author David Killilea More articles by this author Katja Bruckner More articles by this author Arnold Kahn More articles by this author Pankaj Kapahi More articles by this author Marshall Stoller More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...