A Drosophila melanogaster model identifies a critical role for zinc in initiating urinary stone formation. Thomas Chi¹, Man Su Kim², Nichole Bond¹, Sven Lang³, Joe Miller¹, Gulinuer Muteliefu³, Katja Bruckner¹, Arnie Kahn³, Marshall Stoller¹, Pankaj Kapahi³. 1) UCSF, San Francisco, CA; 2) College of Pharmacy, Inje University, Republic of Korea; 3) Buck Institute for Research on Aging, Novato, CA.

   Ectopic biomineralization is a driving force for kidney stones and other disorders where calcium hydroxyapatite is believed to serve as a nidus for mineralized deposits leading to calcification. Initiating factors for the calcification process are poorly understood. We developed a Drosophila model for urinary stone disease and screened for genetic inhibitors of stone formation. Here we show that zinc (Zn²⁺) is present in both Drosophila melanogaster Malpighian tubule stones and human renal biopsy material and plays a critical role in initiating urinary stones. We screened mineralization-associated human disease genes for their ability to induce stones in fly tubules. Upon xanthine dehydrogenase (Xdh) inhibition, flies formed 70% more stones compared to controls. Hydroxyapatite was confirmed in fly stones with a fluorescent bisphosphonate dye stain. Targeted screening of 50 genes of interest was then performed using concurrent inhibition with Xdh suppression. This identified 10 suppressors that mitigated fly stone formation. A member of the ZnT zinc transporter family conferred the greatest rescue, replicated with zinc chelation drug feeds. To better understand the mechanism by which zinc exerted its effects, synchrotron radiation-based analysis was performed on stone samples. This demonstrated the presence of Zn²⁺ in both Drosophila and human stones, implying that Zn²⁺ plays an important, previously unrecognized structural role in the initiation of human kidney stones. Our results implicate Zn²⁺ as a critical component for initiating stone formation whose manipulation could be leveraged as a therapeutic target. This work demonstrates for the first time translational utility of a genetically based Drosophila model for urinary stone disease with implications of applicability across multiple diseases involving ectopic biomineralization.