A Drosophila Model Identifies a Critical Role for Zinc in Mineralization for Kidney Stone Disease

Abstract

Ectopic calcification is a driving force for a variety of diseases, including kidney stones and atherosclerosis, but initiating factors remain largely unknown. Given its importance in seemingly divergent disease processes, identifying fundamental principal actors for ectopic calcification may have broad translational significance. Here we establish a Drosophila melanogaster model for ectopic calcification by inhibiting xanthine dehydrogenase whose deficiency leads to kidney stones in humans and dogs. Micro X-ray absorption near edge spectroscopy (μXANES) synchrotron analyses revealed high enrichment of zinc in the Drosophila equivalent of kidney stones, which was also observed in human kidney stones and Randall’s plaques (early calcifications seen in human kidneys thought to be the precursor for renal stones). To further test the role of zinc in driving mineralization, we inhibited zinc transporter genes in the ZnT family and observed suppression of Drosophila stone formation. Taken together, genetic, dietary, and pharmacologic interventions to lower zinc confirm a critical role for zinc in driving the process of heterogeneous nucleation that eventually leads to stone formation. Our findings open a novel perspective on the etiology of urinary stones and related diseases, which may lead to the identification of new preventive and therapeutic approaches.

Animal models of urinary stone disease

“…5) [79]. This study also demonstrated that pharmacologic inhibition of XDH with allopurinol yielded similar tubule concretions.…”

“…The conventional method to determining stone composition, Fourier Transform Infrared Spectroscopy (FTIR), demonstrated that Xdh knockdown fly stones contained xanthine [79]. However, using targeted metabolomics, these stones were also found to contain hypoxanthine.…”

“…Zinc, an essential mineral, has been identified in the formation of both human stones and Drosophila Malpighian tubule concretions [79]. Analyzing the mineral components of fly concretions, human Randall's plaques, and human xanthine stones demonstrated that calcium (Ca), magnesium (Mg) and zinc (Zn) were the major metal components within each specimen.…”

“…6) [79]. A high yeast diet -the equivalent of a high protein diet in humans e resulted in a high rate of stone formation, while a low yeast diet resulted in minimal stone formation.…”

Proteomic changes in response to crystal formation inDrosophilaMalpighian tubules

“…24 Chi et al proposed that zinc facilitates calcification given the presence of non-trace levels of zinc in fly crystals, human xanthine stones and CaOx plaques. By inhibiting zinc transporter genes a suppression of Drosophila crystals formation were observed.…”