title: 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.
authors.affiliation: Department of Urology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Chi
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Republic of Korea; The Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Man Su
authors.initials: MS
authors.lastname: Kim
authors.affiliation: The Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Sven
authors.initials: S
authors.lastname: Lang
authors.affiliation: The Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Neelanjan
authors.initials: N
authors.lastname: Bose
authors.affiliation: The Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Arnold
authors.initials: A
authors.lastname: Kahn
authors.affiliation: Department of Urology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Flechner
authors.affiliation: Department of Urology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Blaschko
authors.affiliation: The Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Zee
authors.affiliation: The Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Gulinuer
authors.initials: G
authors.lastname: Muteliefu
authors.affiliation: The Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Nichole
authors.initials: N
authors.lastname: Bond
authors.affiliation: The Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Marysia
authors.initials: M
authors.lastname: Kolipinski
authors.affiliation: The Advanced Light Source, Lawrence Berkeley National Lab, Berkeley, California, United States of America.
authors.forename: Sirine C
authors.initials: SC
authors.lastname: Fakra
authors.affiliation: Department of Medicine, Division of Nephrology, Medical College of Wisconsin, Zablocki VA Medical Center, Milwaukee, Wisconsin, United States of America.
authors.forename: Neil
authors.initials: N
authors.lastname: Mandel
authors.affiliation: Department of Urology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Joe
authors.initials: J
authors.lastname: Miller
authors.affiliation: The Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Arvind
authors.initials: A
authors.lastname: Ramanathan
authors.affiliation: Nutrition & Metabolism Center, Children's Hospital Oakland Research Institute, Oakland, California, United States of America.
authors.forename: David W
authors.initials: DW
authors.lastname: Killilea
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California, United States of America; Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, California, United States of America; Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Katja
authors.initials: K
authors.lastname: Brückner
authors.affiliation: The Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Kapahi
authors.affiliation: Department of Urology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Marshall L
authors.initials: ML
authors.lastname: Stoller
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D004044:Dietary Proteins / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005029:Ethylenediamines / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007669:Kidney Calculi / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008317:Malpighian Tubules / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D056928:X-Ray Absorption Spectroscopy; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D002614:Chelating Agents; D004044:Dietary Proteins; D029721:Drosophila Proteins; D005029:Ethylenediamines; D034741:RNA, Small Interfering; D000493:Allopurinol; D014968:Xanthine Dehydrogenase; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine