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

PLoS One

Man Su Kim¹  Marshall L. Stoller²  Joe Miller³  Tiffany Zee⁴  Thomas Chi⁴  Arvind Ramanathan⁴  Sarah D. Blaschko⁴  Pankaj Kapahi⁵  Katja Brückner⁶  Neil Mandel⁷  Gulinuer Muteliefu⁸  Marysia Kolipinski⁸  Sirine C. Fakra⁸  Sven Lang⁸  Arnold Kahn⁸  Neelanjan Bose⁸  David W. Killilea⁸  Lawrence Flechner⁸  Nichole Bond⁸ 

[1] College of Pharmacy, Inje University, Gimhae, Republic of Korea;Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, California, United States of America;Department of Medicine, Division of Nephrology, Medical College of Wisconsin, Zablocki VA Medical Center, Milwaukee, Wisconsin, United States of America;Department of Urology, University of California San Francisco, San Francisco, California, United States of America;Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California, United States of America;Nutrition & Metabolism Center, Children’s Hospital Oakland Research Institute, Oakland, California, United States of America;The Advanced Light Source, Lawrence Berkeley National Lab, Berkeley, California, United States of America;The Buck Institute for Research on Aging, Novato, California, United States of America

关键词: Zinc;    Calcification;    RNA interference;    Drosophila melanogaster;    Kidney stones;    Zinc transporters;    Diet;    Absorption spectroscopy;   

DOI  :  10.1371/journal.pone.0124150

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY