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A Drosophila model identifies a critical role for zinc in mineralization for kidney stone disease.

Chi T, Kim MS, Lang S, Bose N, Kahn A, Flechner L, Blaschko SD, Zee T, Muteliefu G, Bond N, Kolipinski M, Fakra SC, Mandel N, Miller J, Ramanathan A, Killilea DW, Brückner K, Kapahi P, Stoller ML - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of California San Francisco, San Francisco, California, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Drosophila concretions, human Randall’s plaques, and human kidney stones show enrichment of zinc.(A) Micro-X-ray fluorescence (μXRF) maps of Da-GAL4, UAS-Xdh RNAi /+ concretions (left panel, scale bar: 10 μm) and human Randall’s plaques (right panel, scale bar: 100 μm) demonstrate the presence of zinc in red and calcium in green. (B) μXRF elemental analysis of the samples from (A) demonstrate similar elemental composition for both Da-GAL4, UAS-Xdh RNAi /+ concretions (left panel) and human Randall’s plaques (right panel), including the presence of calcium (Ca), iron (Fe), and zinc (Zn). (C) Transmission electron microscopy imaging of concretions in the lumen of the Malpighian tubule demonstrates the presence of ring-like structures, as indicated by the yellow arrows (left panel, scale bar: 500 μm). Ring structures with homologous appearance are seen in Randall’s plaques taken from a human renal papilla biopsy material (right panel, scale bar: 100 μm) when imaged in a similar fashion. (D) ICP-OES analysis of pooled fly concretion samples from 300 dissected tubule specimens demonstrates the presence of calcium (Ca), magnesium (Mg), and zinc (Zn) (left panel, n = 2 biological replicates). These levels are mirrored in human xanthine stone samples (right panel, n = 2 biological replicates). Data shown are the mean ± SEM.
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pone.0124150.g002: Drosophila concretions, human Randall’s plaques, and human kidney stones show enrichment of zinc.(A) Micro-X-ray fluorescence (μXRF) maps of Da-GAL4, UAS-Xdh RNAi /+ concretions (left panel, scale bar: 10 μm) and human Randall’s plaques (right panel, scale bar: 100 μm) demonstrate the presence of zinc in red and calcium in green. (B) μXRF elemental analysis of the samples from (A) demonstrate similar elemental composition for both Da-GAL4, UAS-Xdh RNAi /+ concretions (left panel) and human Randall’s plaques (right panel), including the presence of calcium (Ca), iron (Fe), and zinc (Zn). (C) Transmission electron microscopy imaging of concretions in the lumen of the Malpighian tubule demonstrates the presence of ring-like structures, as indicated by the yellow arrows (left panel, scale bar: 500 μm). Ring structures with homologous appearance are seen in Randall’s plaques taken from a human renal papilla biopsy material (right panel, scale bar: 100 μm) when imaged in a similar fashion. (D) ICP-OES analysis of pooled fly concretion samples from 300 dissected tubule specimens demonstrates the presence of calcium (Ca), magnesium (Mg), and zinc (Zn) (left panel, n = 2 biological replicates). These levels are mirrored in human xanthine stone samples (right panel, n = 2 biological replicates). Data shown are the mean ± SEM.

Mentions: Drosophila fly stones were analyzed using micro X-ray fluorescence (μXRF) mapping to determine their elemental compositions. μXRF mapping at 11keV with 15 micron / pixel and 2.5 micron / pixel resolution demonstrated the consistent presence of both calcium (Ca) and Zn in each specimen (Fig 2A). μXRF spectra recorded at 14 keV of randomly selected regions of the samples demonstrated an abundance of Ca and Zn, with trace amounts of iron (Fig 2B).


A Drosophila model identifies a critical role for zinc in mineralization for kidney stone disease.

Chi T, Kim MS, Lang S, Bose N, Kahn A, Flechner L, Blaschko SD, Zee T, Muteliefu G, Bond N, Kolipinski M, Fakra SC, Mandel N, Miller J, Ramanathan A, Killilea DW, Brückner K, Kapahi P, Stoller ML - PLoS ONE (2015)

Drosophila concretions, human Randall’s plaques, and human kidney stones show enrichment of zinc.(A) Micro-X-ray fluorescence (μXRF) maps of Da-GAL4, UAS-Xdh RNAi /+ concretions (left panel, scale bar: 10 μm) and human Randall’s plaques (right panel, scale bar: 100 μm) demonstrate the presence of zinc in red and calcium in green. (B) μXRF elemental analysis of the samples from (A) demonstrate similar elemental composition for both Da-GAL4, UAS-Xdh RNAi /+ concretions (left panel) and human Randall’s plaques (right panel), including the presence of calcium (Ca), iron (Fe), and zinc (Zn). (C) Transmission electron microscopy imaging of concretions in the lumen of the Malpighian tubule demonstrates the presence of ring-like structures, as indicated by the yellow arrows (left panel, scale bar: 500 μm). Ring structures with homologous appearance are seen in Randall’s plaques taken from a human renal papilla biopsy material (right panel, scale bar: 100 μm) when imaged in a similar fashion. (D) ICP-OES analysis of pooled fly concretion samples from 300 dissected tubule specimens demonstrates the presence of calcium (Ca), magnesium (Mg), and zinc (Zn) (left panel, n = 2 biological replicates). These levels are mirrored in human xanthine stone samples (right panel, n = 2 biological replicates). Data shown are the mean ± SEM.
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Related In: Results  -  Collection

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pone.0124150.g002: Drosophila concretions, human Randall’s plaques, and human kidney stones show enrichment of zinc.(A) Micro-X-ray fluorescence (μXRF) maps of Da-GAL4, UAS-Xdh RNAi /+ concretions (left panel, scale bar: 10 μm) and human Randall’s plaques (right panel, scale bar: 100 μm) demonstrate the presence of zinc in red and calcium in green. (B) μXRF elemental analysis of the samples from (A) demonstrate similar elemental composition for both Da-GAL4, UAS-Xdh RNAi /+ concretions (left panel) and human Randall’s plaques (right panel), including the presence of calcium (Ca), iron (Fe), and zinc (Zn). (C) Transmission electron microscopy imaging of concretions in the lumen of the Malpighian tubule demonstrates the presence of ring-like structures, as indicated by the yellow arrows (left panel, scale bar: 500 μm). Ring structures with homologous appearance are seen in Randall’s plaques taken from a human renal papilla biopsy material (right panel, scale bar: 100 μm) when imaged in a similar fashion. (D) ICP-OES analysis of pooled fly concretion samples from 300 dissected tubule specimens demonstrates the presence of calcium (Ca), magnesium (Mg), and zinc (Zn) (left panel, n = 2 biological replicates). These levels are mirrored in human xanthine stone samples (right panel, n = 2 biological replicates). Data shown are the mean ± SEM.
Mentions: Drosophila fly stones were analyzed using micro X-ray fluorescence (μXRF) mapping to determine their elemental compositions. μXRF mapping at 11keV with 15 micron / pixel and 2.5 micron / pixel resolution demonstrated the consistent presence of both calcium (Ca) and Zn in each specimen (Fig 2A). μXRF spectra recorded at 14 keV of randomly selected regions of the samples demonstrated an abundance of Ca and Zn, with trace amounts of iron (Fig 2B).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of California San Francisco, San Francisco, California, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus