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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 (?XANES) 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.

SUBMITTER: Chi T

PROVIDER: S-EPMC4430225 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Chi Thomas T Kim Man Su MS Lang Sven S Bose Neelanjan N Kahn Arnold A Flechner Lawrence L Blaschko Sarah D SD Zee Tiffany T Muteliefu Gulinuer G Bond Nichole N Kolipinski Marysia M Fakra Sirine C SC Mandel Neil N Miller Joe J Ramanathan Arvind A Killilea David W DW Brückner Katja K Kapahi Pankaj P Stoller Marshall L ML

PloS one 20150513 5

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 ...[more]

PMID: 25970330

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Project description:Individuals with autosomal dominant polycystic kidney disease have a higher incidence of stone formation than the general population. However, there are no cystic animal models known to develop stones. Cystic mice compound heterozygous for hypomorphic Pkd1V and Pkd1RC alleles develop cystic kidneys within a few weeks of birth but live beyond 20 wk of age, allowing for the study of cystic comorbidities including stone formation. Cystic Pkd1V/RC mice were euthanized at 3, 13, or 26 wk of age, and their kidneys were analyzed by microcomputed tomography (µCT) for stone formation. Mice had occasional mineral aggregates that could be detected by µCT analysis at 3 wk of age. At 13 or 26 wk of age, numerous white masses were visible beneath the kidney surface. µCT analysis confirmed the masses to be large mineral stone deposits throughout the renal cortex, with mineral content increasing with age. Staining of histological sections with alizarin red and von Kossa suggested that the stone deposits were composed primarily of calcium and phosphate. Microdissection confirmed stones localized within cyst lumens. Analysis of individual stones by µCT and infrared spectroscopy confirmed apatite mineral composition. Urinalysis revealed elevated levels of phosphate and citrate at 3 wk of age and lower pH and elevated levels of calcium and citrate at 13 wk of age, suggesting altered phosphate and calcium homeostasis as a potential cause of mineralization and renal stone formation. This is the first animal model exhibiting overt kidney stone formation in the context of cystic kidney disease.NEW & NOTEWORTHY Compound heterozygous Pkd1V/RC mice were found to form calcium phosphate-containing stones within cysts of the renal cortex by 13 wk of age. This is the first polycystic kidney disease animal model exhibiting spontaneous stone formation. A growing body of evidence suggests a link between renal stone formation and cystic kidney disease. This mouse model may be useful for studying the interplay between stone and cyst formation and the functional role of polycystins in mineral homeostasis.

Project description:BackgroundKidney stone disease (KSD) is a multifactorial disease involving both environmental and genetic factors, whose pathogenesis remains unclear. This study aims to explore the hub genes related to stone formation that could serve as potential therapeutic targets.MethodsBased on the GSE73680 dataset with 62 samples, differentially expressed genes (DEGs) between Randall's plaque (RP) tissues and normal tissues were screened and weighted gene co-expression network analysis (WGCNA) was applied to identify key modules associated with KSD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to explore the biological functions. The protein-protein interaction (PPI) network was constructed to identify hub genes. Meanwhile, CIBERSORT and ssGSEA analysis were used to estimate the infiltration level of the immune cells. The correlations between hub genes and immune infiltration levels were also investigated. Finally, the top hub gene was selected for further GSEA analysis.ResultsA total of 116 DEGs, including 73 up-regulated and 43 down-regulated genes, were screened in the dataset. The red module was identified as the key module correlated with KSD. 53 genes were obtained for functional enrichment analysis by taking the intersection of DEGs and genes in the red module. GO analysis showed that these genes were mainly involved in extracellular matrix organization (ECM) and extracellular structure organization, and others. KEGG analysis revealed that the pathways of aldosterone-regulated sodium reabsorption, cell adhesion molecules, arachidonic acid (AA) metabolism, and ECM-receptor interaction were enriched. Through PPI network construction, 30 hub genes were identified. CIBERSORT analysis revealed a significantly increased proportion of M0 macrophages, while ssGSEA revealed no significant differences. Among these hub genes, SPP1, LCN2, MMP7, MUC1, SCNN1A, CLU, SLP1, LAMC2, and CYSLTR2 were positively correlated with macrophages infiltration. GSEA analysis found that positive regulation of JNK activity was enriched in RP tissues with high SPP1 expression, while negative regulation of IL-1β production was enriched in the low-SPP1 subgroup.ConclusionsThere are 30 hub genes associated with KSD, among which SPP1 is the top hub gene with the most extensive links with other hub genes. SPP1 might play a pivotal role in the pathogenesis of KSD, which is expected to become a potential therapeutic target, while its interaction with macrophages in KSD needs further investigation.

Project description:BackgroundKidney stones or nephrolithiasis is a chronic metabolic disease characterized by renal colic and hematuria. Currently, a pathogenetic mechanism resulting in kidney stone formation remains elusive. We performed a multi-omic study investigating urinary microbial compositions and metabolic alterations during nephrolithiasis.MethodUrine samples from healthy and individuals with nephrolithiasis were collected for 16S rRNA gene sequencing and liquid chromatography-mass spectroscopy. Microbiome and metabolome profiles were analyzed individually and combined to construct interactome networks by bioinformatic analysis.ResultsDistinct urinary microbiome profiles were determined in nephrolithiasis patients compared with controls. Thirty-nine differentially abundant taxa between controls and nephrolithiasis patients were identified, and Streptococcus showed the most significant enrichment in nephrolithiasis patients. We also observed significantly different microbial compositions between female and male nephrolithiasis patients. The metabolomic analysis identified 112 metabolites that were differentially expressed. Two significantly enriched metabolic pathways, including biosynthesis of unsaturated fatty acids and tryptophan metabolism, were also identified in nephrolithiasis patients. Four potentially diagnostic metabolites were also identified, including trans-3-hydroxycotinine, pyroglutamic acid, O-desmethylnaproxen, and FAHFA (16:0/18:2), and could function as biomarkers for the early diagnosis of nephrolithiasis. We also identified three metabolites that contributed to kidney stone size. Finally, our integrative analysis of the urinary tract microbiome and metabolome identified distinctly different network characteristics between the two groups.ConclusionsOur study has characterized important profiles and correlations among urinary tract microbiomes and metabolomes in nephrolithiasis patients for the first time. These results shed new light on the pathogenesis of nephrolithiasis and could provide early clinical biomarkers for diagnosing the disease.

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

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

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