Identification of genomic biomarkers for concurrent diagnosis of drug-induced renal tubular injury using a large-scale toxicogenomics database

Kondo, Chiaki; Minowa, Yohsuke; Uehara, Takeki; Okuno, Yasushi; Nakatsu, Noriyuki; Ono, Atsushi; Maruyama, Toshiyuki; Kato, Ikuo; Yamate, Jyoji; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro

doi:10.1016/j.tox.2009.09.003

Cited by 57 publications

(26 citation statements)

References 23 publications

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“…Ceruloplasmin protects tissue damage from oxidative injury via its oxido-reductive activity by inhibiting conversion of Fe (III) (ferric) to Fe (II) (ferrous) states of iron in the Fenton reaction resulting in (1) decreased lipid peroxidation, (2) suppression of hydroxyl radicals, and (3) diminished generation of other free radicals, also known as reactive oxygen species (ROS) [28,29] . Increased expression of kidney ceruloplasmin has been reported in uranium-induced nephrotoxicity [30,31] , cisplastin-induced nephrotoxicity [32] and other toxic insults to the kidney, including the uremic complications of chronic kidney disease [33,34] . The critical role of the organ-specific ceruloplasmin in protecting organ damage is highlighted by the condition of aceruloplasminemia, in which many tissues show tissue damage, probably from oxidative injury [35] .…”

Section: Resultsmentioning

confidence: 99%

In Diabetic Kidney Disease Urinary Exosomes Better Represent Kidney Specific Protein Alterations Than Whole Urine

et al. 2015

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Background: Predicting or diagnosing underlying kidney disease by analyzing whole urine remains the mainstay of nephrology practice. However, whole urine is a poor compartment to assess many structural changes in the kidney because whole urine contains only a few proteins derived from the kidney itself. Urinary exosomes, on the other hand, which are derived from the kidney, contain proteins secreted by the kidney. We experimentally tested the hypothesis that ‘urinary exosomes more faithfully represent changes in the kidney tissue than whole urine'. A direct comparison between whole urine and urine exosomal levels of two chosen kidney disease markers, gelatinase and ceruloplasmin, was carried out on diabetic kidney disease patients. Methods: Urinary exosomes were separated from whole urine by sequential centrifugation including ultra-centrifugation. Gelatinase activity was measured using fluorosceinated gelatin as the substrate, and ceruloplasmin was measured by sandwich ELISA. A few kidney specimens from patients biopsied for atypical features were histochemically stained for validation of the biochemical results. Results: We found that changes in both, gelatinase (decreased activity) and ceruloplasmin (increased levels), in the urinary exosomes of diabetic kidney patients were in agreement with the alterations of these two proteins in the kidney tissue. In contrast, the levels of these two proteins in whole urine were highly variable and did not correlate with levels in the diabetic kidney tissue. Conclusion: In conclusion, these results confirmed our hypothesis that protein markers in urinary exosomes better reflected the underlying protein changes in the kidney than in whole urine samples.

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Section: Resultsmentioning

confidence: 99%

In Diabetic Kidney Disease Urinary Exosomes Better Represent Kidney Specific Protein Alterations Than Whole Urine

et al. 2015

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“…By applying a toxicogenomic approach, researchers can determine how gene expression responses to exposure to toxic substances are linked to toxic outcome, a process called phenotypic anchoring (Paules, 2003). Toxicogenomics can also be used to identify molecular targets and biomarker genes, and has been used to investigate hepatotoxicity (Harrill et al, 2009;Heinloth et al, 2004;Hirode et al, 2009;Kiyosawa et al, 2007;Uehara et al, 2008Low et al, 2011), nephrotoxicity (Huang et al, 2001;Kharasch et al, 2006;Kondo et al, 2009;Luhe et al, 2003;Ozaki et al, 2010), and cardiotoxicity (Mori et al, 2010). A large number of toxicogenomic studies have focused on the nephrotoxicity of various prototypical compounds in rats.…”

Section: Introductionmentioning

confidence: 99%

Predictive genomic biomarkers for drug-induced nephrotoxicity in mice

et al. 2012

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-The present study aimed to establish candidate biomarker genes for the early detection of nephrotoxicity in mice, with a particular focus on nephrotoxicity caused by polyene macrolides. Comprehensive gene expression changes were evaluated using microarrays in a mouse model in which acute nephrotoxicity was induced by amphotericin B deoxycholate, trade name Fungizone. The upregulated genes identified through microarray analysis of kidney tissue of Fungizone-treated mice included several genes that have been reported as nephrotoxicity biomarkers in rats, and 14 genes were selected as candidate nephrotoxicity biomarkers. The usefulness of these genes as nephrotoxicity biomarkers in mice was evaluated further through expression profiling under several experimental conditions using real time RT-PCR. Expression of genes encoding kidney injury molecule 1, lipocalin 2, tissue inhibitor of metalloproteinase 1, and secreted phosphoprotein 1 was highly upregulated by Fungizone, nystatin, natamycin, amphotericin B methyl ester, and liposomal amphotericin B, and their area under the ROC curve values were more than 0.95. These genes were more sensitive at detecting nephrotoxicity than traditional clinical chemistry and histopathology parameters. This study provides novel evidence that these nephrotoxicity biomarker genes identified are translatable to mice, and that they are useful for early and sensitive detection of nephrotoxicity.

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“…Among these, Kim-1 was the most quantitatively upregulated. In addition, several studies have also demonstrated renal expression changes of genes encoding acute kidney injury biomarkers in response to injury induced by a variety of nephrotoxicants: Kim-1, metallopeptidase inhibitor 1 (TIMP1), clusterin, osteopontin, and neutrophil gelatinase-associated lipocalin/lipocalin 2 (NGAL) (Ichimura et al, 2004;Rached et al, 2008;Wang et al, 2008;Zhou et al, 2008;Kondo et al, 2009). 4.1.5.2.…”

Section: "Omics" Technologiesmentioning

confidence: 99%

Review of current and “omics” methods for assessing the toxicity (genotoxicity, teratogenicity and nephrotoxicity) of herbal medicines and mushrooms

Ouédraogo

Baudoux

Stévigny

et al. 2012

Journal of Ethnopharmacology

124

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Identification of genomic biomarkers for concurrent diagnosis of drug-induced renal tubular injury using a large-scale toxicogenomics database

Cited by 57 publications

References 23 publications

In Diabetic Kidney Disease Urinary Exosomes Better Represent Kidney Specific Protein Alterations Than Whole Urine

In Diabetic Kidney Disease Urinary Exosomes Better Represent Kidney Specific Protein Alterations Than Whole Urine

Predictive genomic biomarkers for drug-induced nephrotoxicity in mice

Review of current and “omics” methods for assessing the toxicity (genotoxicity, teratogenicity and nephrotoxicity) of herbal medicines and mushrooms

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