Identification of genes involved in gentamicin-induced nephrotoxicity in rats – A toxicogenomic investigation

N, Ozaki; Matheis, Katja; Gamber, M.; Feidl, T.; Nolte, Thomas; Kalkuhl, Arno; Deschl, Ulrich

doi:10.1016/j.etp.2009.07.004

Cited by 33 publications

(30 citation statements)

References 81 publications

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“…One highly up-regulated gene in this group was caveolin 2 (＞8-fold change), which plays a key role in transcytosis of specific membrane proteins and ligands in endothelial cells (Hansen and Nichols, 2009). Additionally, our results were consistent with a previous report where described the modulation in genes related to "intracellular vesicle movement" after gentamycin-induced renal injury (Ozaki et al, 2009). …”

Section: Discussionsupporting

confidence: 82%

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Effects of Mercuric Chloride on Gene Expression in NRK-52E Cells

Ahn¹,

Baik²,

Ko³

et al. 2010

Genomics & Informatics

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Mercuric chloride, a model nephrotoxicant was used to elucidate time-and dose-dependent global gene expression changes associated with proximal tubular toxicity. Rat kidney cell lines NRK-52E cells were exposed for 2, 6 and 12 hours and with 3 different doses of mercuric chloride. Cell viability assay showed that mercuric chloride had toxic effects on NRK-52E cells causing 20% cell death (IC20) at 40μM concentration. We set this IC20 as high dose concentration and 1/5 and 1/25 concentration of LC20 were used as mid and low concentration, respectively. Analyses of microarray data revealed that 738 genes were differentially expressed (more than two-fold change and p＜0.05) by low concentration of mercuric chloride at least one time point in NRK-52E cells. 317 and 2,499 genes were differentially expressed at mid and high concentration of mercuric chloride, respectively. These deregulated genes showed a primary involvement with protein trafficking (CAV2, CANX, CORO1B), detoxification (GSTs) and immunity and defense (HMOX1, NQO1). Several of these genes were previously reported to be up-regulated in proximal tubule cells treated with nephrotoxicants and might be aid in promoting the predictive biomarkers for nephrotoxicity.

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Section: Discussionsupporting

confidence: 82%

“…Up-regulation of ATF3 mRNA was also reported previously to be induced by gentamycin treatment and after ischemic and nephrotoxic acute renal failure (Ozaki et al, 2009, Yuen et al, 2006. We detected 21 known genes common in all 3 concentration treatment group.…”

Section: Discussionmentioning

confidence: 56%

Effects of Mercuric Chloride on Gene Expression in NRK-52E Cells

Ahn¹,

Baik²,

Ko³

et al. 2010

Genomics & Informatics

View full text Add to dashboard Cite

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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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“…CyclinG1 (Ccng1) has been shown in several studies to be upregulated independently of the technology or the tested compound. 22,31,46 In addition, Compugen Ltd. identified this marker and included it into its Genes are sorted alphabetically by gene symbols. Direction of regulation is signed by an arrow.…”

Section: Discussionmentioning

confidence: 99%

An Exploratory Evaluation of the Utility of Transcriptional and Urinary Kidney Injury Biomarkers for the Prediction of Aristolochic Acid–Induced Renal Injury in Male Rats

et al. 2013

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The predictive value of different urinary and transcriptional biomarkers was evaluated in a proof-of-principle toxicology study in rats using aristolochic acid (AA), a known nephrotoxic agent. Male Wistar rats were orally dosed with 0.1, 1, or 10 mg/kg for 12 days. Urine was collected on days 1, 5, and 12 over 24 hours. Gene expression analysis was also conducted using quantitative realtime polymerase chain reaction and Illumina whole-genome chips. Protein biomarkers (Kim-1, Timp-1, vascular endothelial growth factor, osteopontin, clusterin, cystatin C, calbindin D-28K, b2-microglobulin, a-glutathione S-transferase, GSTY1b, RPA-1, and neutrophil gelatinase-associated lipocalin) were measured in these urine samples. Treatment with AA resulted in a slight dose-and/or time-dependent increase in urinary b2-microglobulin, lipocalin 2, and osteopontin before an increase in serum creatinine or serum urea nitrogen was observed. A strong decrease in urinary calbindin D-28K was also detected. The Compugen Ltd. prediction model scored both the 1-and 10-mg/kg AA dose groups as positive for nephrotoxicity despite the absence of renal histopathological changes. In addition, several previously described transcriptional biomarkers were identified as early predictors of renal toxicity as they were detected before morphological alterations had occurred. Altogether, these findings demonstrated the predictive values of renal biomarkers approved by the Food and Drug Administration, European Medicines Agency, and Pharmaceuticals & Medical Devices Agency in AA-induced renal injury in rats and confirmed the utility of renal transcriptional biomarkers for detecting progression of compound-induced renal injury in rats. In addition, several transcriptional biomarkers identified in this exploratory study could present early predictors of renal tubular epithelium injury in rats.Keywords aristolochic acid, nephrotoxicity biomarker, lipocalin 2/NGAL, osteopontin, prediction model, Nrf-2 signalingThe early detection of renal damage has been an important challenge in pharmaceutical drug development. Serum creatinine or serum urea nitrogen (SUN), the major clinicopathological markers currently employed to identify changes in kidney function, are not suitable for the early detection of acute kidney injury (AKI). Due to the functional reserve of the kidney, changes in these clinical markers appear late, when as much as two-thirds of the renal biomass has been lost. 33In the past few decades, intensive research has been conducted to identify additional more accurate biomarkers for clinical and preclinical safety assessment. 8,12 This whole process has been driven by the Predictive Safety Testing Consortium and the International Life Science Institute/Health and Environmental Sciences Institute. In the study reported here, our objective was to evaluate the predictive (observation of adverse events on a molecular basis before morphological and/or physiological alterations are established) performance of several novel urinary and transcription...

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Identification of genes involved in gentamicin-induced nephrotoxicity in rats – A toxicogenomic investigation

Cited by 33 publications

References 81 publications

Effects of Mercuric Chloride on Gene Expression in NRK-52E Cells

Effects of Mercuric Chloride on Gene Expression in NRK-52E Cells

Predictive genomic biomarkers for drug-induced nephrotoxicity in mice

An Exploratory Evaluation of the Utility of Transcriptional and Urinary Kidney Injury Biomarkers for the Prediction of Aristolochic Acid–Induced Renal Injury in Male Rats

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