title: Integrated pathway analysis of rat urine metabolic profiles and kidney transcriptomic profiles to elucidate the systems toxicology of model nephrotoxicants.
abstract: In this study, approximately 40 endogenous metabolites were identified and quantified by (1)H NMR in urine samples from male rats dosed with two proximal tubule toxicants, cisplatin and gentamicin. The excreted amount of a majority of those metabolites in urine was found to be dose-dependent and exhibited a strong correlation with histopathology scores of overall proximal tubule damage. MetaCore pathway analysis software (GeneGo Inc.) was employed to identify nephrotoxicant-associated biochemical changes via an integrated quantitative analysis of both urine metabolomic and kidney transcriptomic profiles. Correlation analysis was applied to establish quantitative linkages between pairs of individual metabolite and gene transcript profiles in both cisplatin and gentamicin studies. This analysis revealed that cisplatin and gentamicin treatments were strongly linked to declines in mRNA transcripts for several luminal membrane transporters that handle each of the respective elevated urinary metabolites, such as glucose, amino acids, and monocarboxylic acids. The integrated pathway analysis performed on these studies indicates that cisplatin- or gentamicin-induced renal Fanconi-like syndromes manifested by glucosuria, hyperaminoaciduria, lactic aciduria, and ketonuria might be better explained by the reduction of functional proximal tubule transporters rather than by the perturbation of metabolic pathways inside kidney cells. Furthermore, this analysis suggests that renal transcription factors HNF1alpha, HNF1beta, and HIF-1 might be the central mediators of drug-induced kidney injury and adaptive response pathways.
authors.affiliation: Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. ethan_xu@merck.com, qiuwei_xu@merck.com
authors.forename: Ethan Yixun
authors.initials: EY
authors.lastname: Xu
authors.forename: Ally
authors.initials: A
authors.lastname: Perlina
authors.forename: Heather
authors.initials: H
authors.lastname: Vu
authors.forename: Sean P
authors.initials: SP
authors.lastname: Troth
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Brennan
authors.forename: Amy G
authors.initials: AG
authors.lastname: Aslamkhan
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Xu
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000473:pathology / Q000652:urine; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity*; D015415:Biomarkers / Q000652:urine; D002945:Cisplatin / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005839:Gentamicins / Q000633:toxicity*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008660:Metabolism; D046228:Microarray Analysis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics / Q000378:metabolism; D049490:Systems Biology / Q000379:methods; D013598:Systems Theory
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D015415:Biomarkers; D005839:Gentamicins; D051538:Hepatocyte Nuclear Factor 1-alpha; C497444:Hif1a protein, rat; C496489:Hnf1a protein, rat; C068755:Hnf1b protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C495676:Slc5a1 protein, rat; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D051539:Hepatocyte Nuclear Factor 1-beta; D002945:Cisplatin