Integrated Pathway Analysis of Rat Urine Metabolic Profiles and Kidney Transcriptomic Profiles To Elucidate the Systems Toxicology of Model Nephrotoxicants

• Published in: Chemical research in toxicology Vol. 21; no. 8; pp. 1548 - 1561
• Main Authors: Xu, Ethan Yixun, Perlina, Ally, Vu, Heather, Troth, Sean P, Brennan, Richard J, Aslamkhan, Amy G, Xu, Qiuwei
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.08.2008
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - pathology; Acute Kidney Injury - urine; Animals; Anti-Bacterial Agents - toxicity; Antineoplastic Agents - toxicity; Biomarkers - urine; Cisplatin - toxicity; Dose-Response Relationship, Drug; Gene Expression Profiling; Gene Expression Regulation - drug effects; Gentamicins - toxicity; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - metabolism; Hepatocyte Nuclear Factor 1-beta - genetics; Hepatocyte Nuclear Factor 1-beta - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - pathology; Male; Metabolism; Microarray Analysis; Rats; Rats, Sprague-Dawley; RNA, Messenger - metabolism; Sodium-Glucose Transporter 1 - genetics; Sodium-Glucose Transporter 1 - metabolism; Sodium-Glucose Transporter 2 - genetics; Sodium-Glucose Transporter 2 - metabolism; Systems Biology - methods; Systems Theory
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx800061w

In this study, approximately 40 endogenous metabolites were identified and quantified by 1H 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 HNF1α, HNF1β, and HIF-1 might be the central mediators of drug-induced kidney injury and adaptive response pathways.