title: Evaluation of cadmium-induced nephrotoxicity using urinary metabolomic profiles in sprague-dawley male rats.
abstract: The aim of this study was to investigate urinary metabolomic profiles associated with cadmium (Cd)-induced nephrotoxicity and their potential mechanisms. Metabolomic profiles were measured by high-resolution (1)H-nuclear magnetic resonance (NMR) spectroscopy in the urine of rats after oral exposure to CdCl2 (1, 5, or 25 mg/kg) for 6 wk. The spectral data were further analyzed by a multivariate analysis to identify specific urinary metabolites. Urinary excretion levels of protein biomarkers were also measured and CdCl2 accumulated dose-dependently in the kidney. High-dose (25 mg/kg) CdCl2 exposure significantly increased serum blood urea nitrogen (BUN), but serum creatinine (sCr) levels were unchanged. High-dose CdCl2 (25 mg/kg) exposure also significantly elevated protein-based urinary biomarkers including osteopontin, monocyte chemoattractant protein-1 (MCP-1), kidney injury molecules-1 (Kim-1), and selenium-binding protein 1 (SBP1) in rat urine. Under these conditions, six urinary metabolites (citrate, serine, 3-hydroxyisovalerate, 4-hydroxyphenyllactate, dimethylamine, and betaine) were involved in mitochondrial energy metabolism. In addition, a few number of amino acids such as glycine, glutamate, tyrosine, proline, or phenylalanine and carbohydrate (glucose) were altered in urine after CdCl2 exposure. In particular, the metabolites involved in the glutathione biosynthesis pathway, including cysteine, serine, methionine, and glutamate, were markedly decreased compared to the control. Thus, these metabolites are potential biomarkers for detection of Cd-induced nephrotoxicity. Our results further indicate that redox metabolomics pathways may be associated with Cd-mediated chronic kidney injury. These findings provide a biochemical pathway for better understanding of cellular mechanism underlying Cd-induced renal injury in humans.
authors.affiliation: a College of Pharmacy, Pusan National University , Busan , Republic of Korea.
authors.forename: Yu Kyung
authors.initials: YK
authors.lastname: Lee
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Park
authors.forename: Shiwon
authors.initials: S
authors.lastname: Kim
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Son
authors.forename: Tae Hyung
authors.initials: TH
authors.lastname: Kim
authors.forename: Won Gu
authors.initials: WG
authors.lastname: Kang
authors.forename: Tae Chun
authors.initials: TC
authors.lastname: Jeong
authors.forename: Kyu-Bong
authors.initials: KB
authors.lastname: Kim
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Kwack
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.forename: Suhkmann
authors.initials: S
authors.lastname: Kim
authors.forename: Byung-Mu
authors.initials: BM
authors.lastname: Lee
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000652:urine*; D002104:Cadmium / Q000633:toxicity*; D015815:Cell Adhesion Molecules / Q000652:urine; D018932:Chemokine CCL2 / Q000652:urine; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055442:Metabolome; D015999:Multivariate Analysis; D025341:Principal Component Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D051137:Selenium-Binding Proteins / Q000652:urine
chemical_list: D015415:Biomarkers; D002104:Cadmium; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D051137:Selenium-Binding Proteins; C491766:Ccl2 protein, rat; C110936:Havcr1 protein, rat