title: Cadmium chloride inhibits lactate gluconeogenesis in mouse renal proximal tubules: An in vitro metabolomic approach with (13)C NMR.
abstract: Using isolated mouse renal proximal tubules incubated with lactate as substrate, we have found that the addition of 1-50 μM cadmium chloride (CdCl2) caused a concentration-dependent decrease in lactate utilization, in glucose production and in the cellular level of ATP, coenzyme A, acetyl-coenzyme A and glutathione (reduced and oxidized forms). Combining enzymatic and (13)C NMR measurements in a cellular metabolomic approach, we have shown that, in the presence of 10 μM CdCl2, fluxes through the key-enzymes of gluconeogenesis, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase were greatly depressed by cadmium. This was accompanied by a reduction in fluxes through the enzymes of the tricarboxylic acid cycle. Comparing the mouse and human renal metabolic responses to cadmium, it is interesting to observe that the mouse renal proximal tubule was much more sensitive than the human renal proximal tubule to the adverse effects of CdCl2. As far as renal gluconeogenesis is concerned, the mouse seems to be an appropriate and convenient animal model to study the mechanism of cadmium nephrotoxicity. However, the data obtained in the mouse should be extrapolated to humans with caution because the inhibition of fluxes through the enzymes of the tricarboxylic acid cycle in mouse tubules were not observed in human tubules.
authors.affiliation: Equipe d'accueil 4611, Biochimie et Physiopathologie Métaboliques, Faculté de Médecine Lyon Est, Université de Lyon, Lyon, France.
authors.forename: Hassan
authors.initials: H
authors.lastname: Faiz
authors.affiliation: Equipe d'accueil 4611, Biochimie et Physiopathologie Métaboliques, Faculté de Médecine Lyon Est, Université de Lyon, Lyon, France.
authors.forename: Michelle
authors.initials: M
authors.lastname: Boghossian
authors.affiliation: Equipe d'accueil 4611, Biochimie et Physiopathologie Métaboliques, Faculté de Médecine Lyon Est, Université de Lyon, Lyon, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Martin
authors.affiliation: Metabolys, Inc, Faculté de Médecine Lyon Est, Lyon, France.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Baverel
authors.affiliation: Equipe d'accueil 4611, Biochimie et Physiopathologie Métaboliques, Faculté de Médecine Lyon Est, Université de Lyon, Lyon, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Ferrier
authors.affiliation: Equipe d'accueil 4611, Biochimie et Physiopathologie Métaboliques, Faculté de Médecine Lyon Est, Université de Lyon, Lyon, France. Electronic address: agnes.duplany@univ-lyon1.fr.
authors.forename: Agnès
authors.initials: A
authors.lastname: Conjard-Duplany
mesh_terms: D000818:Animals; D019256:Cadmium Chloride / Q000008:administration & dosage / Q000494:pharmacology*; D002247:Carbon Isotopes; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects* / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000502:physiology; D019344:Lactic Acid / Q000378:metabolism*; D055432:Metabolomics / Q000379:methods*; D051379:Mice
chemical_list: D002247:Carbon Isotopes; D019344:Lactic Acid; D019256:Cadmium Chloride
keywords: (13)C NMR; Cadmium; Lactate; Metabolism; Mouse; Nephrotoxicity