Uranyl nitrate inhibits lactate gluconeogenesis in isolated human and mouse renal proximal tubules: a 13C-NMR study.
As part of a study on uranium nephrotoxicity, we investigated the effect of uranyl nitrate in isolated human and mouse kidney cortex tubules metabolizing the physiological substrate lactate. In the millimolar range, uranyl nitrate reduced lactate removal and gluconeogenesis and the cellular ATP level in a dose-dependent fashion. After incubation in phosphate-free Krebs-Henseleit medium with 5 mM L-[1-13C]-, or L-[2-13C]-, or L-[3-13C]lactate, substrate utilization and product formation were measured by enzymatic and NMR spectroscopic methods. In the presence of 3 mM uranyl nitrate, glucose production and the intracellular ATP content were significantly reduced in both human and mouse tubules. Combination of enzymatic and NMR measurements with a mathematical model of lactate metabolism revealed an inhibition of fluxes through lactate dehydrogenase and the gluconeogenic enzymes in the presence of 3 mM uranyl nitrate; in human and mouse tubules, fluxes were lowered by 20% and 14% (lactate dehydrogenase), 27% and 32% (pyruvate carboxylase), 35% and 36% (phosphoenolpyruvate carboxykinase), and 39% and 45% (glucose-6-phosphatase), respectively. These results indicate that natural uranium is an inhibitor of renal lactate gluconeogenesis in both humans and mice.
Renault
Sophie
S
Métabolomique et Maladies Métaboliques, Institut National de la Santé et de la recherche Médicale, Unit #820, Faculté de Médecine R.T.H. Laennec, Université de Lyon, 7-11 rue G. Paradin, 69372 Lyon Cedex 08, France.
Faiz
Hassan
H
Gadet
Rudy
R
Ferrier
Bernard
B
Martin
Guy
G
Baverel
Gabriel
G
Conjard-Duplany
Agnès
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D005943:Gluconeogenesis / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D014502:Uranyl Nitrate / Q000494:pharmacology*
D000596:Amino Acids; D014502:Uranyl Nitrate; D019344:Lactic Acid; D000255:Adenosine Triphosphate