Contribution à l’étude de la néphrotoxicité de sels d’uranium dans les tubules rénaux proximaux humains et murins : apport de la spectroscopie RMN du 13C

Abstract : As part of a study on uranium nephrotoxicity, we investigated the effect of uranyl nitrate and acetate in isolated human and mouse kidney cortex tubules metabolizing the physiological substrate lactate. In the millimolar range, uranyl nitrate and acetate reduced 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]-, ou L-[2-13C]-, ou 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 reduced 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 effects were associated with a 12% and 36 % decrease in the cellular content of glutathione in human and mouse tubules, respectively. Contrary to what expected because phosphate was supposed to facilitate the entry of uranium, the addition of phosphate in the medium did not enhance the inhibitory effect of 3 mM uranyl nitrate on gluconeogenesis in isolated mouse tubules
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Sophie Renault. Contribution à l’étude de la néphrotoxicité de sels d’uranium dans les tubules rénaux proximaux humains et murins : apport de la spectroscopie RMN du 13C. Médecine humaine et pathologie. Université Claude Bernard - Lyon I, 2009. Français. ⟨NNT : 2009LYO10197⟩. ⟨tel-02156081⟩

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