In vivo comparison between two nephrotoxic agents, sodium fluoride and uranyl nitrate: phenotypic aspects and molecular mechanisms involved
Résumé
Humans can be exposed at low concentrations to nephrotoxic agents with anthropogenic and natural origins such as uranium and fluoride. Nevertheless, there is a lack of knowledge of their mechanisms of nephrotoxicity. This study aims to compare these mechanisms in mouse to identify the cellular and molecular pathways of toxicity.
C57Bl6 mice are exposed by intraperitoneal injection of uranyl nitrate (UN) (0, 2, 4, 5 mg/kg) or sodium fluoride (NaF) (0, 2, 5, 7.5, 10 mg/kg) and euthanized 48h and 72h later. Renal phenotypic aspects and biological mechanisms are evaluated by urinary biochemistry, gene and protein expressions, enzyme activity, and histological analyses. Exposure to UN and NaF induces nephrotoxicity in a dose-dependent manner. 5 mg/kg of UN induces mild histopathological alterations and respectively 44 and 6-fold increase in gene expressions of nephrotoxicity markers KIM1 and osteopontin. In comparison, 10 mg/kg of NaF induces high nephrotoxicity with histopathological alterations scored as severe and late appearing parameters of toxicity whereas 7.5 mg/kg induces mild histopathological scoring and gene expressions of KIM1 and clusterin enhanced respectively by 70 and 4-fold compared to control. No signs of nephrotoxicity are observed below 5 mg/kg of NaF. Clusterin is respectively increased by 2.4 and 4.4-fold in urines after 7.5 and 10 mg/kg injection of NaF. Apoptosis is evaluated through caspases 3/7 activity which is increased by 210% after UN treatment (5mg/kg) whereas NaF does not induce apoptosis. Inflammation is implied in UN and NaF acute nephrotoxicity as shown by gene and in situ overexpressions of ICAM and VCAM.
UN and NaF acute exposures resulted in dose and time-dependent nephrotoxicity with a higher nephrotoxicity after 72h. Inflammation and apoptosis are both involved in UN or NaF toxicity. These observations allow us to identify the mechanisms that will be studied in a low-dose exposure protocol after a chronic exposure.
Domaines
Sciences du Vivant [q-bio]
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