In Vivo Comparison of the Phenotypic Aspects and Molecular Mechanisms of Two Nephrotoxic Agents, Sodium Fluoride and Uranyl Nitrate

Abstract

Because of their nephrotoxicity and presence in the environment, uranium (U) and fluoride (F) represent risks to the global population. There is a general lack of knowledge regarding the mechanisms of U and F nephrotoxicity and the underlying molecular pathways. The present study aims to compare the threshold of the appearance of renal impairment and to study apoptosis and inflammation as mechanisms of nephrotoxicity. C57BL/6J male mice were intraperitoneally treated with a single dose of U (0, 2, 4 and 5 mg/kg) or F (0, 2, 5, 7.5 and 10 mg/kg) and euthanized 72 h after. Renal phenotypic characteristics and biological mechanisms were evaluated by urine biochemistry, gene/protein expression, enzyme activity, and (immuno)histological analyses. U and F exposures induced nephrotoxicity in a dose-dependent manner, and the highest concentrations induced severe histopathological alterations as well as increased gene expression and urinary excretion of nephrotoxicity biomarkers. KIM-1 gene expression was induced starting at 2 mg/kg U and 7.5 mg/kg F, and this increase in expression was confirmed through in situ detection of this biomarker of nephrotoxicity. Both treatments induced inflammation as evidenced by cell adhesion molecule expression and in situ levels, whereas caspase 3/7-dependent apoptosis was increased only after U treatment. Overall, a single dose of F or U induced histopathologic evidence of nephrotoxicity renal impairment and inflammation in mice with thresholds under 7.5 mg/kg and 4 mg/kg, respectively.

A switchable sensor and scavenger: detection and removal of fluorinated chemical species by a luminescent metal–organic framework

“…1,2 However, when Fintake is beyond 0.05 mg kg -1 per day, it will become one of the most toxic and dangerous elements. [3][4][5][6] Excessive consumption of Fhas been proven to be the main cause of dental and bone fluorosis. [7][8][9][10] Chronic absorption of excess amount of Fions would cause gastric and kidney disorders and even death.…”

Fluoride-induced apoptosis in non-skeletal tissues of experimental animals: A systematic review and meta-analysis

“…8 b) and the publication bias evaluated through the Egger's test showed evidence of publication bias (Egger's regression intercept 5.41, t = 5.71, p < 0.0001). The results were unchanged after exclusion of three studies with high risk of bias [ 25 , 29 , 36 ](SMD = 4.60, 95% CI: 3.28; 5.93, Z = 6.78, p < 0.0001; I 2 = 90%, p < 0.0001; Egger's regression intercept 5.32, t = 5.16, p < 0.0001).

Fig.

…”

Environmentally Relevant Levels of Depleted Uranium Impacts Dermal Fibroblast Proliferation, Viability, Metabolic Activity, and Scratch Closure

“…We hypothesize these elevated responses in metabolism with increasing time is a byproduct of upregulated apoptosis. Previous studies on other cultured tissues at levels from 100 M to 1 mM have presented evidence for cytochrome-c and caspase-3/9 dependent necrosis [ 16 , 40 ]. However, these factors are also found to mediate intrinsic apoptosis; therefore, these same mechanisms may be responsible for the observed increase in metabolism at lower levels of UN.…”