TY - JOUR
T1 - Sub-chronic exposure to fluoride impacts the response to a subsequent nephrotoxic treatment with gentamicin
AU - Cárdenas-González, Mariana
AU - Jacobo Estrada, Tania
AU - Rodríguez-Muñoz, Rafael
AU - Barrera-Chimal, Jonatan
AU - Bobadilla, Norma A.
AU - Barbier, Olivier C.
AU - Del Razo, Luz M.
N1 - Publisher Copyright:
© 2016 John Wiley & Sons, Ltd.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - Fluoride is an important groundwater contaminant, and more than 200 million people are exposed to high fluoride levels in drinking water, the major source of fluoride exposure. Exposure above 2ppm of fluoride is associated with renal impairment in humans. In rats, moderate levels of fluoride induce kidney injury at early stages in which the glomerular filtration rate (GFR) is not altered. In the present study, we investigated if sub-nephrotoxic stimulus induced by fluoride might impact the response to a subsequent nephrotoxic treatment with gentamicin. Male Wistar rats (~21days) were exposed to 0, 15 or 50ppm of fluoride through drinking water during 40days. Afer that, rats were co-exposed to gentamicin (40mgkg-1day-1, 7days). Gentamicin induced a marked decrease in the GFR and an increase in urinary levels as well as the protein and mRNA expression of biomarkers of early kidney injury, such as Kim-1. Interestingly, gentamicin nephrotoxicity was less pronounced in groups previously exposed to fluoride than in the group only treated with gentamicin. Fluoride induced Hsp72, a cytoprotective molecule, which might have improved the response against gentamicin. Moreover, fluoride decreased the expression of megalin, a molecule necessary for internalization of gentamicin into the proximal tubule, potentially reducing gentamicin accumulation. The present results suggest that fluoride reduced gentamicin-induced nephrotoxicity by inducing a compensatory response carried out by Hsp72 and by decreasing gentamicin accumulation. These findings should not be interpreted to suggest that fluoride is a protective agent as megalin deficiency could lead to serious adverse effects on the kidney physiology.
AB - Fluoride is an important groundwater contaminant, and more than 200 million people are exposed to high fluoride levels in drinking water, the major source of fluoride exposure. Exposure above 2ppm of fluoride is associated with renal impairment in humans. In rats, moderate levels of fluoride induce kidney injury at early stages in which the glomerular filtration rate (GFR) is not altered. In the present study, we investigated if sub-nephrotoxic stimulus induced by fluoride might impact the response to a subsequent nephrotoxic treatment with gentamicin. Male Wistar rats (~21days) were exposed to 0, 15 or 50ppm of fluoride through drinking water during 40days. Afer that, rats were co-exposed to gentamicin (40mgkg-1day-1, 7days). Gentamicin induced a marked decrease in the GFR and an increase in urinary levels as well as the protein and mRNA expression of biomarkers of early kidney injury, such as Kim-1. Interestingly, gentamicin nephrotoxicity was less pronounced in groups previously exposed to fluoride than in the group only treated with gentamicin. Fluoride induced Hsp72, a cytoprotective molecule, which might have improved the response against gentamicin. Moreover, fluoride decreased the expression of megalin, a molecule necessary for internalization of gentamicin into the proximal tubule, potentially reducing gentamicin accumulation. The present results suggest that fluoride reduced gentamicin-induced nephrotoxicity by inducing a compensatory response carried out by Hsp72 and by decreasing gentamicin accumulation. These findings should not be interpreted to suggest that fluoride is a protective agent as megalin deficiency could lead to serious adverse effects on the kidney physiology.
KW - Fluoride
KW - Gentamicin
KW - Hsp72
KW - Kidney injury
KW - Kim-1
KW - Megalin
UR - http://www.scopus.com/inward/record.url?scp=84954366996&partnerID=8YFLogxK
U2 - 10.1002/jat.3186
DO - 10.1002/jat.3186
M3 - Artículo
SN - 0260-437X
VL - 36
SP - 309
EP - 319
JO - Journal of Applied Toxicology
JF - Journal of Applied Toxicology
IS - 2
ER -