title: Sub-chronic exposure to fluoride impacts the response to a subsequent nephrotoxic treatment with gentamicin.
abstract: 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 2 ppm 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 (~21 days) were exposed to 0, 15 or 50 ppm of fluoride through drinking water during 40 days. Afer that, rats were co-exposed to gentamicin (40 mg kg(-1) day(-1), 7 days). 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.
authors.affiliation: Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), México, D. F., Mexico.
authors.forename: Mariana
authors.initials: M
authors.lastname: Cárdenas-González
authors.affiliation: Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), México, D. F., Mexico.
authors.forename: Tania
authors.initials: T
authors.lastname: Jacobo Estrada
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), México, D. F., Mexico.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rodríguez-Muñoz
authors.affiliation: Unidad de Fisiología Molecular. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, D. F., Mexico.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Barrera-Chimal
authors.affiliation: Unidad de Fisiología Molecular. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, D. F., Mexico.
authors.forename: Norma A
authors.initials: NA
authors.lastname: Bobadilla
authors.affiliation: Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), México, D. F., Mexico.
authors.forename: Olivier C
authors.initials: OC
authors.lastname: Barbier
authors.affiliation: Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), México, D. F., Mexico.
authors.forename: Luz M
authors.initials: LM
authors.lastname: Del Razo
mesh_terms: D000818:Animals; D005459:Fluorides / Q000633:toxicity*; D005839:Gentamicins / Q000633:toxicity*; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects*; D007687:Kidney Tubules, Proximal / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000139:chemically induced*
chemical_list: D005839:Gentamicins; D005459:Fluorides
keywords: Hsp72; Kim‐1; fluoride; gentamicin; kidney injury; megalin