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.

Nephroprotective Effect of Cilastatin against Gentamicin-Induced Renal Injury In Vitro and In Vivo without Altering Its Bactericidal Efficiency

“…Our results are consistent with these observations, showing increased HSP-27 and decreased HSP-70 in the kidneys after treatment with gentamicin. Cilastatin restored the levels of both HSPs, thus helping to mitigate the effect of gentamicin, as other authors have shown [ 35 ].…”

“…Indeed, there is a direct relationship between the presence of stress and activation/inhibition of HSPs [ 16 ] and in several models of nephrotoxicity, HSP-27 is overexpressed owing to its antioxidant and antiapoptotic role [ 33 ]. Likewise, HSP-70 has a reduced function when gentamicin specifically binds to it, which has been linked to increased renal toxicity [ 34 , 35 ]. Our results are consistent with these observations, showing increased HSP-27 and decreased HSP-70 in the kidneys after treatment with gentamicin.…”

“…It is well known that gentamicin-induced AKI occurs mainly after accumulation of the drug inside the cells [ 1 , 2 , 5 , 7 , 8 ] and that megalin plays a critical role in binding and the uptake of gentamicin in RPTECs [ 5 , 7 , 35 , 36 ]. In fact, it has been proposed as the main route for the entry and accumulation of gentamicin and therefore the main target in the prevention of gentamicin-induced nephrotoxicity [ 1 , 2 , 5 , 7 , 35 , 36 , 37 ]. Very recently, Hori et al concluded that the megalin blockade with cilastatin efficiently suppresses the nephrotoxicity induced by antibiotics (gentamicin, colistin and vancomycin) and chemotherapy agents (cisplatin), although they could not determine the Kd value for binding gentamicin, cisplatin or cilastatin to megalin [ 36 ].…”

Pharmacokinetics and Toxicokinetics Roles of Membrane Transporters at Kidney Level

“…However, there is evidence that accumulation of this element causes various adverse effects in human tissue (82). The kidney, as the main organ in excretion of F, undergoes toxicity by accumulation of renal tubular cells, resulting in oxidative stress and peroxidation of the cell membrane lipids (83,84). Fluoride induces various (82,84).…”

Fluoride Exposure Induces Inhibition of Sodium/Iodide Symporter (NIS) Contributing to Impaired Iodine Absorption and Iodine Deficiency: Molecular Mechanisms of Inhibition and Implications for Public Health

“…Thus, inhibition of megalin or Na+, K+-ATPase can lead to depletion of iodine stores and iodine deficiency. While there are no studies in literature examining the relationship between F exposure in humans and megalin expression, recently it has been found in animal models that chronic F exposure inhibits megalin expression [217]. It has been observed in animal studies that a decrease in megalin expression leads to a decrease in proximal tubule albumin (ALB) reabsorption [218], leading to enhanced urinary excretion.…”