Combined effects of chronic high glucose and fluoride exposure on kidney cells: exploratory in vitro and in vivo study

Fluoride is commonly used in dentistry to prevent dental caries, however, excessive exposure may pose risks to soft tissues, particularly the kidneys, which are responsible for approximately 60% of fluoride excretion. Diabetic nephropathy, a major complication of diabetes mellitus, may share pathogenic pathways with fluoride-induced renal toxicity. However, the combined effects of chronic hyperglycemia and fluoride exposure on kidney cells remain poorly understood. This study investigated the effects of fluoride on murine renal tubular epithelial cells (M-1) and on murine kidneys under normal and hyperglycemic conditions. M-1 cells were cultured under high-glucose conditions (22.5 mM) and/or treated with fluoride (1 µM or 5 µM) for 24 to 72 h. Diabetic C57BL/6J mice received drinking water containing fluoride (10 mgF/L or 50 mgF/L) for 21 days. Evaluations included cell viability and morphology in vitro, collagen deposition in renal tissue by birefringence analysis, and expression of the kidney injury marker KIM-1 by immunofluorescence in both models. M-1 cells exposed to fluoride alone showed increased viability at 72 h, while KIM-1 expression was elevated in high-glucose and high-glucose + 1 µM fluoride conditions, suggesting a stress or adaptive response. In diabetic mice, glomerular collagen accumulation, indicative of early fibrosis, was observed but attenuated by fluoride treatment. However, high KIM-1 levels in fluoride-treated diabetic mice, particularly at the higher dose, indicated potential kidney injury. These results highlight a complex, dual role of F in the diabetic kidney, potentially protecting against glomerular fibrosis while exacerbating tubular injury at high doses. Careful monitoring of F exposure is needed, especially in areas with endemic fluorosis and high chronic kidney disease risk.