Renal mechanisms in type 2 diabetes: combined effects of chronic fluoride and hyperglycemia in vivo and in vitro

• Ano de defesa: 2025
• Autor(a) principal: Ribeiro, Laura
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: eng
• Instituição de defesa: Biblioteca Digitais de Teses e Dissertações da USP
• Palavras-chave em Português: Diabetes mellitus; Flúor; Fluoride; Kidney; Proteoma; Proteomics; Rim
• Link de acesso: https://www.teses.usp.br/teses/disponiveis/25/25149/tde-02122025-095754/

Fluoride (F) is widely used in dentistry to prevent dental caries, however, chronic exposure above recommended levels may pose risk to soft tissues, particularly the kidneys, which are responsible for approximately 60% of systemic F excretion. Diabetic nephrotoxicity (DN), a common complication of diabetes mellitus (DM), shares potential pathogenic mechanisms with F-induced renal damage. Nevertheless, the combined effects of chronic hyperglycemia and F exposure on kidney structure and function remain poorly understood. This study investigated morphological and proteomic changes in the kidneys of diabetic mice treated with two concentrations (10mgF/L and 50mgF/L), as well as the effects of F on murine renal tubular epithelial cells (M-1 line) under normal and hyperglycemic conditions. In vivo, diabetic C57BL/6J mice were treated with F in drinking water for 21 days following streptozotocin-induced diabetes. Diabetic groups (D0, D10, and D50) exhibited focal inflammatory infiltrates, Bowmans capsule thinning, increased PAS reactivity in the periglomerular region, mild mesangial proliferation, and perivascular fibrosis. In diabetic mice, both F treatments reduced early glomerular fibrosis as shown by collagen birefringence, yet increased KIM-1 staining, particularly in the HG+F5 group, pointed to potential renal damage. Proteomic analysis showed that low-dose F (10mgF/L) upregulated proteins associated with glycolysis, the TCA cycle, and oxidative phosphorylation, while highdose F (50mgF/L) downregulated these pathways, suggesting impaired mitochondrial function and increased oxidative stress. In vitro M-1 cells exposed to F (1µM or 5µM) under high glucose (HG) conditions showed increased cell viability and altered morphology after 72 hours, along with enhanced expression of the kidney injury marker KIM-1, especially in the HG and HG+F1 groups, indicating a possible adaptive or stress response. In conclusion, F exposure in diabetic conditions exerts dose-dependent and context-specific effects on the kidney. While low doses may trigger metabolic adaptations and reduce fibrosis, higher doses appear to impair mitochondrial function and increase cellular stress. These findings underscore the complex role of F in diabetic kidney health and support the importance of monitoring F exposure in vulnerable populations.