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Rutin mitigates fluoride-induced nephrotoxicity by inhibiting ROS-mediated lysosomal membrane permeabilization and
Yue Ma1, Panpan Xu1, Hengrui Xing1
1Department of Preventive Medicine, School of Medicine, Shihezi University, Shihezi, Xinjiang, People's Republic of China; Key Laboratory for Prevention and Control of Emerging Infectious Diseases and Public Health Security, the Xinjiang Production and Construction Corps, Shihezi, Xinjiang, People's Republic of China; Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi, Xinjiang, People's Republic of China; NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases(First Affiliated Hospital, School of Medicine, Shihezi University), People's Republic of China.
Abstract:
Fluoride is known to induce nephrotoxicity; however, the underlying mechanisms remain incompletely understood. Therefore, this study aims to explore the roles and mechanisms of lysosomal membrane permeabilization (LMP) and the GSDME/HMGB1 axis in fluoride-induced nephrotoxicity and the protective effects of rutin. Rutin, a naturally occurring flavonoid compound known for its antioxidative and anti-inflammatory properties, is primarily mediated by inhibiting oxidative stress and reducing proinflammatory markers. To that end, we established in vivo and in vitro models. In the in vivo study, rats were exposed to sodium fluoride (NaF) throughout pregnancy and up until 2 months after birth. In parallel, we employed in vitro models using HK-2 cells treated with NaF, n-acetyl-L-cysteine (NAC), or rutin. We assessed lysosomal permeability through immunofluorescence and analyzed relevant protein expression via western blotting. Our findings showed that NaF exposure increased ROS levels, resulting in enhanced LMP and increased cathepsin B (CTSB) and D (CTSD) expression. Furthermore, the exposure to NaF resulted in the upregulation of cleaved PARP1, cleaved caspase-3, GSDME-N, and HMGB1 expressions, indicating cell death and inflammation-induced renal damage. Rutin mitigates fluoride-induced nephrotoxicity by suppressing ROS-mediated LMP and the GSDME/HMGB1 axis, ultimately preventing fluoride-induced renal toxicity occurrence and development. In conclusion, our findings suggest that NaF induces renal damage through ROS-mediated activation of LMP and the GSDME/HMGB1 axis, leading to pyroptosis and inflammation. Rutin, a natural antioxidative and anti-inflammatory dietary supplement, offers a novel approach to prevent and treat fluoride-induced nephrotoxicity.
Insights
Sodium fluoride (NaF) causes kidney damage by increasing oxidative stress, lysosomal membrane permeabilization (LMP), and pyroptosis via the GSDME/HMGB1 pathway. The natural compound rutin protects against this fluoride-induced nephrotoxicity.
Area of Science:
- Toxicology
- Cell Biology
- Biochemistry
Background:
- Fluoride exposure is a known cause of kidney damage (nephrotoxicity), but the exact mechanisms are not fully understood.
- Lysosomal membrane permeabilization (LMP) and the Gasdermin E (GSDME)/High-mobility group box 1 (HMGB1) signaling pathway are implicated in cellular damage and inflammation.
Purpose of the Study:
- To investigate the roles of LMP and the GSDME/HMGB1 axis in fluoride-induced nephrotoxicity.
- To explore the protective effects of rutin, a natural flavonoid, against fluoride-induced kidney damage.
Main Methods:
- Established in vivo (rat models) and in vitro (HK-2 cells) models of fluoride exposure.
- Assessed lysosomal permeability using immunofluorescence and analyzed protein expression (e.g., CTSB, CTSD, GSDME, HMGB1, caspase-3) via western blotting.
- Measured reactive oxygen species (ROS) levels to evaluate oxidative stress.
Main Results:
- Sodium fluoride (NaF) exposure increased ROS levels, leading to enhanced LMP and elevated expression of cathepsin B (CTSB) and D (CTSD).
- NaF upregulated cleaved PARP1, cleaved caspase-3, GSDME-N, and HMGB1, indicating pyroptosis and inflammation-induced renal damage.
- Rutin administration suppressed ROS production, mitigated LMP, and inhibited the GSDME/HMGB1 axis, thereby reducing fluoride-induced nephrotoxicity.
Conclusions:
- Fluoride induces renal damage through ROS-mediated activation of LMP and the GSDME/HMGB1 pathway, resulting in pyroptosis and inflammation.
- Rutin demonstrates significant protective effects against fluoride-induced nephrotoxicity by targeting oxidative stress and inflammatory pathways.
- Rutin represents a potential therapeutic strategy for preventing and treating fluoride-induced kidney damage.
