Objective:To investigate the protective effect of grape seed proanthocyanidin extract(GSPE) on fluoride-induced nephrotoxicity and study the possible role of the nuclear factor E2-related factor 2 (Nrf2) signaling pathway.Methods:Twenty-four male Sprague-Dawley (SD) rats (aged 8 weeks, weighing 240 - 260 g) were randomly divided into four groups using a random number table: control group, GSPE group, sodium fluoride (NaF) group, and NaF + GSPE group, with 6 rats in each group. The control group was fed a standard diet for 28 d. The GSPE group was administered GSPE (100 mg/kg) via gavage daily for 28 d. The NaF group was fed a standard diet for 7 d, followed by NaF solution (600 mg/kg) for 21 d. A drinking-water-borne fluorosis rat model was established. The NaF + GSPE group was pretreated with GSPE (100 mg/kg) for 7 d follwed by NaF solution (600 mg/kg) for 21 d. At the end of the experiment, the levels of renal oxidative stress were assessed by measuring malondialdehyde (MDA) and reduced glutathione (GSH) levels, catalase (CAT) and superoxide dismutase (SOD) activities. Renal function was evaluated by analyzing the levels of serum creatinine (Cr), blood urea nitrogen (BUN), and Urea. Renal pathological changes and apoptosis levels were examined using hematoxylin-eosin (HE) staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, respectively. Additionally, the expression levels of Nrf2 signaling pathway-related proteins [Nrf2, heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO-1), and caspase-3] were detected by Western blot.Results:Compared with the control group, the NaF group had higher level of renal MDA, lower level of GSH, and lower activities of CAT and SOD( P < 0.001). Compared with the NaF group, the NaF + GSPE group had lower level of renal MDA, higher level of GSH, and higher activities of CAT and SOD ( P < 0.001). The serum Cr, BUN, and Urea levels were significantly elevated in the NaF group compared to the control group ( P < 0.001), while these parameters were significantly reduced in the NaF + GSPE group relative to the NaF group ( P < 0.001). The HE staining results showed that the glomerular volume increased and the basement membrane thickened; renal tubules disruption of cellular structure, with degeneration, dilation, or shedding of renal tubular epithelial cells; inflammatory cell infiltration can be seen in the renal interstitium in the NaF group of rats. Compared with the NaF group, the pathological changes in the NaF + GSPE group were significantly improved. The TUNEL results showed that the apoptosis rates of renal cells in the NaF and NaF + GSPE groups [(26.82 ± 2.25)%, (12.83 ± 1.32)%] were higher than those in the control group [(6.22 ± 0.62)%, P < 0.001], and in the NaF + GSPE group was lower than that in the NaF group ( P < 0.001). Compared with the control group, the NaF group showed expression levels of Nrf2 (nuclear), HO-1, NQO-1, activated caspase-3 protein were higher, while the expression level of Nrf2 (cytoplasmic) protein was lower. Compared with the NaF group, the NaF + GSPE group had higher expression levels of Nrf2 (nuclear, cytoplasmic), HO-1, and NQO-1 proteins, and lower expression level of activated caspase-3 protein ( P < 0.001). Conclusion:GSPE can alleviate the nephrotoxicity induced by fluoride, which may be related to activating the Nrf2 signaling pathway to enhance the body's antioxidant capacity and reduce the level of renal cell apoptosis.

Objective:To investigate the protective effect of grape seed proanthocyanidin extract(GSPE) on fluoride-induced nephrotoxicity and study the possible role of the nuclear factor E2-related factor 2 (Nrf2) signaling pathway.Methods:Twenty-four male Sprague-Dawley (SD) rats (aged 8 weeks, weighing 240 - 260 g) were randomly divided into four groups using a random number table: control group, GSPE group, sodium fluoride (NaF) group, and NaF + GSPE group, with 6 rats in each group. The control group was fed a standard diet for 28 d. The GSPE group was administered GSPE (100 mg/kg) via gavage daily for 28 d. The NaF group was fed a standard diet for 7 d, followed by NaF solution (600 mg/kg) for 21 d. A drinking-water-borne fluorosis rat model was established. The NaF + GSPE group was pretreated with GSPE (100 mg/kg) for 7 d follwed by NaF solution (600 mg/kg) for 21 d. At the end of the experiment, the levels of renal oxidative stress were assessed by measuring malondialdehyde (MDA) and reduced glutathione (GSH) levels, catalase (CAT) and superoxide dismutase (SOD) activities. Renal function was evaluated by analyzing the levels of serum creatinine (Cr), blood urea nitrogen (BUN), and Urea. Renal pathological changes and apoptosis levels were examined using hematoxylin-eosin (HE) staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, respectively. Additionally, the expression levels of Nrf2 signaling pathway-related proteins [Nrf2, heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO-1), and caspase-3] were detected by Western blot.Results:Compared with the control group, the NaF group had higher level of renal MDA, lower level of GSH, and lower activities of CAT and SOD( P < 0.001). Compared with the NaF group, the NaF + GSPE group had lower level of renal MDA, higher level of GSH, and higher activities of CAT and SOD ( P < 0.001). The serum Cr, BUN, and Urea levels were significantly elevated in the NaF group compared to the control group ( P < 0.001), while these parameters were significantly reduced in the NaF + GSPE group relative to the NaF group ( P < 0.001). The HE staining results showed that the glomerular volume increased and the basement membrane thickened; renal tubules disruption of cellular structure, with degeneration, dilation, or shedding of renal tubular epithelial cells; inflammatory cell infiltration can be seen in the renal interstitium in the NaF group of rats. Compared with the NaF group, the pathological changes in the NaF + GSPE group were significantly improved. The TUNEL results showed that the apoptosis rates of renal cells in the NaF and NaF + GSPE groups [(26.82 ± 2.25)%, (12.83 ± 1.32)%] were higher than those in the control group [(6.22 ± 0.62)%, P < 0.001], and in the NaF + GSPE group was lower than that in the NaF group ( P < 0.001). Compared with the control group, the NaF group showed expression levels of Nrf2 (nuclear), HO-1, NQO-1, activated caspase-3 protein were higher, while the expression level of Nrf2 (cytoplasmic) protein was lower. Compared with the NaF group, the NaF + GSPE group had higher expression levels of Nrf2 (nuclear, cytoplasmic), HO-1, and NQO-1 proteins, and lower expression level of activated caspase-3 protein ( P < 0.001). Conclusion:GSPE can alleviate the nephrotoxicity induced by fluoride, which may be related to activating the Nrf2 signaling pathway to enhance the body's antioxidant capacity and reduce the level of renal cell apoptosis.