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Ginsenoside Rg5 Ameliorates Cisplatin-Induced Nephrotoxicity in Mice through Inhibition of Inflammation, Oxidative Stress, and Apoptosis

View Article: PubMed Central - PubMed

ABSTRACT

Although cisplatin is an effective anti-cancer agent that is widely used for treating various types of malignant solid tumors, the nephrotoxicity induced by cisplatin severely limits its clinical application. The present study was designed to explore the potential protective effect of ginsenoside Rg5, a rare ginsenoside generated during steaming ginseng, on cisplatin-induced nephrotoxicity in a mouse experimental model. The possible mechanisms underlying this nephroprotective effect were also investigated for the first time. Rg5 was given at doses of 10 and 20 mg/kg for 10 consecutive days. On Day 7, a single nephrotoxic dose of cisplatin (25 mg/kg) was injected to mice. Cisplatin administration resulted in renal dysfunction as evidenced by increase in serum creatinine (CRE) and blood urea nitrogen (BUN) levels. In addition, cisplatin increased the level of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), the makers of lipid peroxidation, and depleted glutathione (GSH) content and superoxide dismutase (SOD) activity in renal tissues. These effects were associated with the significantly increased levels of cytochrome P450 E1 (CYP2E1), 4-hydroxynonenal (4-HNE), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, nuclear factor-kappa B (NF-κB) p65, and cyclooxygenase-2 (COX-2) in renal tissues. However, pretreatment with ginsenoside Rg5 significantly attenuated the renal dysfunction, oxidative stress and inflammation response induced by cisplatin. Furthermore, ginsenoside Rg5 supplementation inhibited activation of apoptotic pathways through increasing Bcl-2 and decreasing Bax expression levels. Histopathological examination further confirmed the nephroprotective effect of Rg5. Collectively, these results clearly suggest that Rg5-mediated alleviation of cisplatin-induced nephrotoxicity may be related to its anti-oxidant, anti-apoptotic and anti-inflammatory effects.

No MeSH data available.


Effects of ginsenoside Rg5 on the expression of 4-hydroxynonenal (4-HNE). The expression level of 4-HNE (Red) in macrophages isolated from different groups was assessed by immunofluorescence. Representative immunofluorescence images were taken at 400×. 4’,6-Diamidino-2-phenylindole (DAPI) (blue) was used as a nuclear counterstain.
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nutrients-08-00566-f005: Effects of ginsenoside Rg5 on the expression of 4-hydroxynonenal (4-HNE). The expression level of 4-HNE (Red) in macrophages isolated from different groups was assessed by immunofluorescence. Representative immunofluorescence images were taken at 400×. 4’,6-Diamidino-2-phenylindole (DAPI) (blue) was used as a nuclear counterstain.

Mentions: As mentioned earlier, oxidative stress damage is involved in the mechanisms of cisplatin-induced nephrotoxicity [34]. As shown in Figure 3, cisplatin exposure resulted in dramatic decrease of GSH content and SOD activity along with increase of MDA, compared to the normal group (p < 0.01). In contrast, pretreatment with 10 and 20 mg/kg of ginsenoside Rg5 for 10 days significantly decreased MDA level and restored the antioxidant status as demonstrated by increase in GSH content and SOD activity (p < 0.05). These data suggest that ginsenoside Rg5 alleviated oxidative injury in kidney via up-regulating anti-oxidant enzyme activity. Concomitantly, the expression of the CYP2E1 metabolizing enzyme, which was increased by cisplatin, was reduced by Rg5 in a dose-dependent manner (Figure 4). These results suggest that administration of Rg5 protects the kidneys from cisplatin-induced oxidative stress. To verify whether oxidative stress is related to the development of cisplatin-induced nephrotoxicity in vivo, lipid peroxidation was confirmed using 4-HNE staining. At 72 h after cisplatin treatment, strong 4-HNE fluorescence intensities were detected in the tubular epithelium of the kidney of mice treated with cisplatin alone. However, Rg5 pretreatment for seven days significantly decreased fluorescence intensities, especially in the group with dosage of 20 mg/kg. The sites of lipid peroxidation were highly correlated with the necrotic regions in the kidney. Consistent with the 4-HNE staining, quantitative MDA analysis showed an increase of lipid peroxidation after cisplatin exposure, but this was significantly blocked by pretreatment with Rg5 (Figure 5).


Ginsenoside Rg5 Ameliorates Cisplatin-Induced Nephrotoxicity in Mice through Inhibition of Inflammation, Oxidative Stress, and Apoptosis
Effects of ginsenoside Rg5 on the expression of 4-hydroxynonenal (4-HNE). The expression level of 4-HNE (Red) in macrophages isolated from different groups was assessed by immunofluorescence. Representative immunofluorescence images were taken at 400×. 4’,6-Diamidino-2-phenylindole (DAPI) (blue) was used as a nuclear counterstain.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5037551&req=5

nutrients-08-00566-f005: Effects of ginsenoside Rg5 on the expression of 4-hydroxynonenal (4-HNE). The expression level of 4-HNE (Red) in macrophages isolated from different groups was assessed by immunofluorescence. Representative immunofluorescence images were taken at 400×. 4’,6-Diamidino-2-phenylindole (DAPI) (blue) was used as a nuclear counterstain.
Mentions: As mentioned earlier, oxidative stress damage is involved in the mechanisms of cisplatin-induced nephrotoxicity [34]. As shown in Figure 3, cisplatin exposure resulted in dramatic decrease of GSH content and SOD activity along with increase of MDA, compared to the normal group (p < 0.01). In contrast, pretreatment with 10 and 20 mg/kg of ginsenoside Rg5 for 10 days significantly decreased MDA level and restored the antioxidant status as demonstrated by increase in GSH content and SOD activity (p < 0.05). These data suggest that ginsenoside Rg5 alleviated oxidative injury in kidney via up-regulating anti-oxidant enzyme activity. Concomitantly, the expression of the CYP2E1 metabolizing enzyme, which was increased by cisplatin, was reduced by Rg5 in a dose-dependent manner (Figure 4). These results suggest that administration of Rg5 protects the kidneys from cisplatin-induced oxidative stress. To verify whether oxidative stress is related to the development of cisplatin-induced nephrotoxicity in vivo, lipid peroxidation was confirmed using 4-HNE staining. At 72 h after cisplatin treatment, strong 4-HNE fluorescence intensities were detected in the tubular epithelium of the kidney of mice treated with cisplatin alone. However, Rg5 pretreatment for seven days significantly decreased fluorescence intensities, especially in the group with dosage of 20 mg/kg. The sites of lipid peroxidation were highly correlated with the necrotic regions in the kidney. Consistent with the 4-HNE staining, quantitative MDA analysis showed an increase of lipid peroxidation after cisplatin exposure, but this was significantly blocked by pretreatment with Rg5 (Figure 5).

View Article: PubMed Central - PubMed

ABSTRACT

Although cisplatin is an effective anti-cancer agent that is widely used for treating various types of malignant solid tumors, the nephrotoxicity induced by cisplatin severely limits its clinical application. The present study was designed to explore the potential protective effect of ginsenoside Rg5, a rare ginsenoside generated during steaming ginseng, on cisplatin-induced nephrotoxicity in a mouse experimental model. The possible mechanisms underlying this nephroprotective effect were also investigated for the first time. Rg5 was given at doses of 10 and 20 mg/kg for 10 consecutive days. On Day 7, a single nephrotoxic dose of cisplatin (25 mg/kg) was injected to mice. Cisplatin administration resulted in renal dysfunction as evidenced by increase in serum creatinine (CRE) and blood urea nitrogen (BUN) levels. In addition, cisplatin increased the level of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), the makers of lipid peroxidation, and depleted glutathione (GSH) content and superoxide dismutase (SOD) activity in renal tissues. These effects were associated with the significantly increased levels of cytochrome P450 E1 (CYP2E1), 4-hydroxynonenal (4-HNE), tumor necrosis factor (TNF)-&alpha;, interleukin (IL)-1&beta;, nuclear factor-kappa B (NF-&kappa;B) p65, and cyclooxygenase-2 (COX-2) in renal tissues. However, pretreatment with ginsenoside Rg5 significantly attenuated the renal dysfunction, oxidative stress and inflammation response induced by cisplatin. Furthermore, ginsenoside Rg5 supplementation inhibited activation of apoptotic pathways through increasing Bcl-2 and decreasing Bax expression levels. Histopathological examination further confirmed the nephroprotective effect of Rg5. Collectively, these results clearly suggest that Rg5-mediated alleviation of cisplatin-induced nephrotoxicity may be related to its anti-oxidant, anti-apoptotic and anti-inflammatory effects.

No MeSH data available.