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. 2017 Mar 4;23:1129-1140.
doi: 10.12659/msm.903217.

Gypenosides Inhibits Xanthine Oxidoreductase and Ameliorates Urate Excretion in Hyperuricemic Rats Induced by High Cholesterol and High Fat Food (Lipid Emulsion)

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Gypenosides Inhibits Xanthine Oxidoreductase and Ameliorates Urate Excretion in Hyperuricemic Rats Induced by High Cholesterol and High Fat Food (Lipid Emulsion)

Minxia Pang et al. Med Sci Monit. .
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Abstract

BACKGROUND The aim of this study was to study the effects of gypenosides (GPS) on lowering uric acid (UA) levels in hyperuricemic rats induced by lipid emulsion (LE) and the related mechanisms. GPS are natural saponins extracted from Gynostemma pentaphyllum. MATERIAL AND METHODS Forty-eight male SD rats were randomly divided into six groups: normal, model, two positive controls, and two GPS treated groups (two different doses of GPS). The normal group rats were fed a basic diet, and the other rats were orally pretreated with LE. Urine and blood were collected at regular intervals. Full automatic biochemical analyzer was used to detect the concentration levels of serum UA (SUA), serum creatinine (SCr), BUN, and urine UA (UUA), and urine creatinine (UCr) and fractional excretion of UA (FEUA). ELISA kits were used to detect enzymes activities: xanthine oxidase (XOD), adenosime deaminase (ADA), guanine deaminase (GDA), and xanthine dehydrogenase (XDH). Immunohistochemistry was used to observe kidney changes and protein (URAT1, GLUT9, and OAT1) expression levels. RT-PCR was used to detect the relevant mRNA expression levels. RESULTS Treatment with GPS significantly reduced the SUA, prevented abnormal weight loss caused by LE, and improved kidney pathomorphology. Treatment with GPS also decreased the levels of XOD, ADA, and XDH expression, increased the kidney index and FEUA, downregulated URAT1 and GLUT9 expression and upregulated OAT1 expression in the kidney. CONCLUSIONS GPS may be an effective treatment for hyperuricemia via a decrease in xanthine oxidoreductase through the XOD/XDH system; and via an increase in urate excretion through regulating URAT1, GLUT9, and OAT1 transporters.

Conflict of interest statement

Conflict of interests

The authors declare that they have no conflict of interests.

Figures

Figure 1
Figure 1
GPS effect on body weight in hyperuricemic rats (n=8). NC – normal control; LE – Lipid Emulsion contained high cholesterol and high fat food group; APC – Lipid Emulsion with positive control of Allopurinol group; BPC – Lipid Emulsion with positive control Benzobromarone group; GPS-H – Lipid Emulsion with high dose of Gypenosides (60 mg/kg body weight); GPS-L – Lipid Emulsion with low dose of Gypenosides (15 mg/kg body weight).
Figure 2
Figure 2
GPS decreased serum uric acid levels in hyperuricemic rats (n=8). NC – normal control; LE – Lipid Emulsion contained high cholesterol and high fat food group; APC – Lipid Emulsion with positive control of Allopurinol group; BPC – Lipid Emulsion with positive control Benzobromarone group; GPS-H – Lipid Emulsion with high dose of Gypenosides (60 mg/kg body weight); GPS-L – Lipid Emulsion with low dose of Gypenosides (15 mg/kg body weight). The effect of GPS on serum UA was detected at 4 (A), 6 (B), 8 (C) weeks after administration. The data were expressed as mean ±SD. # P<0.05; ## P<0.01, compared with normal control group; * P<0.05; ** P<0.01, compared with Lipid Emulsion group.
Figure 3
Figure 3
GPS promoted renal excretion of uric acid and improved renal function in hyperuricemic rats (n=8). NC – normal control; LE – Lipid Emulsion contained high cholesterol and high fat food group; APC – Lipid Emulsion with positive control of Allopurinol group; BPC – Lipid Emulsion with positive control Benzobromarone group; GPS-H – Lipid Emulsion with high dose of Gypenosides (60 mg/kg body weight); GPS-L – Lipid Emulsion with low dose of Gypenosides (15 mg/kg body weight). The effect of GPS on Urine UA (A), Urine Cr (B), Serum Cr (C), Serum BUN (E), kidney index (D) and FEUA (F) were detected at 8 weeks after administration. The data were expressed as mean ±SD. # P<0.05; ## P<0.01, compared with normal control group; * P<0.05; ** P<0.01, compared with Lipid Emulsion group.
Figure 4
Figure 4
GPS modulated the expression of mURAT1, mGLUT9 and mOAT1 in the kidney. NC – normal control; LE – Lipid Emulsion contained high cholesterol and high fat food group; APC – Lipid Emulsion with positive control of Allopurinol group; BPC – Lipid Emulsion with positive control Benzobromarone group; GPS-H – Lipid Emulsion with high dose of Gypenosides (60 mg/kg body weight); GPS-L – Lipid Emulsion with low dose of Gypenosides (15 mg/kg body weight). The effect of GPS on mURAT1 (A), mGLUT9 (B), mOAT (C) were detected at 8 weeks after administration. The data were expressed as mean ±SD. # P<0.05; ## P<0.01, compared with normal control group; * P<0.05; ** P<0.01, compared with Lipid Emulsion group.
Figure 5
Figure 5
GPS decreased serum and liver XOD, ADA, liver XDH and GDA in hyperuricemic rats (n=8). NC – normal control; LE – Lipid Emulsion contained high cholesterol and high fat food group; APC – Lipid Emulsion with positive control of Allopurinol group; BPC – Lipid Emulsion with positive control Benzobromarone group; GPS-H – Lipid Emulsion with high dose of Gypenosides (60 mg/kg body weight); GPS-L – Lipid Emulsion with low dose of Gypenosides (15 mg/kg body weight). The effect of GPS on serum XOD (A), serum ADA (C), liver XOD (B), liver ADA (D), liver GDA (E) and liver XDH (F) were detected at 8 weeks after administration. The data were expressed as mean ±SD. # P<0.05; ## P<0.01, compared with normal control group; * P<0.05; ** P<0.01, compared with Lipid Emulsion group.
Figure 6
Figure 6
Histopathological and immunohistochemical findings of URAT1, GLUT9 and OAT1 in rat’s kidney. NC – normal control; LE – Lipid Emulsion contained high cholesterol and high fat food group; APC – Lipid Emulsion with positive control of Allopurinol group; BPC – Lipid Emulsion with positive control Benzobromarone group; GPS-H – Lipid Emulsion with high dose of Gypenosides (60 mg/kg body weight); GPS-L – Lipid Emulsion with low dose of Gypenosides (15 mg/kg body weight). (A) Hematoxylin-eosin stainingof a serial section (original magnification 200×); (B) URAT1 (original magnification 400×); (C) GLUT9 (original magnification 400×); (D) OAT1 (original magnification 400×). GPS improved kidney histopathological changes in the hyperuricemic rats.
Figure 7
Figure 7
Catabolism of purine nucleotides. Xanthine oxidoreductose (XOR) catazyles the oxidation of hypoxanthine and the oxidation of xanthine to uric acid, by utilizing either NAD+ or O2. As a results of these reactions, superoxide anion (O2) and hydrogen peroxide (H2O2), are produced. XDH prefers NAD+ as the susbtrate and XOD prefers O2. Uric acid is the final oxidation product of purine (adenine and guanine) metabolism in humans and higher primates. The anti-hyperuricemia effect of GPS may be related to a decrease in Xanthine Oxidoreductase through the XOD/XDH system. “×”– inhibit.
Figure 8
Figure 8
Uric acid removal. (A) Under normal conditions, UA is the end product of purine metabolism in humans and higher primates, the average uric acid pool in the normal human body is 1200 mg, every day produce UA is about 750 mg and excrete about 500~1000 mg. About 70% of the daily turnover of uric acid humans is excreted by the kidneys, while the other 30% enters the intestine where it is further broken down by colonic bacteria and eliminated. (B) Excessive consumption of fatty and sweet foods, like high cholesterol and high fat food affect the kidney functions, and the absorption of uric acid in the proximal tubule increased or (and) secretion function decreased by renal tubular dysfunction, the serum level of uric acid will increase and hyperuricemia will occur. GPS possibly has the uricosuric activity mediated by the regulation of renal mURAT1, mGLUT9 and mOAT1 in hyperuricemic rats.

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