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Protective effects of cortex fraxini coumarines against oxonate-induced hyperuricemia and renal dysfunction in mice
Jian-Mei Li1, Xian Zhang, Xing Wang
1State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China.
Abstract:
The aim of the present study was to investigate the effects of cortex fraxini coumarines esculetin, esculin, fraxetin and fraxin on renal dysfunction and expression abnormality of renal organic ion transporters in hyperuricemic animals. Mice were orally given 250 mg/kg oxonate for seven consecutive days to induce hyperuricemia and renal dysfunction. After 1h of oxonate induction daily, animals were orally treated with esculetin, esculin, fraxetin and fraxin at 20 and 40 mg/kg, respectively. Esculetin, esculin, fraxetin and fraxin significantly decreased serum urate, creatinine and blood urea nitrogen levels and increased urine urate and creatinine excretion in hyperuricemic mice. Esculetin and esculin up-regulated expressions of renal organic anion transporter 1 (mOAT1), organic cation and carnitine transporters (mOCT1-2 and mOCTN1-2), but failed to affect renal glucose transporter 9 (mGLUT9) and urate transporter 1 (mURAT1) in this model. Fraxetin specifically inhibited renal mURAT1, while fraxin extensively interacted with renal mGLUT9, mURAT1, mOAT1 and mOCT1 in hyperuricemic mice. Furthermore, esculetin, fraxetin and fraxin increased mABCG2 mRNA expression and decreased its protein levels in renal apical membrane in hyperuricemic mice. These results indicate that esculetin and esculin have beneficial effects on hyperuricemia and renal dysfunction, resulting in restoration of mOAT1, mOCT1-2 and mOCTN1-2, and fraxetin and fraxin enhance urate excretion partly by inhibiting mURAT1 or mGLUT9 in kidney of hyperuricemic mice. Regulation of mABCG2 by cortex fraxini coumarines may be partly contributed to their beneficial actions. This study provides an evidence to support clinical therapeutic effects of cortex fraxini coumarines on hyperuricemia with renal dysfunction.
Insights
Cortex fraxini coumarins like esculetin and esculin improve kidney function in hyperuricemia by restoring organic ion transporters. Fraxetin and fraxin also aid in urate excretion by affecting specific transporters.
Area of Science:
- Pharmacology
- Nephrology
- Natural Products Chemistry
Background:
- Hyperuricemia is linked to renal dysfunction and altered expression of renal organic ion transporters.
- Cortex fraxini coumarins are natural compounds with potential therapeutic benefits.
Purpose of the Study:
- To investigate the effects of esculetin, esculin, fraxetin, and fraxin on renal dysfunction and organic ion transporter expression in hyperuricemic mice.
- To elucidate the mechanisms by which these coumarins impact urate homeostasis and kidney function.
Main Methods:
- Induction of hyperuricemia and renal dysfunction in mice using oxonate.
- Oral administration of esculetin, esculin, fraxetin, and fraxin at different doses.
- Measurement of serum and urine urate, creatinine, and blood urea nitrogen levels.
- Analysis of the expression of renal organic ion transporters (mOAT1, mOCT1-2, mOCTN1-2, mGLUT9, mURAT1, mABCG2) using molecular techniques.
Main Results:
- All tested coumarins significantly reduced serum urate, creatinine, and blood urea nitrogen, while increasing urinary urate and creatinine excretion.
- Esculetin and esculin upregulated renal organic anion transporter 1 (mOAT1) and organic cation/carnitine transporters (mOCT1-2, mOCTN1-2).
- Fraxetin inhibited renal urate transporter 1 (mURAT1), and fraxin affected renal glucose transporter 9 (mGLUT9), mURAT1, mOAT1, and mOCT1.
- Esculetin, fraxetin, and fraxin modulated the expression of ATP-binding cassette sub-family G member 2 (mABCG2).
Conclusions:
- Esculetin and esculin demonstrate beneficial effects on hyperuricemia and renal dysfunction by restoring specific organic ion transporters.
- Fraxetin and fraxin contribute to enhanced urate excretion through inhibition of mURAT1 and/or mGLUT9.
- Modulation of mABCG2 by these coumarins may contribute to their therapeutic actions.
- Cortex fraxini coumarins show promise for clinical use in treating hyperuricemia with renal dysfunction.
