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.