Protective effects of cortex fraxini coumarines against oxonate-induced hyperuricemia and renal dysfunction in mice

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.