Glucocorticoids Increase Renal Excretion of Urate in Mice by Downregulating Urate Transporter 1.
Drug Metab Dispos
; 47(11): 1343-1351, 2019 11.
Article
en En
| MEDLINE
| ID: mdl-31519697
ABSTRACT
Both nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids have been widely used for the treatment of gout, a disease promoted by an excess body burden of uric acid (UA); however, their effects on the homeostasis of UA remain poorly understood. The present study showed that 1-week treatments with three NSAIDs (ibuprofen, diclofenac, and indomethacin) had little effect on UA homeostasis in mice, whereas 1-week low doses (1 and 5 mg/kg) of dexamethasone (DEX) significantly decreased serum UA by about 15%. Additionally, low doses of DEX also resulted in increases in hepatic UA concentration and urinary UA excretion, which were associated with an induction of xanthine oxidoreductase (XOR) in the liver and a downregulation of urate transporter 1 (URAT1) in the kidney, respectively. Neither 75 mg/kg DEX nor 100 mg/kg pregnenolone-16α-carbonitrile altered UA concentrations in serum and livers of mice, suggesting that the effect of DEX on UA homeostasis was not due to the pregnane X receptor pathway. Further in vitro studies demonstrated that glucocorticoid receptor (GR) was involved in DEX-mediated downregulation of URAT1. Knockdown of both p65 and c-Jun completely blocked the effect of DEX on URAT1, suggesting that GR regulates URAT1 via its interaction with both nuclear factor κB and activator protein 1 signaling pathways. To conclude, the present study identifies, for the first time, a critical role of glucocorticoids in regulating UA homeostasis and elucidates the mechanism for GR-mediated regulation of URAT1 in mice. SIGNIFICANCE STATEMENT This study demonstrates, for the first time, a critical role of glucocorticoid receptor in regulating urate transporter 1 in mouse kidney.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Ácido Úrico
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Dexametasona
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Transportadores de Anión Orgánico
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Riñón
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Drug Metab Dispos
Asunto de la revista:
FARMACOLOGIA
Año:
2019
Tipo del documento:
Article