Abstract

Aim Gout is the chronic manifestation of hyperuricemia triggered by urate precipitation in joints and tendons, affecting 41 million adults worldwide. Promoting excretion of urate is the most important strategy for treating gout. To date, there is still no effective method for facilitating urate excretion. The uricosuric effect of estradiol (E2) has been uncovered, yet the precise mechanism remains unclear. This study aims to investigate the mechanism of E2 promoting urate excretion. Methods Immunohistochemistry (IHC) was utilized to detect gene expression in human kidney, RNA sequencing was used to screen E2-targeted genes in renal tubular epithelial cell line HK-2 cells, co-immunoprecipitation (Co-IP) was utilized to identify protein-protein interaction, and hyperuricemia (HUA) mouse model was established using potassium oxonate and yeast polysaccharide. Results E2 facilitates urate excretion by decreasing glucose transporter 9 (GLUT9) expression. Besides, E2 decreases GLUT9 expression by activating transmembrane protein 106B (TMEM106B)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT1 serine/threonine kinase 1 (AKT1) via estrogen receptor β (ERβ) in HK-2 cells. Moreover, E2 blocks urate uptake of HK-2 cells by ERβ/TMEM106B/PI3K/AKT1/GLUT9 pathway in vitro and in vivo . Conclusion These findings reveal that E2 promotes urate excretion by reducing GLUT9 expression via activating ERβ/TMEM106B/PI3K/AKT1 pathway in renal tubular epithelial cells, which provide novel targets and insights for gout treatment.