2. Academic Validation
  3. Estradiol facilitates urate excretion by reducing GLUT9 expression via ERβ/TMEM106B/PI3K/AKT1 pathway in renal tubular epithelial cells

Estradiol facilitates urate excretion by reducing GLUT9 expression via ERβ/TMEM106B/PI3K/AKT1 pathway in renal tubular epithelial cells

  • Int J Biochem Cell Biol. 2026 Jun-Jul:195-196:106940. doi: 10.1016/j.biocel.2026.106940.
Haijun Liu 1,  Zizi Xiao 2,  Shulin Yue 3,  Yuhong Liu 2,  Xia Ouyang 2,  Kangxia Long 2,  Nemin Liu 2,  Xiaomin Wang 2,  Yu Min 4
Affiliations

Affiliations

  • 1 Department of Rheumatology and Immunology, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou 511400, China. Electronic address: [email protected].
  • 2 Department of Rheumatology and Immunology, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou 511400, China.
  • 3 Department of Renal Pathology, Guangzhou KingMed Medical Laboratory Center, Guangzhou 510006, China.
  • 4 Rehabilitation Medicine, Rehabilitation Medicine Institute of Panyu District, The Affiliated Panyu Central Hospital of Guangzhou Medical University, China.
PMID: 41825791 DOI: 10.1016/j.biocel.2026.106940
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.

Keywords

Estradiol; Estrogen receptor β; GLUT9; Gout; TMEM106B; Urate excretion.

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