Abstract: TH-PO0229
Role and Mechanism of the IRF8-Integrin β8 Signaling Pathway in Renal Tubular Epithelial Cells in Diabetic Kidney Disease
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Author
- Deng, Bowen, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China
Background
Diabetic kidney disease (DKD) is a major complication of diabetes and a leading cause of chronic kidney disease and end-stage renal disease. Renal tubulointerstitial fibrosis, characterized by fibroblast activation and extracellular matrix deposition, is a key pathological feature driving DKD progression. Interferon regulatory factor 8 (IRF8) is involved in tumor immunity, cell proliferation, and myeloid cell differentiation; however, its role in DKD remains unclear.
Methods
A UK Biobank–based GWAS, kidney specimens from DKD patients, and two DKD mouse models (db/db and STZ-induced mice) were used to analyze IRF8 expression and its association with renal injury risk. High glucose–stimulated HK-2 cells were used to evaluate the effect of hyperglycemia on IRF8 expression in vitro. To investigate the protective role of IRF8 in DKD, AAV-mediated IRF8 overexpression was performed in db/db mice, followed by assessment of renal fibrosis by histological staining, immunohistochemistry, and Western blots. Lentiviral IRF8-overexpressing HK-2 cells, conditioned medium–treated NRK-49F fibroblasts, and Integrin β8 siRNA knockdown experiments were further conducted to explore the role of the IRF8/Integrin β8/TGF-β1 signaling pathway in fibroblast activation and extracellular matrix accumulation.
Results
IRF8 expression was significantly downregulated in renal tubular epithelial cells during DKD progression, and genetic analysis suggested that IRF8 variants were associated with renal injury risk in diabetic patients, indicating a protective role for IRF8. Consistently reduced IRF8 expression was observed in DKD patients, db/db and STZ-induced mice, and high glucose–stimulated HK-2 cells. Functional studies showed that IRF8 overexpression alleviated fibroblast activation and collagen deposition in the tubulointerstitial region. Mechanistically, IRF8 downregulation promoted fibroblast activation and tubulointerstitial fibrosis through the Integrin β8/TGF-β1 axis by reducing Integrin β8 expression and activating TGF-β1 signaling under high glucose conditions.
Conclusion
IRF8 is downregulated in both humans and mice tubular epithelial cells during DKD process. Downregulation of IRF8 in renal tubular epithelial cells activates TGF-β1 by inhibiting Integrin β8, thereby promoting fibroblast activation and extracellular matrix deposition, and ultimately mediating the progression of DKD.