Abstract: TH-PO0373
Role of the Post-Translational ISGylation of IRF9 in Diabetes-Induced Podocyte Injury
Session Information
- Glomerular Diseases: Genetics to Therapeutics
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Lv, Zhimei, Shandong Provincial Hospital, Jinan, Shandong, China
- Chai, Shouyu, Shandong Provincial Hospital, Jinan, Shandong, China
- Shen, Ning, Shandong Provincial Hospital, Jinan, Shandong, China
- Ma, Baoze, Shandong Provincial Hospital, Jinan, Shandong, China
- Hu, Jinxiu, Shandong Provincial Hospital, Jinan, Shandong, China
- Wang, Rong, Shandong Provincial Hospital, Jinan, Shandong, China
Background
Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease, with podocyte injury being a key event in its progression. Here, by performing single-cell regulatory network inference and clustering (SCENIC) analysis between DKD and normal kidney samples, we found a significant increase in interferon regulatory factor 9 (IRF9) transcriptional activity in the podocytes of DKD kidneys. However, the role of IRF9 in DKD remains poorly understood.
Methods
Kidney tissue from DKD patients and high glucose-treated podocytes were employed to investigate IRF9 expression and localization. RNA sequencing was performed to elucidate the role of IRF9 in podocyte injury. Co-immunoprecipitation, in-situ proximity ligation assay (PLA), and surface plasmon resonance (SPR) were performed to confirm the binding between IRF9 and ISG15. ISGylation and ubiquitination assays were used to examine the potential effects of ISG15 on IRF9 expression. Podocyte-specific IRF9 deletion and overexpression mice and podocyte-specific ISG15 knockdown mice were established to assess kidney injury in vivo.
Results
IRF9 protein expression was increased in the podocytes of DKD patients, without changes in IRF9 mRNA expression, and IRF9 expression was negatively correlated with eGFR and positively correlated with 24 h urinary protein. In cultured human podocytes, high glucose stimulated IRF9 protein expression without affecting IRF9 mRNA expression. Silencing IRF9 alleviated high glucose-induced podocyte injury, whereas IRF9 overexpression exacerbated podocyte injury. IRF9 induced podocyte injury via inflammasome activation and pyroptosis. Interestingly, high glucose increased IRF9 protein expression by stimulating ISG15 expression, which promoted IRF9 ISGylation and subsequently inhibited IRF9 ubiquitination to increase IRF9 protein stability. In vivo, podocyte-specific deletion of IRF9 or podocyte-specific knockdown of ISG15 attenuated podocyte and glomerular injury in streptozotocin-induced diabetic mice fed a high-fat diet; in contrast, the podocyte-specific overexpression of IRF9 exacerbated podocyte and glomerular injury in these diabetic mice.
Conclusion
Targeting ISG15-IRF9 could be a potential novel therapy for podocyte injury in DKD.