Abstract: TH-PO0288
DDIT4 Promotes Podocyte Injury and Apoptosis via DDX58 in Diabetic Kidney Disease
Session Information
- Glomerular Diseases: Cell Biology
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
- Lang, Yating, Shandong Provincial Hospital, Jinan, Shandong, China
- Shang, Jiazhen, Shandong Provincial Hospital, Jinan, Shandong, China
- Yang, Meilin, Shandong Provincial Hospital, Jinan, Shandong, China
- Fan, Xiaoting, Shandong Provincial Hospital, Jinan, Shandong, China
- Lv, Xincong, Shandong Provincial Hospital, Jinan, Shandong, China
- Wang, Rong, Shandong Provincial Hospital, Jinan, Shandong, China
Background
Diabetic kidney disease (DKD) is one of the severe diabetic complications characterized by podocytes injury. Our previous studies found that fat-mass and obesity-associated protein (FTO) was associated with podocyte injury. Here, using RNA-seq and MeRIP-seq, we identified DNA damage inducible transcript 4 (DDIT4) as a target of FTO-mediated m6A modification. However, the mechanism of m6A modification of DDIT4 and its role in podocyte injury of DKD remain unclear.
Methods
RNA-seq, MeRIP-seq, dot blot assay, dual-luciferase reporter gene assay, RNA stability assay and RNA immunoprecipitation (RIP) assay were performed to validate FTO-mediated m6A modification of DDIT4. Kidney tissue from patients with DKD and high glucose-treated podocytes were used to examined DDIT4 expression and localization. Spearman analysis was used to evaluate the correlation between DDIT4 and kidney function. Podocyte injury and apoptosis were evaluated by flow cytometry, TUNEL, qRT-PCR, and western blotting. Proteomic analysis, co-immunoprecipitation(co-IP), proximity ligation assay (PLA), and truncation experiments identified the DDIT4–DDX58 interaction and functional domains. Podocyte-specific DDIT4 knockout mice and AAV9-mediated DDX58 silencing were generated for in vivo studies.
Results
DDIT4 is a target of FTO-mediated m6A modification. FTO knockdown reduces its m6A level and expression, whereas the m6A reader YTHDF2 recognizes and stabilizes DDIT4 mRNA. DDIT4 was upregulated in podocytes of DKD patients and negatively correlated with eGFR and positively correlated with 24 h urinary protein. DDIT4 silencing alleviated high glucose-induced podocyte injury and apoptosis, whereas its overexpression exacerbated these effects. Mechanistically, the amino acid 72–262 domain of DDIT4 interacted with DDX58 to promote podocyte injury and apoptosis. In vivo, podocyte-specific deletion of DDIT4 or DDX58 protected against podocyte and glomerular injury in high-fat diet/streptozotocin-induced diabetic mice.
Conclusion
FTO upregulates DDIT4 expression via YTHDF2-mediated m6A modification. DDIT4 interacts with DDX58 to induce podocyte injury and apoptosis, identifying a potential therapeutic target for DKD.