Abstract: TH-PO0289
DUSP8 Ameliorates Podocyte Mitochondrial Dysfunction via PRAS40 Dephosphorylation 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
- Lv, Zhimei, Shandong Provincial Hospital, Jinan, Shandong, China
- Zeng, Zhitao, Shandong Provincial Hospital, Jinan, Shandong, China
- Liu, Yue, Shandong Provincial Hospital, Jinan, Shandong, China
- Zhang, Xia, Shandong Provincial Hospital, Jinan, Shandong, China
- Yu, Qun, Shandong Provincial Hospital, Jinan, Shandong, China
- Wang, Rong, Shandong Provincial Hospital, Jinan, Shandong, China
Background
Mitochondrial dysfunction is a central event in podocyte injury during diabetic kidney disease (DKD). Although dual-specificity phosphatases have been reported to exert renoprotective effects by preserving mitochondrial function, the specific role of DUSP8 in maintaining podocyte mitochondrial homeostasis in DKD remains unclear.
Methods
The expression and localization of DUSP8 was examined in high glucose-treated podocytes, human DKD renal biopsies, db/db mice, and streptozotocin/high-fat diet (STZ/HFD)-induced DKD mice. Spearman analysis was used to evaluate the correlation between DUSP8 and kidney function. Podocyte injury and mitochondrial function were evaluated via real-time PCR, Western blot, oxygen consumption rate, MitoSOX Red, Calcein, TMRE/JC-1staining. Phosphoproteomics was performed to identify PRAS40 as a direct substrate of DUSP8. Proximity Ligation Assay and Co-immunoprecipitation were used to verify the interaction between DUSP8 and PRAS40. Chromatin immunoprecipitation and luciferase reporter assays were used to assess the regulation of HDAC1 on DUSP8. Podocyte-specific Dusp8 knockout mice were generated to determine the role of DUSP8 in kidney injury in vivo.
Results
Here, we observed downregulation of DUSP8 in DKD patients, in db/db and STZ/HFD mice, as well as in podocytes exposed to high glucose. Glomerular DUSP8 levels were positively correlated with estimated glomerular filtration rate and negatively correlated with the urinary albumin-to-creatinine ratio and serum creatinine. Functional studies demonstrated that DUSP8 alleviated high glucose-induced mitochondrial fission, reactive oxygen species accumulation, mitochondrial permeability transition pore hyperactivation, loss of mitochondrial membrane potential, and podocyte injury. Mechanistically, DUSP8 dephosphorylated PRAS40 at Ser202 via its phosphatase activity, thereby mitigating high glucose induced mitochondrial injury in podocytes. Furthermore, we identified that HDAC1 epigenetically silenced DUSP8 transcription by deacetylating histone H3 lysine 27 (H3K27) at its promoter. In vivo, the podocyte-specific deletion of Dusp8 exacerbated podocyte and glomerular injury in STZ/HFD-induced DKD mice.
Conclusion
HDAC1/DUSP8/PRAS40 signaling axis is a novel regulator of podocyte mitochondrial homeostasis in DKD, providing a mechanistic framework and a potential therapeutic target for DKD.