Abstract: FR-PO0184
BCKDK Phosphorylates PPM1B to Induce Renal Tubular Epithelial Cell Senescence and Promote Diabetic Kidney Disease Progression
Session Information
- Diabetic Kidney Disease: Metabolic, Mitochondrial, and Inflammatory Mechanisms
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Cardiovascular-Kidney-Metabolic Health
- 601 Cardiovascular-Kidney-Metabolic Health: Basic
Authors
- Wang, Xingyue, Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Dai, Chunsun, Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Zhou, Yang, Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
Background
Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, with renal tubular premature aging emerging as a key pathogenic driver. Branched-chain ketoacid dehydrogenase kinase (BCKDK) is markedly upregulated in DKD kidneys, yet its role in regulating cellular senescence remains undefined. This study investigates whether BCKDK promotes DKD progression by inducing proximal tubular cell senescence via a novel PPM1B-p38 MAPK-p53 signaling axis.
Methods
Renal tissues from DKD patients and non-diabetic controls were analyzed for BCKDK expression and senescence markers. To causality, we generated tamoxifen-inducible, proximal tubule-specific BCKDK knockout mice. DKD was induced using streptozotocin (STZ) combined with high-fat diet and unilateral nephrectomy. Primary mouse proximal tubular cells (PTCs) and HEK293T cells were subjected to high-glucose challenge, with BCKDK and PPM1B manipulated via siRNA, overexpression plasmids, and CRISPR/Cas9. Protein interactions and post-translational modifications were assessed by co-immunoprecipitation and phosphorylation assays.
Results
BCKDK expression was significantly elevated in renal tubules of DKD patients and positively correlated with markers of cellular senescence. Tubule-specific BCKDK deletion in diabetic mice markedly attenuated renal senescence and injury. Mechanistically, BCKDK directly bound to and phosphorylated PPM1B at Ser386, targeting PPM1B for proteasomal degradation. BCKDK-mediated downregulation of PPM1B led to sustained activation of the p38 MAPK-p53 signaling cascade, driving expression of senescence-associated secretory phenotype (SASP) factors. Restoration of PPM1B or inhibition of p38 MAPK rescued the pro-senescent phenotype induced by BCKDK overexpression.
Conclusion
This study identifies BCKDK as a critical promoter of renal tubular senescence in DKD through phosphorylation-dependent degradation of PPM1B and subsequent p38 MAPK-p53 activation. Targeting the BCKDK-PPM1B axis may represent a novel therapeutic strategy to attenuate DKD progression.
Funding
- Government Support – Non-U.S.