Abstract: TH-PO0286
DCLK1 Integrates Senescence, Inflammation, and Fibrosis Signaling to Promote the Progression of 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
- Guan, Chen, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Cheng, Shasha, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Tian, Lei, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Li, Xiaogang, Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background
DKD is driven by interconnected processes, including cellular senescence, inflammation and fibrosis. Here, we define the role and mechanisms of doublecortin-like kinase 1 (DCLK1) as a central upstream regulator that coordinates these pathogenic processes in DKD and evaluated the effect of PROTAC-mediated DCLK1 degradation in DKD treatment.
Methods
The expression of DCLK1 and the effect of its targeting with either an inhibitor or a newly developed PROTAC (DC1) were evaluated in streptozotocin-induced diabetic mice, db/db mice, and high glucose (HG)-treated HK-2 cells as well as tubular-specific Dclk1 knockout mice and CRISPR/Cas9-mediated Dclk1-deficient HK-2 cells by immunoblotting, qRT-PCR, immunoprecipitation-mass spectrometry, co-immunoprecipitation, and ChIP assays.
Results
DCLK1 was markedly upregulated in renal tubular epithelial cells in diabetic kidneys and HG-treated HK-2 cells and correlated with fibrosis and renal dysfunction in human DKD datasets. Tubular-specific Dclk1 deletion attenuated renal injury, cellular senescence, inflammation, and fibrosis, in diabetic mouse kidneys. Similarly, DCLK1 depletion in HK-2 cells suppressed HG-induced tubular injury markers, and factors associated with fibrosis and senescence-associated phenotypes, such as inflammatory cytokines. Consistently, pharmacological inhibition or PROTAC-mediated degradation of DCLK1 markedly reduced renal inflammation, senescence, and fibrosis in DKD mouse models. Proteomic and pathway analyses linked DCLK1 to p53 signaling, TNFα/NF-κB signaling, inflammatory responses, and epithelial-mesenchymal transition. Mechanistically, DCLK1 directly interacted with p53, NF-κB/p65, and Smad3, promoting their phosphorylation and activation and resulting in the increase of p53/p21 mediated senescence, NF-κB/p65 mediated inflammatory cytokine production, and Smad3-dependent profibrotic gene expression. Moreover, Smad3, p53 and p65 transcriptionally activated Dclk1, forming a positive feedback loop that amplified fibrotic signaling.
Conclusion
DCLK1 functions as a central pathogenic signaling hub that integrates senescence, inflammation, and fibrosis through coordinated activation of its novel identified partners, including p53, NF-κB, and Smad3, in DKD. Targeting DCLK1 with inhibitor and PROTAC represents a promising therapeutic strategy for DKD.
Funding
- NIDDK Support