Abstract: FR-PO0776
Transforming Growth Factor β-Induced Protein (TGFBI) and the Progression of Glomerular Diseases
Session Information
- Glomerular Diseases: Cell Homeostasis and Novel Injury Mechanisms
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Bitzer, Markus, University of Michigan, Ann Arbor, Michigan, United States
- Williams, Julie, AstraZeneca PLC, Gothenburg, Sweden
- O'Connor, Christopher Lund, University of Michigan, Ann Arbor, Michigan, United States
- Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States
- Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
- Cederblad, Linda, AstraZeneca PLC, Gothenburg, Sweden
- Ebefors, Kerstin, Goteborgs universitet, Gothenburg, Västra Götaland County, Sweden
- Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
- Ju, Wenjun, University of Michigan, Ann Arbor, Michigan, United States
Background
Chronic kidney disease (CKD) may lead to kidney failure necessitating kidney replacement therapy. TGF-β1 promotes podocyte loss, renal fibrosis and CKD progression, yet no intervention strategy has reached clinical practice due to the pleiotropy of the pathway. We aim to identify TGF-β1-regulated genes that mediate podocyte loss and determine the association with TGF-β1/SMAD signalling and disease progression in patients with kidney disease.
Methods
Gene expression in kidney tissue from patient biopsies and TGF-β1 transgenic mice was associated with relevant outcomes. Podocyte density was determined by immunohistochemistry staining. Impact on podocyte loss was assessed in vitro. Association of TGFBI with kidney outcomes was evaluated using Kaplan-Meier curve. The TGF-β1/SMAD signalling pathway activation score (TGFPAS) was created using a z-score method based on the expression of 48 SMAD-regulated genes.
Results
In micro-dissected glomeruli of PRECISE samples TGF-β1 was the most significant upstream regulator of genes associated with podocyte loss. TGFβ-induced (TGFBI), a TGF-β1 target gene, was identified as the top gene whose higher expression in the kidney was associated with lower podocyte density in patients with CKD (-0.51, p<0.001) and in TGF-β1 transgenic mice developing progressive glomerular sclerosis (r=-0.69, p<0.001). Higher TGFBI mRNA is associated with increased risk of CKD progression in humans and more advanced kidney damage in mice. The strong correlation between TGFBI and the TGFPAS (r=0.85, p<0.001) in the kidney suggested that TGFBI may mediate and represent TGF-β1 signaling associated with kidney damage. To examine the role of TGFBI in podocyte damage, we exposed human podocytes to TGFBI protein and observed increased podocyte detachment and actin cytoskeletal rearrangement. Furthermore, urinary TGFBI protein level showed a strong association with TGFPAS and adverse kidney outcomes in CKD.
Conclusion
Podocyte loss may be a molecular mechanism underlying the association of TGFBI with podocyte density and CKD progression. This study supports TGFBI as a therapeutic target and a biomarker for monitoring intra-kidney TGF-β1 signaling and associated kidney damage.
Funding
- NIDDK Support – AstraZeneca