Abstract: FR-PO0242
TGFβRI Signaling Activates the MCP1-CCR2 Axis to Promote Macrophage-Mediated Kidney Injury
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 2
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Novaes, Antonio S., Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Ekperikpe, Ubong S., Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Yu, Liping, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Daehn, Ilse S., Icahn School of Medicine at Mount Sinai, New York, New York, United States
Group or Team Name
- Daehn Lab
Background
Sustained inflammation accelerates kidney damage and disease progression. We have previously shown that ligand-independent activation of TGFβR1 in proximal tubules results in rapid epithelial cell injury and death, as well as immune cell infiltration. This study aimed to determine the mechanisms by which tubular TGFβR1 activation promotes recruitment of inflammatory cells that promote pathogenesis.
Methods
In vivo studies were performed in doxycycline-inducible Pax8Tgfbr1 mice with proximal tubular activation of TGFβR1 signaling. Mice received clodronate liposomes (macrophage depletion) or RS102895 (CCR2 antagonist) to inhibit macrophage recruitment. Kidney injury was assessed by histology, KIM1, tubular injury scoring, apoptosis, and blood urea nitrogen (BUN). The presence of Macrophages, dendritic cells and T-cells was evaluated by immunofluorescence of F4/80, CD11c CD3 positive cells. Cytokine and chemokine profiles were examined by Luminex. Cell death and oxidative stress were assessed by TUNEL, 8oxoG, and electron paramagnetic resonance (EPR).
Results
Canonical TGFβ signaling induced by Doxycycline (Dox) was confirmed in Pax8Tgfbr1 mice and isolated PTECs by increased Tgfbr1 expression and phospho-SMAD2 or nuclear translocation of SMAD2/3. Markers of tubular injury, inflammation, oxidative stress, and cell death were increased after 5 days of Dox. However, TGFβR1 activation in cultured Pax8Tgfbr1 PTECs did not induce cell death, but increased expression of the pro-inflammatory mediators MCP1, VEGF, and GM-CSF expression. Co-treatment of Dox-treated Pax8Tgfbr1 mice with clodronate or RS102895 significantly reduced F4/80-positive macrophage infiltration, tubular injury, KIM1 expression, and BUN levels.
Conclusion
As acute and chronic kidney diseases are characterized by TGFβ activation and tubular injury, our finding that TGFβ signaling in the tubular epithelium alone drives inflammation has far reaching implications for elucidation of the molecular mechanisms involved in pathogenesis and that targeting the macrophage/CCR2 axis presents a promising therapeutic strategy for treating inflammatory kidney diseases.
Funding
- NIDDK Support