Abstract: TH-PO494
TNFα Inhibition Decreases Fibrosis After Ischemia-Reperfusion Injury
Session Information
- CKD: Mechanisms - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Abdelmageed, Mai, School of Medicine, Washington University in Saint Louis, St. Louis, Missouri, United States
- Kefalogianni, Eirini, Washington University School of Medicine, St. Louis, Missouri, United States
- Herrlich, Andreas, Washington University in St. Louis, St. Louis, Missouri, United States
Background
Renal fibrosis is a frequent complication of acute kidney injury (AKI) and sustained EGFR activation in tubule cells is a hallmark of this process. We have previously shown that injury-induced a disintegrin and metalloproteinase 17 (ADAM17) drives maladaptive repair and kidney fibrosis after injury, but the implicated ADAM17 substrates are unknown. At least two of the main physiological substrates of ADAM17 are upregulated by kidney injury, pro-TNFα and pro-EGFR ligands. ADAM17 releases the active forms of these molecules from the cell surface. We examined the individual contribution of TNFα and EGFR-dependent pathways using FDA-approved drugs in mice: (murine) Etanercept and erlotinib.
Methods
FVB-N mice were subjected to severe bilateral ischemia-reperfusion-injury (IRI) and assigned to 4 treatment groups: (1) vehicle, (2) murine Etanercept (soluble TNFα inhibitor scavenger), (3) Erlotinib (EGFR kinase inhibitor), (4) Erlotinib plus Etanercept. Treatments were started Day 0. Sham surgeries were performed as additional controls. Kidney injury and fibrosis were assessed by biochemical parameters and kidney tissue stains (Fibronectin, α-SMA and picrosirius red). GFR was measured by transdermal monitoring of FITC-sinistrin clearance. Phospho-EGFR levels were detected in kidney lysates by western blotting.
Results
All groups showed the same degree of initial kidney injury. Etanercept or Erlotinib individually significantly decreased renal fibrosis by approximately 40% compared to vehicle-treated mice, but there was no additive protective effect when the drug combination was used. In kidney lysates, Erlotinib (alone or in the combination) decreased EGFR phosphorylation, while Etanercept alone had no effect on p-EGFR.
Conclusion
Etanercept treatment significantly reduced fibrosis after AKI without affecting EGFR activation, and additional EGFR inhibition in combinatorial drug treatment did not further improve outcomes. This suggests that TNFα in the context of AKI-induced fibrosis acts downstream of EGFR. This opens a potentially new therapeutic window for etanercept, a well-tolerated FDA-approved drug, in human AKI.
Funding
- NIDDK Support