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TNF or EGFR inhibition equally block AKI-to-CKD transition: opportunities for etanercept treatment
Mai M Abdelmageed1,2, Eirini Kefaloyianni1,2, Akshayakeerthi Arthanarisami1,2
1Washington University School of Medicine in Saint Louis, Department of Medicine, St. Louis, MO, USA.
Background:
Inflammation is a key driver of the transition of acute kidney injury to progressive fibrosis and chronic kidney disease (AKI-to-CKD transition). Blocking a-disintegrin-and-metalloprotease-17 (ADAM17)-dependent ectodomain shedding, in particular of epidermal growth factor receptor (EGFR) ligands and of the type 1 inflammatory cytokine tumor necrosis factor (TNF), reduces pro-inflammatory and pro-fibrotic responses after ischemic AKI or unilateral ureteral obstruction (UUO), a classical fibrosis model. Metalloprotease or EGFR inhibition show significant undesirable side effects in humans. In retrospective studies anti-TNF biologics reduce the incidence and progression of CKD in humans. Whether TNF has a role in AKI-to-CKD transition and how TNF inhibition compares to EGFR inhibition is largely unknown.
Methods:
Mice were subjected to bilateral renal ischemia-reperfusion injury or unilateral ureteral obstruction. Kidneys were analyzed by histology, immunohistochemistry, qPCR, western blot, mass cytometry, scRNA sequencing, and cytokine profiling.
Results:
Here we show that TNF or EGFR inhibition reduce AKI-to-CKD transition and fibrosis equally by about 25%, while combination has no additional effect. EGFR inhibition reduced kidney TNF expression by about 50% largely by reducing accumulation of TNF expressing immune cells in the kidney early after AKI, while TNF inhibition did not affect EGFR activation or immune cell accumulation. Using scRNAseq data we show that TNF is predominantly expressed by immune cells in AKI but not in proximal tubule cells (PTC), and PTC-TNF knockout did not affect AKI-to-CKD transition in UUO. Thus, the anti-inflammatory and anti-fibrotic effects of the anti-TNF biologic etanercept in AKI-to-CKD transition rely on blocking TNF that is released from immune cells recruited or accumulating in response to PTC-EGFR signals.
Conclusion:
Short-term anti-TNF biologics during or after AKI could be helpful in the prevention of AKI-to-CKD transition.
Insights
Blocking tumor necrosis factor (TNF) or epidermal growth factor receptor (EGFR) equally reduces kidney fibrosis progression. TNF inhibition is effective by targeting immune cells, suggesting anti-TNF biologics may prevent chronic kidney disease after acute kidney injury.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Inflammation drives acute kidney injury (AKI) to chronic kidney disease (CKD) progression.
- ADAM17-dependent shedding of EGFR ligands and TNF reduces inflammation and fibrosis post-AKI.
- Anti-TNF biologics show promise in reducing CKD incidence and progression in humans.
Purpose of the Study:
- To investigate the role of TNF in AKI-to-CKD transition.
- To compare the efficacy of TNF inhibition versus EGFR inhibition in preventing AKI-to-CKD transition.
- To elucidate the mechanisms underlying TNF and EGFR inhibition in AKI-to-CKD transition.
Main Methods:
- Mice underwent renal ischemia-reperfusion injury or unilateral ureteral obstruction.
- Kidney tissues were analyzed using histology, immunohistochemistry, qPCR, western blot, mass cytometry, and scRNA sequencing.
- Cytokine profiling was performed to assess inflammatory markers.
Main Results:
- Both TNF and EGFR inhibition reduced AKI-to-CKD transition and fibrosis by approximately 25%, with no additive benefit from combination therapy.
- EGFR inhibition decreased kidney TNF expression by reducing TNF-expressing immune cell accumulation.
- TNF inhibition primarily targets immune cell-derived TNF, independent of EGFR activation or immune cell accumulation.
Conclusions:
- TNF and EGFR inhibition are equally effective in mitigating AKI-to-CKD transition and fibrosis.
- Anti-TNF biologics may prevent AKI-to-CKD transition by inhibiting TNF released from immune cells.
- Short-term anti-TNF biologic therapy during or after AKI could be a strategy to prevent CKD progression.
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