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Kidney Week

Abstract: PO0438

TNF Drives AKI-to-CKD Transition Downstream of Proximal Tubule EGFR

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Abdelmageed, Mai, Washington University in St Louis, St Louis, Missouri, United States
  • Kefalogianni, Eirini, Washington University in St Louis, St Louis, Missouri, United States
  • Arthanarisami, Akshayakeerthi, Washington University in St Louis, St Louis, Missouri, United States
  • Khamissi, Fatima Zohra, Washington University in St Louis, St Louis, Missouri, United States
  • Atkinson, Jeffrey J., Washington University in St Louis, St Louis, Missouri, United States
  • Herrlich, Andreas, Washington University in St Louis, St Louis, Missouri, United States
Background

Inflammation is a key driver of fibrosis and progression of human chronic kidney disease (CKD), often caused or worsened by acute kidney injury (AKI-to-CKD transition). Sustained epidermal-growth-factor-receptor (EGFR) activation in injured proximal-tubule-cells (PTC) is strongly pro-inflammatory and has emerged as a key paradigm in AKI-to-CKD transition and CKD progression. Whether the key Type 1 inflammatory cytokine tumor-necrosis-factor (TNF) has a role in CKD progression and how TNF relates to the PTC-EGFR pathway is unknown.

Methods

We compared mice treated with control, TNF-inhibition (etanercept, TNF-scavenger), EGFR-inhibition (erlotinib, EGFR-kinase-inhibitor) or their combination in an AKI-to-CKD bilateral renal-ischemia-reperfusion model.

Results

TNF- or EGFR-inhibition did not affect initial kidney injury, but significantly overlapped in reducing kidney injury-upregulated cytokines and equally strongly reduced kidney fibrosis, while combination treatment had no additive effect, suggesting EGFR and TNF act in the same fibrosis pathway. TNF exerted its profibrotic effects downstream of PTC-EGFR, as TNF-inhibition did not affect tubular EGFR activation in vivo. Consistent with this, TNF-PTC-KO did not reduce inflammation or fibrosis, suggesting that PTC-derived TNF does not contribute to profibrotic PTC-EGFR activation. Kidney single-cell-RNAseq analysis identified macrophages, dendritic cells and T cells, but not PTC, as dominant TNF sources after AKI. Only EGFR-inhibition, but not TNF-inhibition significantly blocked injury-induced kidney ingress of macrophages, however, macrophage numbers where equal one month after AKI independent of treatment. Thus EGFR-inhibition reduces ingress and accumulation of TNF-producing proinflammatory and profibrotic immune cells whereas TNF-inhibition mechanistically largely acts by neutralizing their proinflammatory and profibrotic activities.

Conclusion

Our work provides mechanistic background to motivate examination of TNF pathway inhibition in human AKI or CKD.

Funding

  • NIDDK Support