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Kidney Week

Abstract: TH-PO463

Proximal Tubule-Derived Amphiregulin Amplifies and Integrates Profibrotic EGFR Signals in Kidney Fibrosis

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

  • Kefalogianni, Eirini, Washington University School of Medicine, St. Louis, Missouri, United States
  • Keerthi raja, Manikanda raja, University of South Carolina, Columbia, South Carolina, United States
  • Schumacher, Julian, Washington University in St. Louis, St. Louis, Missouri, United States
  • Waikar, Sushrut S., Harvard Medical School, Boston, Massachusetts, United States
  • Herrlich, Andreas, Washington University in St. Louis, St. Louis, Missouri, United States
Background

Sustained activation of epidermal-growth-factor-receptor (EGFR) in proximal-tubule-cells (PTCs) is a hallmark of progressive kidney fibrosis after acute-kidney-injury (AKI) and in chronic-kidney-disease (CKD), but the molecular mechanism(s) and particular EGFR ligands involved are unknown.

Methods

We studied EGFR activation in PTCs and in primary tubular cells isolated from injured kidneys in vitro. To determine the role of amphiregulin (AREG), a highly injury-upregulated low-affinity EGFR ligand in vivo, we used ischemia-reperfusion-injury (IRI) or unilateral-ureteral-obstruction (UUO) in AREG PTC-KO mice, or injection of soluble AREG (sAREG) into mice with PTC-KO of its releasing enzyme, a-disintegrin-and-metalloprotease-17 (ADAM17), and into ADAM17 hypomorphic mice. Serum AREG was measured by ELISA in a CKD patient cohort.

Results

We show that Yes-associated-protein-1 (YAP1)-dependent upregulation of AREG transcript and protein amplifies AREG signaling in a positive feedback loop and integrates signals of other moderately injury-upregulated low-affinity EGFR ligands (epiregulin, epigen, TGFα), which we show also require sAREG and YAP1 to induce sustained EGFR activation in PTCs in vitro. In vivo, sAREG injection sufficed to reverse protection from fibrosis after IRI in ADAM17 hypomorphic mice, and to reverse the corresponding protective PTC phenotype in injured ADAM17 PTC-knockout mice. AREG was necessary for the development of fibrosis, as AREG PTC-knockout mice were protected from fibrosis after IRI or UUO. In a nephrectomy cohort (n=78) of CKD patients, serum sAREG negatively correlated with kidney function.

Conclusion

Our results identify AREG as a key player in injury-induced kidney fibrosis and suggest therapeutic or diagnostic applications of sAREG in kidney disease.

Funding

  • NIDDK Support