In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 30, No. 12 ( 2019-12), p. 2370-2383
Abstract:
Sustained activation of EGF receptor (EGFR) in proximal tubule cells (PTCs) is a hallmark of fibrotic CKD, but the molecular mechanism(s) involved are unknown. Here, we show that the injury-upregulated, low-affinity EGFR ligand amphiregulin (AREG) amplifies its own signaling in PTCs and integrates signals of other moderately injury-upregulated EGFR ligands by inducing the transcriptional regulator Yes-associated protein 1 (YAP1). In vivo , AREG is necessary and sufficient to induce kidney fibrosis after injury, as AREG PTC-knockout mice exhibit protection and soluble AREG injection suffices to reverse protection in mice that cannot release EGFR ligands from PTCs. Our results identify AREG as a critical driver of the transition of kidney injury to fibrosis. Background Sustained activation of EGF receptor (EGFR) in proximal tubule cells is a hallmark of progressive kidney fibrosis after AKI and in CKD. However, the molecular mechanisms and particular EGFR ligands involved are unknown. Methods We studied EGFR activation in proximal tubule cells and primary tubular cells isolated from injured kidneys in vitro . To determine in vivo the role of amphiregulin, a low-affinity EGFR ligand that is highly upregulated with injury, we used ischemia-reperfusion injury or unilateral ureteral obstruction in mice with proximal tubule cell–specific knockout of amphiregulin. We also injected soluble amphiregulin into knockout mice with proximal tubule cell–specific deletion of amphiregulin’s releasing enzyme, the transmembrane cell-surface metalloprotease, a disintegrin and metalloprotease-17 (ADAM17), and into ADAM17 hypomorphic mice. Results Yes-associated protein 1 (YAP1)–dependent upregulation of amphiregulin transcript and protein amplifies amphiregulin signaling in a positive feedback loop. YAP1 also integrates signals of other moderately injury-upregulated, low-affinity EGFR ligands (epiregulin, epigen, TGF α ), which also require soluble amphiregulin and YAP1 to induce sustained EGFR activation in proximal tubule cells in vitro . In vivo , soluble amphiregulin injection sufficed to reverse protection from fibrosis after ischemia-reperfusion injury in ADAM17 hypomorphic mice; injected soluble amphiregulin also reversed the corresponding protective proximal tubule cell phenotype in injured proximal tubule cell–specific ADAM17 knockout mice. Moreover, the finding that proximal tubule cell–specific amphiregulin knockout mice were protected from fibrosis after ischemia-reperfusion injury or unilateral ureteral obstruction demonstrates that amphiregulin was necessary for the development of fibrosis. Conclusions Our results identify amphiregulin as a key player in injury-induced kidney fibrosis and suggest therapeutic or diagnostic applications of soluble amphiregulin in kidney disease.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2019030321
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2019
detail.hit.zdb_id:
2029124-3
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