title: ADAM17 substrate release in proximal tubule drives kidney fibrosis.
abstract: Kidney fibrosis following kidney injury is an unresolved health problem and causes significant morbidity and mortality worldwide. In a study into its molecular mechanism, we identified essential causative features. Acute or chronic kidney injury causes sustained elevation of a disintegrin and metalloprotease 17 (ADAM17); of its cleavage-activated proligand substrates, in particular of pro-TNFα and the EGFR ligand amphiregulin (pro-AREG); and of the substrates' receptors. As a consequence, EGFR is persistently activated and triggers the synthesis and release of proinflammatory and profibrotic factors, resulting in macrophage/neutrophil ingress and fibrosis. ADAM17 hypomorphic mice, specific ADAM17 inhibitor-treated WT mice, or mice with inducible KO of ADAM17 in proximal tubule (Slc34a1-Cre) were significantly protected against these effects. In vitro, in proximal tubule cells, we show that AREG has unique profibrotic actions that are potentiated by TNFα-induced AREG cleavage. In vivo, in acute kidney injury (AKI) and chronic kidney disease (CKD, fibrosis) patients, soluble AREG is indeed highly upregulated in human urine, and both ADAM17 and AREG expression show strong positive correlation with fibrosis markers in related kidney biopsies. Our results indicate that targeting of the ADAM17 pathway represents a therapeutic target for human kidney fibrosis.
authors.affiliation: Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Eirini
authors.initials: E
authors.lastname: Kefaloyianni
authors.affiliation: Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Muthu Lakshmi
authors.initials: ML
authors.lastname: Muthu
authors.affiliation: Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Jakob
authors.initials: J
authors.lastname: Kaeppler
authors.affiliation: Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Sun
authors.affiliation: Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Venkata
authors.initials: V
authors.lastname: Sabbisetti
authors.affiliation: Institute for Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
authors.forename: Athena
authors.initials: A
authors.lastname: Chalaris
authors.affiliation: Institute for Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Eitan
authors.initials: E
authors.lastname: Wong
authors.affiliation: Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Sagi
authors.affiliation: Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Sushrut S
authors.initials: SS
authors.lastname: Waikar
authors.affiliation: Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Helmut
authors.initials: H
authors.lastname: Rennke
authors.affiliation: Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Humphreys
authors.affiliation: Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.affiliation: Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrlich
mesh_terms: D000072198:ADAM17 Protein / Q000378:metabolism*; D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology*; D066258:Amphiregulin / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism; D005355:Fibrosis; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb
chemical_list: D066258:Amphiregulin; C493558:Slc34a2 protein, mouse; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; D066246:ErbB Receptors; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse