title: A disintegrin and metalloproteinase 17 (ADAM17) mediates epidermal growth factor receptor transactivation by angiotensin II on hepatic stellate cells.
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR) transactivation induced by angiotensin II (Ang II) participates in the progression of various diseases. A disintegrin and metalloproteinase 17 (ADAM17) is thought to promote renal fibrosis, cardiac hypertrophy with fibrosis and atherosclerosis by activation of the EGFR through secretion of EGFR ligands. The purpose of this study was to investigate whether Ang II-induced EGFR transactivation occurs on hepatic stellate cells (HSCs) and whether the reaction is mediated via ADAM17.
  
  
  METHODS
  Ang II-induced EGFR transactivation and cellular proliferation of the human HSC line LI90 were investigated using Western blotting and ATP assay, respectively. Ang II-induced secretion of mature amphiregulin into the cell culture medium was evaluated by enzyme-linked immunosorbent assay (ELISA).
  
  
  RESULTS
  An inhibitor of ADAM17, TAPI-1, as well as antagonists of EGFR and angiotensin II type-1 receptor (AT1), attenuated Ang II-induced EGFR transactivation and proliferation of LI90 cells. Furthermore, silencing of ADAM17 inhibited Ang II-induced secretion of mature amphiregulin in addition to EGFR transactivation.
  
  
  CONCLUSIONS
  These results indicate that ADAM17 mediates Ang II-induced EGFR transactivation on HSCs, and that this process may participate in the progression of liver fibrosis.
authors.affiliation: Department of Pathology, School of Medicine, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwa-Gun, Iwate 028-3694, Japan. Electronic address: hioikawa@iwate-med.ac.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Oikawa
authors.affiliation: Department of Pathology, School of Medicine, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwa-Gun, Iwate 028-3694, Japan; Department of Tumor Biology, Institute of Biomedical Science, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwa-Gun, Iwate 028-3694, Japan.
authors.forename: Chihaya
authors.initials: C
authors.lastname: Maesawa
authors.affiliation: Department of Internal Medicine, School of Medicine, Iwate Medical University, Uchimaru 19-1, Morioka, Iwate 020-8505, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tatemichi
authors.affiliation: Department of Tumor Biology, Institute of Biomedical Science, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwa-Gun, Iwate 028-3694, Japan; Department of Surgery, School of Medicine, Iwate Medical University, Uchimaru 19-1, Morioka, Iwate 020-8505, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nishinari
authors.affiliation: Department of Pathology, School of Medicine, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwa-Gun, Iwate 028-3694, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Nishiya
authors.affiliation: Department of Pathology, School of Medicine, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwa-Gun, Iwate 028-3694, Japan; Department of Internal Medicine, School of Medicine, Iwate Medical University, Uchimaru 19-1, Morioka, Iwate 020-8505, Japan.
authors.forename: Hisata
authors.initials: H
authors.lastname: Mizugai
authors.affiliation: Department of Pathology, School of Medicine, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwa-Gun, Iwate 028-3694, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Ikeda
authors.affiliation: Department of Internal Medicine, School of Medicine, Iwate Medical University, Uchimaru 19-1, Morioka, Iwate 020-8505, Japan.
authors.forename: Kanta
authors.initials: K
authors.lastname: Oikawa
authors.affiliation: Department of Internal Medicine, School of Medicine, Iwate Medical University, Uchimaru 19-1, Morioka, Iwate 020-8505, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takikawa
authors.affiliation: Department of Pathology, School of Medicine, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwa-Gun, Iwate 028-3694, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Masuda
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D066258:Amphiregulin; D000804:Angiotensin II / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation; D004151:Dipeptides / Q000494:pharmacology; D018450:Disease Progression; D066255:EGF Family of Proteins; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism*; D020868:Gene Silencing; D006023:Glycoproteins / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008103:Liver Cirrhosis / Q000503:physiopathology
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D004151:Dipeptides; D066255:EGF Family of Proteins; D006023:Glycoproteins; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; C092152:N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2'-naphthyl)alanylalanine, 2-aminoethylamide; D000804:Angiotensin II; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: ADAM17; Amphiregulin; Angiotensin II; EGFR transactivation; Hepatic stellate cell