title: Inhibition of EGF Receptor Blocks the Development and Progression of Peritoneal Fibrosis.
abstract: Inhibitors of EGF receptor (EGFR) have antifibrotic effects in several organs, but the effect of these inhibitors on the development of peritoneal fibrosis is unknown. Here, we explored the therapeutic effect of gefitinib, a specific inhibitor of EGFR, on the development and progression of peritoneal fibrosis in a rat model. Daily intraperitoneal injections of chlorhexidine gluconate induced peritoneal fibrosis, indicated by thickening of the submesothelial area with an accumulation of collagen fibrils and activation of myofibroblasts, accompanied by time-dependent phosphorylation of EGFR. Administration of gefitinib immediately after injury prevented the onset of peritoneal fibrosis and delayed administration after the onset of peritoneal fibrosis halted fibrosis progression. Gefitinib treatment abrogated the increased phosphorylation of EGFR, Smad3, signal transducer and activator of transcription 3, and NF-κB during peritoneal fibrosis; it also inhibited the accompanying overproduction of TGF-β1 and proinflammatory cytokines and the infiltration of macrophages to the injured peritoneum. Moreover, gefitinib significantly reduced the peritoneal increase of CD31-positive blood vessels and vascular EGF-positive cells after injury. Finally, gefitinib also attenuated high glucose-induced peritoneal fibrosis in rats and abrogated TGF-β1-induced phosphorylation of Smad3 and the epithelial-to-mesenchymal transition of cultured human peritoneal mesothelial cells. These results demonstrate that EGFR contributes to peritoneal fibrosis, inflammation, and angiogenesis, suggesting that EGFR inhibitors may have therapeutic potential in attenuating peritoneal fibrosis.
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China;
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China;
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China;
authors.forename: Chongxiang
authors.initials: C
authors.lastname: Xiong
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China;
authors.forename: Liuqing
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China;
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Shi
authors.affiliation: School of Life Science and Technology, Advanced Institute of Translational Medicine, Tongji University, Shanghai, China;
authors.forename: Andong
authors.initials: A
authors.lastname: Qiu
authors.affiliation: Department of Nephrology, Shanghai Songjiang District Central Hospital, Shanghai, China;
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Zang
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Providence, China; and.
authors.forename: Haiping
authors.initials: H
authors.lastname: Mao
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Medicine, Rhode Island Hospital and Alpert School of Medicine, Brown University, Providence, Rhode Island szhuang@lifespan.org.
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
mesh_terms: D000818:Animals; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D008297:Male; D056627:Peritoneal Fibrosis / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D053773:Transforming Growth Factor beta1
chemical_list: D011799:Quinazolines; D053773:Transforming Growth Factor beta1; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: TGF-beta; VEGF; epidermal growth factor; fibrosis; peritoneal dialysis; signaling