title: Sustained activation of EGFR triggers renal fibrogenesis after acute kidney injury.
abstract: Severe acute kidney injury (AKI) is frequently accompanied by maladaptive repair and renal fibrogenesis; however, the molecular mechanisms that mediate these acute and chronic consequences of AKI remain poorly understood. In this study, we examined the role of epidermal growth factor receptor (EGFR) in these processes using waved-2 (Wa-2) mice, which have reduced EGFR activity, and their wild-type (WT) littermates after renal ischemia. Renal EGFR phosphorylation was induced within 2 days after ischemia, increased over time, and remained elevated at 28 days in WT mice, but this was diminished in Wa-2 mice. At the early stage of postischemia (2 days), Wa-2 mice developed more severe acute renal tubular damage with less reparative responses as indicated by enhanced tubular cell apoptosis, and reduced dedifferentiation and proliferation as compared to WT animals. At the late stage of postischemia (28 days), Wa-2 mice exhibited a less severe renal interstitial fibrosis as shown by reduced activation/proliferation of renal myofibroblasts and decreased deposition of extracellular matrix proteins. EGFR activation also contributed to cell cycle arrest at the G2/M phase, a cellular event associated with production of profibrogenetic factors, in the injured kidney. Collectively, these results indicate that severe AKI results in sustained activation of EGFR, which is required for reparative response of renal tubular cells initially, but eventually leads to fibrogenesis.
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Tang
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tolbert
authors.forename: Murugavel
authors.initials: M
authors.lastname: Ponnusamy
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Rujun
authors.initials: R
authors.lastname: Gong
authors.forename: George
authors.initials: G
authors.lastname: Bayliss
authors.forename: Haidong
authors.initials: H
authors.lastname: Yan
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism*; D005355:Fibrosis; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; C541485:EGFR protein, mouse; D066246:ErbB Receptors