title: Genetic or pharmacologic blockade of EGFR inhibits renal fibrosis.
abstract: Although enhanced activation of the EGF receptor (EGFR) associates with the development and progression of renal fibrosis, the mechanisms linking these observations are not completely understood. Here, after unilateral ureteral obstruction (UUO), wild-type mice exhibited sustained EGFR phosphorylation in the kidney and developed renal fibrosis that was more severe than the renal fibrosis observed in waved-2 mice, which have reduced EGFR tyrosine kinase activity. Waved-2 mice also showed fewer renal tubular cells arrested at G2/M, reduced expression of α-smooth muscle actin (α-SMA), downregulation of multiple genes encoding profibrogenic cytokines, including TGF-β1, and dephosphorylation of Smad3, STAT3, and ERK1/2. Administration of the specific EGFR inhibitor gefitinib recapitulated this phenotype in wild-type mice after UUO. Furthermore, inactivation of either EGFR or STAT3 reduced UUO-induced expression of lipocalin-2, a molecule associated with the pathogenesis of CKD. In cultured renal interstitial fibroblasts, inhibition of EGFR also abrogated TGF-β1- or serum-induced phosphorylation of EGFR, STAT3, ERK1/2, and Smad3 as well as expression of α-SMA and extracelluar matrix proteins. Taken together, these data suggest that EGFR may mediate renal fibrogenesis by promoting transition of renal epithelial cells to a profibrotic phenotype, increased production of inflammatory factors, and activation of renal interstitial fibroblasts. Inhibition of EGFR may have therapeutic potential for fibrotic kidney disease.
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, China.
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.forename: Jian-Kan
authors.initials: JK
authors.lastname: Guo
authors.forename: Maoyin
authors.initials: M
authors.lastname: Pang
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tolbert
authors.forename: Murugavel
authors.initials: M
authors.lastname: Ponnusamy
authors.forename: Rujun
authors.initials: R
authors.lastname: Gong
authors.forename: George
authors.initials: G
authors.lastname: Bayliss
authors.forename: Lance D
authors.initials: LD
authors.lastname: Dworkin
authors.forename: Haidong
authors.initials: H
authors.lastname: Yan
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D016207:Cytokines / Q000096:biosynthesis; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D007668:Kidney / Q000473:pathology*; D054834:Lipocalins / Q000032:analysis; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D051900:Smad3 Protein / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D014517:Ureteral Obstruction / Q000378:metabolism
chemical_list: D016207:Cytokines; D054834:Lipocalins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases