Genetic or Pharmacologic Blockade of EGFR Inhibits Renal... : Journal of the American Society of Nephrology (original) (raw)

Basic Research

Liu, Na*,†; Guo, Jian-Kan‡; Pang, Maoyin†; Tolbert, Evelyn†; Ponnusamy, Murugavel†; Gong, Rujun†; Bayliss, George†; Dworkin, Lance D.†; Yan, Haidong*; Zhuang, Shougang*,†

*Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China;

†Department of Medicine, Alpert Medical School, Brown University, Rhode Island Hospital, Providence, Rhode Island; and

‡Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut

Correspondence: Dr. Shougang Zhuang, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong New District, 200120 Shanghai, China, and Department of Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Prvidence, RI 02902. Email: [email protected]

Received May 20, 2011

Accepted January 3, 2012

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.