PT  - JOURNAL ARTICLE
AU  - Qian, Yuanyuan
AU  - Peng, Kesong
AU  - Qiu, Chenyu
AU  - Skibba, Melissa
AU  - Huang, Yi
AU  - Xu, Zheng
AU  - Zhang, Yali
AU  - Hu, Jie
AU  - Liang, Dandan
AU  - Zou, Chunpeng
AU  - Wang, Yi
AU  - Liang, Guang
TI  - Novel Epidermal Growth Factor Receptor Inhibitor Attenuates Angiotensin II–Induced Kidney Fibrosis
AID  - 10.1124/jpet.115.228080
DP  - 2016 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 32--42
VI  - 356
IP  - 1
4099  - http://jpet.aspetjournals.org/content/356/1/32.short
4100  - http://jpet.aspetjournals.org/content/356/1/32.full
SO  - J Pharmacol Exp Ther2016 Jan 01; 356
AB  - Chronic activation of renin-angiotensin system (RAS) greatly contributes to renal fibrosis and accelerates the progression of chronic kidney disease; however, the underlying molecular mechanism is poorly understood. Angiotensin II (Ang II), the central component of RAS, is a key regulator of renal fibrogenic destruction. Here we show that epidermal growth factor receptor (EGFR) plays an important role in Ang II–induced renal fibrosis. Inhibition of EGFR activation by novel small molecules or by short hairpin RNA knockdown in Ang II–treated SV40 mesangial cells in vitro suppresses protein kinase B and extracellular signal-related kinase signaling pathways and transforming growth factor-β/Sma- and Mad-related protein activation, and abolishes the accumulation of fibrotic markers such as connective tissue growth factor, collagen IV. The transactivation of EGFR by Ang II in SV40 cells depends on the phosphorylation of proto-oncogene tyrosine-protein kinase Src (c-Src) kinase. Further validation in vivo demonstrates that EGFR small molecule inhibitor successfully attenuates renal fibrosis and kidney dysfunction in a mouse model induced by Ang II infusion. These findings indicate a crucial role of EGFR in Ang II–dependent renal deterioration, and reveal EGFR inhibition as a new therapeutic strategy for preventing progression of chronic renal diseases.