title: Novel Epidermal Growth Factor Receptor Inhibitor Attenuates Angiotensin II-Induced Kidney Fibrosis.
abstract: 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.
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science (Y.Q., K.P., C.Q., M.S., Y.H., Z.X., Y.Z., J.H., D.L., Y.W., and G.L.); Department of Ultrasonography, 2nd Affiliated Hospital (C.Z.), Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science (Y.Q., K.P., C.Q., M.S., Y.H., Z.X., Y.Z., J.H., D.L., Y.W., and G.L.); Department of Ultrasonography, 2nd Affiliated Hospital (C.Z.), Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Kesong
authors.initials: K
authors.lastname: Peng
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science (Y.Q., K.P., C.Q., M.S., Y.H., Z.X., Y.Z., J.H., D.L., Y.W., and G.L.); Department of Ultrasonography, 2nd Affiliated Hospital (C.Z.), Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Chenyu
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science (Y.Q., K.P., C.Q., M.S., Y.H., Z.X., Y.Z., J.H., D.L., Y.W., and G.L.); Department of Ultrasonography, 2nd Affiliated Hospital (C.Z.), Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Melissa
authors.initials: M
authors.lastname: Skibba
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science (Y.Q., K.P., C.Q., M.S., Y.H., Z.X., Y.Z., J.H., D.L., Y.W., and G.L.); Department of Ultrasonography, 2nd Affiliated Hospital (C.Z.), Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science (Y.Q., K.P., C.Q., M.S., Y.H., Z.X., Y.Z., J.H., D.L., Y.W., and G.L.); Department of Ultrasonography, 2nd Affiliated Hospital (C.Z.), Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science (Y.Q., K.P., C.Q., M.S., Y.H., Z.X., Y.Z., J.H., D.L., Y.W., and G.L.); Department of Ultrasonography, 2nd Affiliated Hospital (C.Z.), Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science (Y.Q., K.P., C.Q., M.S., Y.H., Z.X., Y.Z., J.H., D.L., Y.W., and G.L.); Department of Ultrasonography, 2nd Affiliated Hospital (C.Z.), Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science (Y.Q., K.P., C.Q., M.S., Y.H., Z.X., Y.Z., J.H., D.L., Y.W., and G.L.); Department of Ultrasonography, 2nd Affiliated Hospital (C.Z.), Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Liang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science (Y.Q., K.P., C.Q., M.S., Y.H., Z.X., Y.Z., J.H., D.L., Y.W., and G.L.); Department of Ultrasonography, 2nd Affiliated Hospital (C.Z.), Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Chunpeng
authors.initials: C
authors.lastname: Zou
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science (Y.Q., K.P., C.Q., M.S., Y.H., Z.X., Y.Z., J.H., D.L., Y.W., and G.L.); Department of Ultrasonography, 2nd Affiliated Hospital (C.Z.), Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science (Y.Q., K.P., C.Q., M.S., Y.H., Z.X., Y.Z., J.H., D.L., Y.W., and G.L.); Department of Ultrasonography, 2nd Affiliated Hospital (C.Z.), Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China wzmcliangguang@163.com.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D000199:Actins / Q000187:drug effects; D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000187:drug effects; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005355:Fibrosis; D055785:Gene Knockdown Techniques; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D050527:Mesangial Cells / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects; D012097:Repressor Proteins / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000199:Actins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D024141:Collagen Type IV; C499479:Mad protein, mouse; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; C544013:alpha-smooth muscle actin, mouse; D000804:Angiotensin II; D066246:ErbB Receptors; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases