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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Novel Epidermal Growth Factor Receptor Inhibitor Attenuates Angiotensin II–Induced Kidney Fibrosis

Yuanyuan Qian, Kesong Peng, Chenyu Qiu, Melissa Skibba, Yi Huang, Zheng Xu, Yali Zhang, Jie Hu, Dandan Liang, Chunpeng Zou, Yi Wang and Guang Liang
Journal of Pharmacology and Experimental Therapeutics January 2016, 356 (1) 32-42; DOI: https://doi.org/10.1124/jpet.115.228080
Yuanyuan Qian
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
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Kesong Peng
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
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Chenyu Qiu
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
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Melissa Skibba
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
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Yi Huang
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
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Zheng Xu
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
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Yali Zhang
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
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Jie Hu
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
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Dandan Liang
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
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Chunpeng Zou
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
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Yi Wang
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
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Guang Liang
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
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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.

Footnotes

    • Received July 25, 2015.
    • Accepted October 27, 2015.
  • Y.Q. and K.P. contributed equally to this work.

  • This work was supported by the National Natural Science Funding of China (81503123, 81502912, and 21472142), Zhejiang Provincial Natural Science Funding (LQ15H120005, LQ14H310003, and LY13H060007), and High-Level Innovative Talent Funding of Zhejiang Department of Health (2010-017).

  • dx.doi.org/10.1124/jpet.115.228080.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 356 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 356, Issue 1
1 Jan 2016
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

EGFR Inhibition Attenuates Kidney Fibrosis

Yuanyuan Qian, Kesong Peng, Chenyu Qiu, Melissa Skibba, Yi Huang, Zheng Xu, Yali Zhang, Jie Hu, Dandan Liang, Chunpeng Zou, Yi Wang and Guang Liang
Journal of Pharmacology and Experimental Therapeutics January 1, 2016, 356 (1) 32-42; DOI: https://doi.org/10.1124/jpet.115.228080

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

EGFR Inhibition Attenuates Kidney Fibrosis

Yuanyuan Qian, Kesong Peng, Chenyu Qiu, Melissa Skibba, Yi Huang, Zheng Xu, Yali Zhang, Jie Hu, Dandan Liang, Chunpeng Zou, Yi Wang and Guang Liang
Journal of Pharmacology and Experimental Therapeutics January 1, 2016, 356 (1) 32-42; DOI: https://doi.org/10.1124/jpet.115.228080
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