Selective activation of epidermal growth factor receptor in renal proximal tubule induces tubulointerstitial fibrosis

Jessica M. Overstreet, Yinqiu Wang, Xin Wang, Aolei Niu, Leslie S. Gewin, Bing Yao, Raymond C. Harris, Ming Zhi Zhang

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Epidermal growth factor receptor (EGFR) has been implicated in the pathogenesis of diabetic nephropathy and renal fibrosis; however, the causative role of sustained EGFR activation is unclear. Here, we generated a novel kidney fibrotic mouse model of persistent EGFR activation by selectively expressing the EGFR ligand, human heparin-binding EGF-like growth factor (hHB-EGF), in renal proximal tubule epithelium. hHB-EGF expression increased tyrosine kinase phosphorylation of EGFR and the subsequent activation of downstream signaling pathways, including ERK and AKT, as well as the profibrotic TGF-β1/SMAD pathway. Epithelial-specific activation of EGFR was sufficient to promote spontaneous and progressive renal tubulointerstitial fibrosis, as characterized by increased collagen deposition, immune cell infiltration, and α-smooth muscle actin (α-SMA)–positive myofibroblasts. Tubule-specific EGFR activation promoted epithelial dedifferentiation and cell-cycle arrest. Furthermore, EGFR activation in epithelial cells promoted the proliferation of α-SMA+ myofibroblasts in a paracrine manner. Genetic or pharmacologic inhibition of EGFR tyrosine kinase activity or downstream MEK activity attenuated the fibrotic phenotype. This study provides definitive evidence that sustained activation of EGFR in proximal epithelia is sufficient to cause spontaneous, progressive renal tubulointerstitial fibrosis, evident by epithelial dedifferentiation, increased myofibroblasts, immune cell infiltration, and increased matrix deposition.

Original languageEnglish
Pages (from-to)4407-4421
Number of pages15
JournalFASEB Journal
Volume31
Issue number10
DOIs
StatePublished - Oct 2017

Keywords

  • EGFR
  • EMT
  • Epithelial dedifferentiation
  • HB-EGF
  • Tubular dysfunction

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