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Selective activation of epidermal growth factor receptor in renal proximal tubule induces tubulointerstitial fibrosis
- Source :
- The FASEB Journal. 31:4407-4421
- Publication Year :
- 2017
- Publisher :
- Wiley, 2017.
-
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.—Overstreet, J. M., Wang, Y., Wang, X., Niu, A., Gewin, L. S., Yao, B., Harris, R. C., Zhang, M.-Z. Selective activation of epidermal growth factor receptor in renal proximal tubule induces tubulointerstitial fibrosis.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
medicine.medical_specialty
medicine.medical_treatment
Mice, Transgenic
Biology
Kidney
Biochemistry
Kidney Tubules, Proximal
03 medical and health sciences
Paracrine signalling
Internal medicine
Genetics
medicine
Renal fibrosis
Animals
Humans
Epidermal growth factor receptor
Extracellular Signal-Regulated MAP Kinases
Myofibroblasts
Molecular Biology
Protein kinase B
Research
Growth factor
Epithelial Cells
Cell Cycle Checkpoints
Fibrosis
ErbB Receptors
030104 developmental biology
Endocrinology
medicine.anatomical_structure
Tubulointerstitial fibrosis
Cancer research
biology.protein
Signal Transduction
Biotechnology
Subjects
Details
- ISSN :
- 15306860 and 08926638
- Volume :
- 31
- Database :
- OpenAIRE
- Journal :
- The FASEB Journal
- Accession number :
- edsair.doi.dedup.....6a69d1f8bbbbb1f030ca9d580818dbd7