Journal
PHYSIOLOGICAL REPORTS
Volume 5, Issue 18, Pages -Publisher
WILEY
DOI: 10.14814/phy2.13453
Keywords
EGF; HIF-1 alpha; proliferation; proximal tubule cells; VEGF-A
Categories
Funding
- University of Iowa Stead Family Competitive Research Award the Fraternal Order of Eagles Charity Fund
- National Institutes of Health [RO1 DK090053]
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Proximal tubule cell (PTC) proliferation is critical for tubular regeneration and recovery from acute kidney injury. Epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF-A) are important for the maintenance of tubulointerstitial integrity and can stimulate PTC proliferation. We utilized HK-2 cells, an immortalized human PTC line, to characterize the EGF-dependent regulation of VEGF-A secretion and proliferation in PTCs. We demonstrate that EGF stimulates VEGF-A secretion via the EGF receptor (EGFR) and stimulates cell proliferation via activation of the VEGF receptor, VEGFR-2. EGFR activation promotes MAPK (ERK1/2) activation and HIF-1 alpha expression, which are required for basal and EGF-stimulated VEGF-A secretion. EGF also stimulates the phosphorylation of P70S6 kinase (P70S6K), the downstream target of mTORC1. Rapamycin decreased basal and EGF stimulated HIF-1 alpha and enhanced MAPK (ERK1/2) activation, while MAPK (ERK/12) inhibition downregulated HIF-1 alpha expression and the phosphorylation of p70S6K. EGF stimulation of p70S6K was also independent of p-AKT. Inhibition of the mTORC1 pathway with rapamycin abolished phosphorylation of p70S6K but had no effect on VEGF-A secretion, indicating that EGF-stimulated VEGF-A secretion did not require mTORC1 pathway activation. We demonstrate evidence of a complex crosstalk between the MAPK/ERK and mTORC1 pathways, wherein MAPK (ERK1/2) activation stimulates p-P70S6K, while p-P70S6K activation seems to inhibit MAPK (ERK1/2) in EGF-treated HK-2 cells. Our results suggest that EGF stimulates MAPK (ERK1/2) in HK-2 cells, which in turn increases HIF-1 alpha expression and VEGF-A secretion, indicating that VEGF-A mediates EGF-stimulated cell proliferation as an autocrine proximal tubular epithelial cell growth factor.
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