Original Research Article
Src family kinases regulate renal epithelial dedifferentiation through activation of EGFR/PI3K signaling
Version of Record online: 23 JAN 2012
Copyright © 2011 Wiley Periodicals, Inc.
Journal of Cellular Physiology
Volume 227, Issue 5, pages 2138–2144, May 2012
How to Cite
Zhuang, S., Duan, M. and Yan, Y. (2012), Src family kinases regulate renal epithelial dedifferentiation through activation of EGFR/PI3K signaling. J. Cell. Physiol., 227: 2138–2144. doi: 10.1002/jcp.22946
- Issue online: 23 JAN 2012
- Version of Record online: 23 JAN 2012
- Accepted manuscript online: 21 JUL 2011 09:28AM EST
- Manuscript Accepted: 14 JUL 2011
- Manuscript Received: 14 DEC 2010
- National Institutes of Health. Grant Numbers: DK-071997, DK-085065
Dedifferentiation, a process by which differentiated cells become mesenchymal-like proliferating cells, is the first step in renal epithelium repair and occurs in vivo after acute kidney injury and in vitro in primary culture. However, the underlying mechanism remains poorly understood. In this report, we studied the signaling events that mediate dedifferentiation of proximal renal tubular cells (RPTC) in primary culture. RPTC dedifferentiation characterized by increased expression of vimentin concurrent with decreased expression of cytokeratin-18 was observed at 24 h after the initial plating of freshly isolated proximal tubules and persisted for 72 h. At 96 h, RPTC started to redifferentiate as revealed by reciprocal expression of cytokeratin-18 and vimentin and completed at 120 h. Phosphorylation levels of Src, epidermal growth factor receptor (EGFR), AKT (a target of phosphoinositide-3-kinase (PI3K)), and ERK1/2 were increased in the early time course of culture (<72 h). Inhibition of Src family kinases (SFKs) with PP1 blocked EGFR, AKT, and ERK1/2 phosphorylation, as well as RPTC dedifferentiation. Inhibition of EGFR with AG1478 also blocked AKT and ERK1/2 phosphorylation and RPTC dedifferentiation. Although inactivation of the PI3K/AKT pathway with LY294002 inhibited RPTC dedifferentiation, blocking the ERK1/2 pathway with U0126 did not show such an effect. Moreover, inhibition of SFKs, EGFR, PI3K/AKT, but not ERK1/2 pathways abrogated RPTC outgrowth and SFK inhibition decreased RPTC proliferation and migration. These findings demonstrate a critical role of SFKs in mediating RPTC dedifferentiation through activation of the EGFR/PI3K signaling pathway. J. Cell. Physiol. 227: 2138–2144, 2012. © 2011 Wiley Periodicals, Inc.