Requirement of the epidermal growth factor receptor in renal epithelial cell proliferation and migration

Abstract

We showed that renal proximal tubular cells (RPTC) can proliferate and migrate following plating and oxidant or mechanical injury in the absence of exogenous growth factors; however, the mechanisms of this response remain unclear. We examined whether epidermal growth factor receptor (EGFR) signaling is activated following plating and mechanical injury and mediates RPTC proliferation and migration. EGFR, Akt [a target of phosphoinositide-3-kinase (PI3K)], and ERK1/2 were activated after plating and mechanical injury, and their phosphorylation was further enhanced by addition of exogenous EGF. Inactivation of the EGFR with the selective inhibitor AG-1478 completely blocked phosphorylation of EGFR, Akt, and ERK1/2 and blocked cell proliferation and migration after plating and injury. Inhibition of PI3K with LY-294002 blocked Akt phosphorylation and proliferation, whereas U-0126 blocked ERK1/2 phosphorylation but had no effect on proliferation. Furthermore, p38 was phosphorylated following mechanical injury and the p38 inhibitor SB-203580 blocked p38 phosphorylation and cell migration. In contrast, neither PI3K nor ERK1/2 inhibition blocked cell migration. These results show that EGFR activation is required for RPTC proliferation and migration and that proliferation is mediated by PI3K, whereas migration is mediated by p38.

p38 Kinase-mediated Transactivation of the Epidermal Growth Factor Receptor Is Required for Dedifferentiation of Renal Epithelial Cells after Oxidant Injury

“…Our studies have shown that the EGF receptor mediates RPTC proliferation and migration after mechanical injury, plating of renal proximal tubules (22), and H 2 O 2 -induced EGF receptor activation (43). We suggested that the EGF receptor is critical for the regenerative response in renal epithelial cells and can be activated in response to oxidant injury.…”

“…It is up-regulated in rats and rabbits after ischemia/reperfusion injury and in humans with acute renal failure (17)(18)(19). Activation of the EGF receptor with exogenous EGF promotes RPTC proliferation and migration (20,21), and inhibition of the EGF receptor blocks RPTC proliferation and migration (22). Wang and co-workers (23) recently found a profound decrease in the rate of functional and structural recovery of the tubular epithelia after acute renal failure induced by mercuric chloride in mice with an EGF receptor point mutation that reduces the receptor tyrosine kinase activity.…”

Collective migration of an epithelial monolayer in response to a model wound

“…Growth factors and particularly HGF (hepatocyte growth factors) are known to promote scattering and motility of epithelial cells and have a proven effect on healing (13)(14)(15). Several theoretical models have thus described the stimulation of the proliferation and migration of the cells by chemical cues such as these growth factors (16)(17)(18), including a possible autocrine activity of the border cells (19).…”

Collective cell migration patterns: Follow the leader

“…The authors have examined the role of the cell-cell contacts by adding growth factors that are known to increase cell motility (10,11) and reduce cell-cell adhesion. In the presence of these growth factors, the cell culture front moves rapidly, and almost all of the leading cells develop polarized shapes with lamellipodia.…”

“…No large-scale patterns or cell columns are found in this case because all of the cells in the moving front behave as leaders. Note that when cells move in a more dispersed manner and do not maintain a strictly continuous front, there also seems to be no pattern-forming or cell column development as a result of the wound-healing motility (10)(11)(12).…”