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1 Department of Pharceutical Sciences, Medical University of South Carolina, Charleston, SC, USA
* To whom correspondence should be addressed. E-mail: Schnell{at}musc.edu.
We have shown 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 extracellular signaling regulated kinase 1/2 (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 AG1478 completely blocked phosphorylation of EGFR, Akt and ERK1/2, and blocked cell proliferation and migration after plating and injury. Inhibition of PI3K with LY294002 blocked Akt phosphorylation and proliferation while U0126 blocked ERK1/2 phosphorylation but had no effect on proliferation. Further, p38 was phosphorylated following mechanical injury and the p38 inhibitor SB203580 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 while migration is mediated by p38.
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