Epiregulin promotes proliferation and migration of renal proximal tubular cells.
Epiregulin is an epidermal growth factor (EGF) member that activates ErBB1 and ErBB4 homodimers and all possible heterodimeric ErbB complexes. Because its role in renal cell regeneration has not been investigated, we assessed the effect of exogenous epiregulin on regeneration of renal proximal tubular cells (RPTC) in primary culture. Epiregulin (10 ng/ml) was equivalent to EGF (10 ng/ml) in enhancing RPTC proliferation and migration. Epiregulin induced activation of the EGF receptor (EGFR), Akt, a downstream kinase of phosphoinositide 3-kinase (PI3K), and extracellular signaling-regulated kinase 1/2 (ERK1/2). Treatment with AG1478, a specific EGFR inhibitor, blocked phosphorylation of EGFR, Akt, ERK1/2, proliferation, and migration. Furthermore, inactivation of PI3K with LY-294002 blocked epiregulin-induced RPTC proliferation and, to a lesser extent, migration. However, blockade of ERK1/2 had no such effects. We suggest that epiregulin is a potent mitogen for renal epithelial cells and may contribute to renal regeneration through activation of EGFR and PI3/Akt pathways.
Zhuang
Shougang
S
Dept. of Medicine, Brown University School of Medicine, Providence, RI 02903, USA. szhuang@lifespan.org
Yan
Yan
Y
Daubert
Rebecca A
RA
Schnellmann
Rick G
RG
D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066260:Epiregulin; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D011817:Rabbits; D020032:Tyrphostins / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects
D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D066260:Epiregulin; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D009570:Nitriles; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; C113580:U 0126; C101044:RTKI cpd; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one