Regulation of dedifferentiation and redifferentiation in renal proximal tubular cells by the epidermal growth factor receptor.
Repair of injured renal epithelium is thought to be mediated by surviving renal proximal tubular cells (RPTC) that must dedifferentiate to allow the proliferation and migration necessary for epithelial regeneration. RPTC then redifferentiate to restore tubular structure and function. Current models suggest that epidermal growth factor receptor (EGFR) activation is required for dedifferentiation characterized by enhanced vimentin expression, decreased N-cadherin expression, spindle morphology, and loss of apical-basal polarity after injury. Because an in vitro model of RPTC redifferentiation has not been reported, and the mechanism(s) of redifferentiation has not been determined, we used rabbit RPTC in primary cultures to address these issues. H2O2 induced the dedifferentiated phenotype that persisted >48 h; redifferentiation occurred spontaneously in the absence of exogenous growth factors after 72 to 120 h. Phosphorylation of two tyrosine residues of EGFR increased 12 to 24 h, peaked at 24 h, and declined to basal levels by 48 h after injury. EGFR inhibition during dedifferentiation restored epithelial morphology and apical-basal polarity, and it decreased vimentin expression to control levels 24 h later. In contrast, exogenous epidermal growth factor addition increased vimentin expression and potentiated spindle morphology. p38 mitogen-activated protein kinase (MAPK) and transforming growth factor (TGF)-beta receptor inhibitors did not affect redifferentiation after H2O2 injury. Similar results were observed in a mechanical injury model. These experiments represent a new model for the investigation of RPTC redifferentiation after acute injury and identify a key regulator of redifferentiation: EGFR, independent of p38 MAPK and the TGF-beta receptor.
Hallman
Mark A
MA
Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, 280 Calhoun St., P.O.B. 250140, Charleston, SC 29425, USA.
Zhuang
Shougang
S
Schnellmann
Rick G
RG
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006861:Hydrogen Peroxide; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D010766:Phosphorylation; D011817:Rabbits; D014746:Vimentin / Q000378:metabolism
D015820:Cadherins; D027682:Cation Transport Proteins; D014746:Vimentin; D006861:Hydrogen Peroxide; D066246:ErbB Receptors; D000251:Adenosine Triphosphatases; C021838:sodium-translocating ATPase