title: Deletion of the epidermal growth factor receptor in renal proximal tubule epithelial cells delays recovery from acute kidney injury.
abstract: To determine the role of epidermal growth factor receptor (EGFR) activation in renal functional and structural recovery from acute kidney injury (AKI), we generated mice with a specific EGFR deletion in the renal proximal tubule (EGFR(ptKO)). Ischemia-reperfusion injury markedly activated EGFR in control littermate mice; however, this was inhibited in either the knockout or wild-type mice given erlotinib, a specific EGFR tyrosine kinase inhibitor. Blood urea nitrogen and serum creatinine increased to a comparable level in EGFR(ptKO) and control mice 24 h after reperfusion, but the subsequent rate of renal function recovery was markedly slowed in the knockout mice. Twenty-four hours after reperfusion, both the knockout and the inhibitor-treated mice had a similar degree of histologic renal injury as control mice, but at day 6 there was minimal evidence of injury in the control mice while both EGFR(ptKO) and erlotinib-treated mice still had persistent proximal tubule dilation, epithelial simplification, and cast formation. Additionally, renal cell proliferation was delayed due to decreased ERK and Akt signaling. Thus, our studies provide both genetic and pharmacologic evidence that proximal tubule EGFR activation plays an important role in the recovery phase after acute kidney injury.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ray.harris@vanderbilt.edu
authors.forename: Jianchun
authors.initials: J
authors.lastname: Chen
authors.forename: Jian-Kang
authors.initials: JK
authors.lastname: Chen
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000172:deficiency* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017353:Gene Deletion; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D020127:Recovery of Function; D015427:Reperfusion Injury / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors
chemical_list: D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D003404:Creatinine; D000069347:Erlotinib Hydrochloride; D058539:Phosphatidylinositol 3-Kinase; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases