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Deletion of the epidermal growth factor receptor in renal proximal tubule epithelial cells delays recovery from acute kidney injury.

Chen J, Chen JK, Harris RC - Kidney Int. (2012)

Bottom Line: 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)).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ray.harris@vanderbilt.edu

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.

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Related in: MedlinePlus

Renal proximal tubular epithelial cell epidermal growth factor receptor (EGFR) deletion delayed cell proliferation after ischemia–reperfusion (I–R) injury. Ki67 expression in EGFRptKO or EGFRf/f mouse kidneys was performed at days 2, 4, and 6 after I–R injury (a), and the positive staining cells were counted in each (original magnification × 400) field (b). Values are means±s.e.m. (n=5–8 for each group).
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fig7: Renal proximal tubular epithelial cell epidermal growth factor receptor (EGFR) deletion delayed cell proliferation after ischemia–reperfusion (I–R) injury. Ki67 expression in EGFRptKO or EGFRf/f mouse kidneys was performed at days 2, 4, and 6 after I–R injury (a), and the positive staining cells were counted in each (original magnification × 400) field (b). Values are means±s.e.m. (n=5–8 for each group).

Mentions: I–R-induced AKI is characterized by early, alloantigen-independent inflammation, which may mediate injury.24, 25, 26, 27 To understand whether proximal tubule EGFR was involved in I–R-induced infiltration of neutrophils or macrophages, we assayed the neutrophil marker, Gr-1, and macrophage marker, F4/80, and found that proximal tubule epithelial cell EGFR deletion did not affect infiltration of these cells in response to I–R injury (Supplementary Figures S2 and S3 online). However, Ki67 immunostaining indicated that proximal tubular epithelial cell EGFR deletion delayed cell proliferation after I–R injury (Figure 7). These results indicate that, in the proximal tubule, the EGF RTK phosphorylation cascade that activates the p44/p42 ERKs and Akt is an important mechanism for s renal tubular cell regeneration in response to I–R injury.


Deletion of the epidermal growth factor receptor in renal proximal tubule epithelial cells delays recovery from acute kidney injury.

Chen J, Chen JK, Harris RC - Kidney Int. (2012)

Renal proximal tubular epithelial cell epidermal growth factor receptor (EGFR) deletion delayed cell proliferation after ischemia–reperfusion (I–R) injury. Ki67 expression in EGFRptKO or EGFRf/f mouse kidneys was performed at days 2, 4, and 6 after I–R injury (a), and the positive staining cells were counted in each (original magnification × 400) field (b). Values are means±s.e.m. (n=5–8 for each group).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376190&req=5

fig7: Renal proximal tubular epithelial cell epidermal growth factor receptor (EGFR) deletion delayed cell proliferation after ischemia–reperfusion (I–R) injury. Ki67 expression in EGFRptKO or EGFRf/f mouse kidneys was performed at days 2, 4, and 6 after I–R injury (a), and the positive staining cells were counted in each (original magnification × 400) field (b). Values are means±s.e.m. (n=5–8 for each group).
Mentions: I–R-induced AKI is characterized by early, alloantigen-independent inflammation, which may mediate injury.24, 25, 26, 27 To understand whether proximal tubule EGFR was involved in I–R-induced infiltration of neutrophils or macrophages, we assayed the neutrophil marker, Gr-1, and macrophage marker, F4/80, and found that proximal tubule epithelial cell EGFR deletion did not affect infiltration of these cells in response to I–R injury (Supplementary Figures S2 and S3 online). However, Ki67 immunostaining indicated that proximal tubular epithelial cell EGFR deletion delayed cell proliferation after I–R injury (Figure 7). These results indicate that, in the proximal tubule, the EGF RTK phosphorylation cascade that activates the p44/p42 ERKs and Akt is an important mechanism for s renal tubular cell regeneration in response to I–R injury.

Bottom Line: 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)).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ray.harris@vanderbilt.edu

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.

Show MeSH
Related in: MedlinePlus