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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

Erlotinib administration delayed renal structural and functional recovery from ischemia–reperfusion (I–R) injury. Balb/c mice were administered vehicle or erlotinib daily beginning 1 day before surgery, and blood urea nitrogen (BUN; a) and serum creatinine (b) were measured at different time points after I–R injury as indicated. Histology (original magnification × 200) is indicated for days 1 and 6 after I–R injury (c), and tubular damages were scored as indicated in Materials and Methods (d). Values are means±s.e.m. (n=6–8 for each group). **P<0.001, *P<0.05. NS, nonsignificant.
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fig3: Erlotinib administration delayed renal structural and functional recovery from ischemia–reperfusion (I–R) injury. Balb/c mice were administered vehicle or erlotinib daily beginning 1 day before surgery, and blood urea nitrogen (BUN; a) and serum creatinine (b) were measured at different time points after I–R injury as indicated. Histology (original magnification × 200) is indicated for days 1 and 6 after I–R injury (c), and tubular damages were scored as indicated in Materials and Methods (d). Values are means±s.e.m. (n=6–8 for each group). **P<0.001, *P<0.05. NS, nonsignificant.

Mentions: Erlotinib treatment significantly blocked the functional and structural recovery from I–R injury, although it did not alter the initial renal functional impairment and structural injury, as shown in Figure 3. To determine the effects of erlotinib on tubular epithelial cell proliferation after I–R injury, we performed Ki67 immunostaining. As shown in Figure 4, in vehicle-treated mice, Ki67 immunoreactivity peaked at 48 h, and very few proliferating cells were detected 6 days after reperfusion. However, erlotinib treatment significantly decreased the number of positive staining cells at 48 h after reperfusion and delayed cell proliferation.


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)

Erlotinib administration delayed renal structural and functional recovery from ischemia–reperfusion (I–R) injury. Balb/c mice were administered vehicle or erlotinib daily beginning 1 day before surgery, and blood urea nitrogen (BUN; a) and serum creatinine (b) were measured at different time points after I–R injury as indicated. Histology (original magnification × 200) is indicated for days 1 and 6 after I–R injury (c), and tubular damages were scored as indicated in Materials and Methods (d). Values are means±s.e.m. (n=6–8 for each group). **P<0.001, *P<0.05. NS, nonsignificant.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Erlotinib administration delayed renal structural and functional recovery from ischemia–reperfusion (I–R) injury. Balb/c mice were administered vehicle or erlotinib daily beginning 1 day before surgery, and blood urea nitrogen (BUN; a) and serum creatinine (b) were measured at different time points after I–R injury as indicated. Histology (original magnification × 200) is indicated for days 1 and 6 after I–R injury (c), and tubular damages were scored as indicated in Materials and Methods (d). Values are means±s.e.m. (n=6–8 for each group). **P<0.001, *P<0.05. NS, nonsignificant.
Mentions: Erlotinib treatment significantly blocked the functional and structural recovery from I–R injury, although it did not alter the initial renal functional impairment and structural injury, as shown in Figure 3. To determine the effects of erlotinib on tubular epithelial cell proliferation after I–R injury, we performed Ki67 immunostaining. As shown in Figure 4, in vehicle-treated mice, Ki67 immunoreactivity peaked at 48 h, and very few proliferating cells were detected 6 days after reperfusion. However, erlotinib treatment significantly decreased the number of positive staining cells at 48 h after reperfusion and delayed cell proliferation.

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