Limits...
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.

Show MeSH

Related in: MedlinePlus

Administration of erlotinib inhibited activation of epidermal growth factor receptor (EGFR)-ERK and EGFR-Akt signaling pathways in response to ischemia–reperfusion (I–R) injury. Balb/c mice were administered vehicle or erlotinib daily beginning 1 day before surgery, and renal cortex tissue lysates were prepared at different time points as indicated and subjected to immunoprecipitation (IP; a) or immunoblotting (IB; a and b) analysis by using indicated antibodies. Representative data of 5–6 separate experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3376190&req=5

fig2: Administration of erlotinib inhibited activation of epidermal growth factor receptor (EGFR)-ERK and EGFR-Akt signaling pathways in response to ischemia–reperfusion (I–R) injury. Balb/c mice were administered vehicle or erlotinib daily beginning 1 day before surgery, and renal cortex tissue lysates were prepared at different time points as indicated and subjected to immunoprecipitation (IP; a) or immunoblotting (IB; a and b) analysis by using indicated antibodies. Representative data of 5–6 separate experiments.

Mentions: As an initial evaluation of the role of phosphorylation of EGF RTK in regeneration following I–R injury, we treated mice with erlotinib, an aquinazoline-based agent that competes with adenosine triphosphate for binding with the intracellular catalytic domain of epidermal growth factor receptor (HER1/EGFR) tyrosine kinase, inhibiting phosphorylation.22 We found that EGFR phosphorylation increased after I–R injury and was inhibited by erlotinib. In addition, erlotinib markedly blunted phosphorylation of p44/p42 ERKs and Akt in response to I–R injury as shown in Figure 2a and b. These data confirmed that activation of p44/p42 ERKs and Akt in response to I–R injury are downstream of EGF receptor phosphorylation.


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)

Administration of erlotinib inhibited activation of epidermal growth factor receptor (EGFR)-ERK and EGFR-Akt signaling pathways in response to ischemia–reperfusion (I–R) injury. Balb/c mice were administered vehicle or erlotinib daily beginning 1 day before surgery, and renal cortex tissue lysates were prepared at different time points as indicated and subjected to immunoprecipitation (IP; a) or immunoblotting (IB; a and b) analysis by using indicated antibodies. Representative data of 5–6 separate experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Administration of erlotinib inhibited activation of epidermal growth factor receptor (EGFR)-ERK and EGFR-Akt signaling pathways in response to ischemia–reperfusion (I–R) injury. Balb/c mice were administered vehicle or erlotinib daily beginning 1 day before surgery, and renal cortex tissue lysates were prepared at different time points as indicated and subjected to immunoprecipitation (IP; a) or immunoblotting (IB; a and b) analysis by using indicated antibodies. Representative data of 5–6 separate experiments.
Mentions: As an initial evaluation of the role of phosphorylation of EGF RTK in regeneration following I–R injury, we treated mice with erlotinib, an aquinazoline-based agent that competes with adenosine triphosphate for binding with the intracellular catalytic domain of epidermal growth factor receptor (HER1/EGFR) tyrosine kinase, inhibiting phosphorylation.22 We found that EGFR phosphorylation increased after I–R injury and was inhibited by erlotinib. In addition, erlotinib markedly blunted phosphorylation of p44/p42 ERKs and Akt in response to I–R injury as shown in Figure 2a and b. These data confirmed that activation of p44/p42 ERKs and Akt in response to I–R injury are downstream of EGF receptor phosphorylation.

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