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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

Phospho-epidermal growth factor receptor (EGFR) was the most markedly upregulated receptor tyrosine kinase (RTK) in response to renal ischemia–reperfusion (I–R) injury. Wild-type Balb/c mice were subjected to sham (a) or bilateral renal I–R injury (b). Renal cortex tissue lysates of five mice were pooled and analyzed by Mouse Phospho-Receptor Tyrosine Kinase (Phospho-RTK) Array 48 h after surgery. MSPR, macrophage-stimulating protein receptor; pPDGF-Rα, phosphorylation of platelet-derived growth factor receptor alpha.
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fig1: Phospho-epidermal growth factor receptor (EGFR) was the most markedly upregulated receptor tyrosine kinase (RTK) in response to renal ischemia–reperfusion (I–R) injury. Wild-type Balb/c mice were subjected to sham (a) or bilateral renal I–R injury (b). Renal cortex tissue lysates of five mice were pooled and analyzed by Mouse Phospho-Receptor Tyrosine Kinase (Phospho-RTK) Array 48 h after surgery. MSPR, macrophage-stimulating protein receptor; pPDGF-Rα, phosphorylation of platelet-derived growth factor receptor alpha.

Mentions: To explore the potential receptor tyrosine kinases (RTKs) involved in kidney regeneration in response to I–R injury, we used a mouse phospho-RTK array to analyze the renal cortex tissue lysates after 2 days or 4 days reperfusion following bilateral kidney ischemia, and found that EGFR and ErbB2 were the most markedly phosphorylated kinases among the 39 different phosphorylated mouse RTKs included in the array (Supplementary Figure S1 online) in response to I–R injury within 48 h (Figure 1a and b). The only other positive signals detected indicated minimal phosphorylation of platelet-derived growth factor receptor alpha (PDGF-Rα) and macrophage-stimulating protein receptor (MSPR). After 4 days reperfusion, increased EGFR and ErbB2 activation was still present, albeit at a lower level, and no new tyrosine kinase receptor activation was detected (data not shown). These data indicate EGFR and ErbB2 to be the RTKs most apparently activated during the renal I–R injury repair process.


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)

Phospho-epidermal growth factor receptor (EGFR) was the most markedly upregulated receptor tyrosine kinase (RTK) in response to renal ischemia–reperfusion (I–R) injury. Wild-type Balb/c mice were subjected to sham (a) or bilateral renal I–R injury (b). Renal cortex tissue lysates of five mice were pooled and analyzed by Mouse Phospho-Receptor Tyrosine Kinase (Phospho-RTK) Array 48 h after surgery. MSPR, macrophage-stimulating protein receptor; pPDGF-Rα, phosphorylation of platelet-derived growth factor receptor alpha.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Phospho-epidermal growth factor receptor (EGFR) was the most markedly upregulated receptor tyrosine kinase (RTK) in response to renal ischemia–reperfusion (I–R) injury. Wild-type Balb/c mice were subjected to sham (a) or bilateral renal I–R injury (b). Renal cortex tissue lysates of five mice were pooled and analyzed by Mouse Phospho-Receptor Tyrosine Kinase (Phospho-RTK) Array 48 h after surgery. MSPR, macrophage-stimulating protein receptor; pPDGF-Rα, phosphorylation of platelet-derived growth factor receptor alpha.
Mentions: To explore the potential receptor tyrosine kinases (RTKs) involved in kidney regeneration in response to I–R injury, we used a mouse phospho-RTK array to analyze the renal cortex tissue lysates after 2 days or 4 days reperfusion following bilateral kidney ischemia, and found that EGFR and ErbB2 were the most markedly phosphorylated kinases among the 39 different phosphorylated mouse RTKs included in the array (Supplementary Figure S1 online) in response to I–R injury within 48 h (Figure 1a and b). The only other positive signals detected indicated minimal phosphorylation of platelet-derived growth factor receptor alpha (PDGF-Rα) and macrophage-stimulating protein receptor (MSPR). After 4 days reperfusion, increased EGFR and ErbB2 activation was still present, albeit at a lower level, and no new tyrosine kinase receptor activation was detected (data not shown). These data indicate EGFR and ErbB2 to be the RTKs most apparently activated during the renal I–R injury repair process.

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