Deletion of the epidermal growth factor receptor in renal proximal tubule epithelial cells delays recovery from acute kidney injury.
Deletion of the epidermal growth factor receptor in renal proximal tubule epithelial cells delays recovery from acute kidney injury.
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DOI：
10.1038/ki.2012.43
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发表时间：
2012-07
影响因子：
19.6
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为了确定表皮生长因子受体 (EGFR) 激活在急性肾损伤 (AKI) 肾功能和结构恢复中的作用，我们培育了肾近曲小管中具有特定 EGFR 缺失的小鼠 (EGFRptKO)。缺血再灌注损伤在对照同窝小鼠中显着激活 EGFR；然而，在给予厄洛替尼（一种特定的 EGFR 酪氨酸激酶抑制剂）的基因敲除小鼠或野生型小鼠中，这种现象受到抑制。再灌注24小时后，EGFRptKO小鼠和对照小鼠的血尿素氮和血清肌酐增加到相当的水平，但敲除小鼠随后的肾功能恢复速度明显减慢。再灌注24小时后，敲除小鼠和抑制剂治疗的小鼠均具有与对照小鼠相似程度的组织学肾损伤，但在第6天，对照小鼠中几乎没有损伤的证据，而EGFRptKO和厄洛替尼治疗的小鼠仍具有持续的近端小管扩张、上皮简化和管型形成。此外，由于 ERK 和 Akt 信号传导减弱，肾细胞增殖被延迟。因此，我们的研究提供了遗传和药理学证据，表明近曲小管 EGFR 激活在急性肾损伤后的恢复阶段发挥着重要作用。
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 (EGFRptKO). 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 EGFRptKO 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 EGFRptKO 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.