Kidney-specific reconstitution of the A1 adenosine receptor in A1 adenosine receptor knockout mice reduces renal ischemia-reperfusion injury.
Kidney-specific reconstitution of the A1 adenosine receptor in A1 adenosine receptor knockout mice reduces renal ischemia-reperfusion injury.
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DOI：
10.1038/ki.2008.699
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发表时间：
2009-04
影响因子：
19.6
通讯作者：
Lee, H. Thomas
中科院分区：
文献类型：
--
作者：
Kim, Minjae;Chen, Sean W. C.;Park, Sang Won;Kim, Mihwa;D'Agati, Vivette D.;Yang, Jay;Lee, H. Thomas
腺苷A1受体（A1AR）的基因缺失增加了缺血再灌注损伤后的肾损伤，表明受体激活在体内具有保护作用。在这里，我们通过在A1AR敲除小鼠中表达人类A1AR来验证这一假设。基因敲除小鼠在肾内注射生理盐水或编码增强型绿色荧光蛋白（EGFP）或EGFP-human- a1ar的慢病毒2天后诱导肾缺血再灌注。我们发现后一种方法在敲除小鼠的肾脏中诱导了报告蛋白的强烈表达。与注射生理盐水或对照慢病毒的小鼠相比，肾特异性人a1ar重构小鼠的血浆肌酐、肾小管坏死、细胞凋亡和肾小管炎症均显著降低，这是由损伤后肾脏白细胞浸润、促炎细胞因子和细胞间粘附分子-1表达减少所证明的。此外，两组对照小鼠肾损伤后，近端小管上皮丝状(F)肌动蛋白细胞骨架均有明显破坏，而重组小鼠的肾小管肌动蛋白细胞骨架保存较好，与人类a1ar共定位。与肾损伤减轻一致，热休克蛋白27的表达显著增加，也与保留的f -肌动蛋白细胞骨架共定位。我们的研究结果表明，在肾脏中选择性表达细胞保护性A1ARs可以减轻肾损伤。
Genetic deletion of the adenosine A1 receptor (A1AR) increased renal injury following ischemia-reperfusion injury suggesting that receptor activation is protective in vivo. Here we tested this hypothesis by expressing the human-A1AR in A1AR knockout mice. Renal ischemia-reperfusion was induced in knockout mice 2 days after intrarenal injection of saline or a lentivirus encoding enhanced green fluorescent protein (EGFP) or EGFP-human-A1AR. We found that the latter procedure induced a robust expression of the reporter protein in the kidneys of knockout mice. Mice with kidney-specific human-A1AR reconstitution had significantly lower plasma creatinine, tubular necrosis, apoptosis, and tubular inflammation as evidenced by decreased leukocyte infiltration, pro-inflammatory cytokine, and intercellular adhesion molecule-1 expression in the kidney following injury compared to mice injected with saline or the control lentivirus. Additionally, there were marked disruptions of the proximal tubule epithelial filamentous (F)-actin cytoskeleton in both sets of control mice upon renal injury, whereas the reconstituted mice had better preservation of the renal tubule actin cytoskeleton, which co-localized with the human-A1ARs. Consistent with reduced renal injury, there was a significant increase in heat shock protein-27 expression, also co-localizing with the preserved F-actin cytoskeleton. Our findings suggest that selective expression of cytoprotective A1ARs in the kidney can attenuate renal injury.
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影响因子：
15.9
作者：
HEYMAN, SN;BREZIS, M;ROSEN, S
通讯作者：
ROSEN, S
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通讯作者：
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BREZIS, M
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作者：
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