p53 Is Renoprotective after Ischemic Kidney Injury by Reducing Inflammation
p53 Is Renoprotective after Ischemic Kidney Injury by Reducing Inflammation
复制标题
DOI：
10.1681/asn.2012050469
复制
发表时间：
2013-01-01
影响因子：
13.6
通讯作者：
Dagher, Pierre C.
中科院分区：
文献类型：
--
作者：
Sutton, Timothy A.;Hato, Takashi;Dagher, Pierre C.
在大鼠缺血AKI后，P53促进肾小管细胞凋亡。在这种情况下，急性药物抑制P53是保护性的，但慢性抑制会增强纤维化，表明P53在缺血性AKI中的作用尚不完全清楚。在这里，我们调查了P53基因缺失在缺血性AKI中是否也具有保护作用。令人惊讶的是，与野生型小鼠相比，P53基因敲除小鼠(P53(-/-))的肾脏损伤更严重，并且在缺血后表现出更多和更长时间的白细胞渗透。在野生型小鼠中用匹氟菊酯-α急性抑制P53与在P53(-/-)小鼠中观察到的结果相似。白细胞中缺乏P53的嵌合小鼠遭受与P53(-/-)小鼠相似的损伤，提示白细胞P53在缺血性AKI中起重要作用。与野生型小鼠相比，P53(-/-)和匹非菊酯-α治疗组小鼠肾脏中的巨噬细胞在缺血损伤后的抗炎M2表型所占比例较小。P53(-/-)和匹氟菊酯-α处理的小鼠缺血肾脏也表现出Kruppel样因子-4的表达减少，最后，在P53(-/-)和匹氟菊酯-α处理的小鼠腹膜炎模型中证实了P53的抗炎作用及其对巨噬细胞表型极化的影响。总之，与大鼠不同，炎症是小鼠缺血性AKI的特征；白细胞P53通过减少这种炎症的程度和持续时间以及通过促进抗炎的M2巨噬细胞表型而起到保护作用。J Am Soc Nephrol 24：113-124,2013。DOI：10.1681/ASN.2012050469
In the rat, p53 promotes tubular apoptosis after ischemic AKI. Acute pharmacologic inhibition of p53 is protective in this setting, but chronic inhibition enhances fibrosis, demonstrating that the role of p53 in ischemic AKI is incompletely understood. Here, we investigated whether genetic absence of p53 is also protective in ischemic AKI. Surprisingly, p53-knockout mice (p53(-/-)) had worse kidney injury, compared with wild-type mice, and exhibited increased and prolonged infiltration of leukocytes after ischemia. Acute inhibition of p53 with pifithrin-alpha in wild-type mice mimicked the observations in p53(-/-) mice. Chimeric mice that lacked p53 in leukocytes sustained injury similar to p53(-/-) mice, suggesting an important role for leukocyte p53 in ischemic AKI. Compared with wild-type mice, a smaller proportion of macrophages in the kidneys of p53(-/-) and pifithrin-alpha-treated mice after ischemic injury were the anti-inflammatory M2 phenotype. Ischemic kidneys of p53(-/-) and pifithrin-alpha-treated mice also showed reduced expression of Kruppel-like factor-4, Finally, models of peritonitis in p53(-/-) and pifithrin-alpha-treated mice confirmed the anti-inflammatory role of p53 and its effect on the polarization of macrophage phenotype. In summary, in contrast to the rat, inflammation characterizes ischemic AKI in mice; leukocyte p53 is protective by reducing the extent and duration of this inflammation and by promoting the anti-inflammatory M2 macrophage phenotype. J Am Soc Nephrol 24: 113-124, 2013. doi: 10.1681/ASN.2012050469