Tubular p53 Regulates Multiple Genes to Mediate AKI
Tubular p53 Regulates Multiple Genes to Mediate AKI
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管状 p53 调节多个基因介导 AKI
DOI：
10.1681/asn.2013080902
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发表时间：
2014-10-01
影响因子：
13.6
通讯作者：
Dong, Zheng
中科院分区：
文献类型：
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作者：
Zhang, Dongshan;Liu, Yu;Dong, Zheng
p53在阿基中的致病作用在十年前就被提出，但仍然存在争议。事实上，最近的研究表明，抑制p53可以防止大鼠的缺血性阿基，但会加剧小鼠的阿基。一个有趣的可能性是p53在阿基中具有细胞类型特异性作用。为了确定管状p53的作用，我们产生了两个条件基因敲除小鼠模型，其中p53特异性地从近端小管或其他管状段消融，包括远端小管、Henle袢和髓集合管。近端小管p53敲除（PT-p53-KO）小鼠对缺血性和顺铂肾毒性阿基具有抗性，这通过肾功能、组织学、细胞凋亡和炎症分析来指示。然而，其他管状p53敲除（OT-p53-KO）小鼠对阿基敏感。从机制上讲，阿基与几种已知p53靶基因的上调相关，包括Bax、p53上调的凋亡调节因子-α、p21和Siva，并且这种相关性在PT-p53-KO小鼠中减弱。在整体表达分析中，缺血性阿基在野生型肾皮质组织中诱导了371个基因，但在PT-p53-KO组织中这些基因中的31个基因的诱导被废除。这31个基因包括细胞死亡、代谢、信号转导、氧化应激和线粒体的调节因子。这些结果表明，近端肾小管细胞中的p53促进阿基，而其他肾小管细胞中的p53不促进AKI。
A pathogenic role of p53 in AKI was suggested a decade ago but remains controversial. Indeed, recent work indicates that inhibition of p53 protects against ischemic AKI in rats but exacerbates AKI in mice. One intriguing possibility is that p53 has cell type-specific roles in AKI. To determine the role of tubular p53, we generated two conditional gene knockout mouse models, in which p53 is specifically ablated from proximal tubules or other tubular segments, including distal tubules, loops of Henle, and medullary collecting ducts. Proximal tubule p53 knockout (PT-p53-KO) mice were resistant to ischemic and cisplatin nephrotoxic AKI, which was indicated by the analysis of renal function, histology, apoptosis, and inflammation. However, other tubular p53 knockout (OT-p53-KO) mice were sensitive to AKI. Mechanistically, AKI associated with the upregulation of several known p53 target genes, including Bax, p53-upregulated modulator of apoptosis-α, p21, and Siva, and this association was attenuated in PT-p53-KO mice. In global expression analysis, ischemic AKI induced 371 genes in wild-type kidney cortical tissues, but the induction of 31 of these genes was abrogated in PT-p53-KO tissues. These 31 genes included regulators of cell death, metabolism, signal transduction, oxidative stress, and mitochondria. These results suggest that p53 in proximal tubular cells promotes AKI, whereas p53 in other tubular cells does not.