Zhang Dongshan, Liu Yu, Wei Qingqing, Huo Yuqing, Liu Kebin, Liu Fuyou, Dong Zheng
Departments of Emergency Medicine and Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and Department of Cellular Biology and Anatomy, Vascular Biology Center and Department of Biochemistry and Molecular Biology, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia.
Department of Cellular Biology and Anatomy, Vascular Biology Center and Department of Biochemistry and Molecular Biology, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia.
J Am Soc Nephrol. 2014 Oct;25(10):2278-89. doi: 10.1681/ASN.2013080902. Epub 2014 Apr 3.
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.
十年前就有人提出p53在急性肾损伤（AKI）中具有致病作用，但这一观点仍存在争议。的确，最近的研究表明，抑制p53可保护大鼠免受缺血性AKI的影响，但却会加重小鼠的AKI。一种有趣的可能性是，p53在AKI中具有细胞类型特异性作用。为了确定肾小管p53的作用，我们构建了两种条件性基因敲除小鼠模型，其中p53在近端小管或其他肾小管节段（包括远端小管、髓袢和髓质集合管）中被特异性敲除。通过对肾功能、组织学、细胞凋亡和炎症的分析表明，近端小管p53敲除（PT-p53-KO）小鼠对缺血性和顺铂肾毒性AKI具有抗性。然而，其他肾小管p53敲除（OT-p53-KO）小鼠对AKI敏感。从机制上讲，AKI与几种已知的p53靶基因（包括Bax、p53上调的凋亡调节因子-α、p21和Siva）的上调有关，而这种关联在PT-p53-KO小鼠中减弱。在全局表达分析中，缺血性AKI在野生型肾皮质组织中诱导了371个基因，但其中31个基因的诱导在PT-p53-KO组织中被消除。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，近端小管细胞中的p53促进AKI，而其他肾小管细胞中的p53则不然。
