Targeted deletion of p53 in the proximal tubule prevents ischemic renal injury.
Targeted deletion of p53 in the proximal tubule prevents ischemic renal injury.
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DOI：
10.1681/asn.2013121270
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发表时间：
2014-12
期刊：
影响因子：
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通讯作者：
Y. Ying;Jinu Kim;Sherry Westphal;Kelly E Long;B. Padanilam
中科院分区：
文献类型：
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作者：
Y. Ying;Jinu Kim;Sherry Westphal;Kelly E Long;B. Padanilam
p53对肾功能不全、炎症和肾小管细胞死亡（缺血性肾损伤（IRI）的标志性特征）的作用尚未明确。在这里，我们研究了近端小管细胞（PTC）特异性p53激活对小鼠肾缺血/再灌注损伤的短期和长期后果的作用。IRI后，与野生型小鼠相比，PTC特异性缺失p53（p53敲除[KO]）的小鼠全肾p53及其靶基因表达水平降低，肾功能改善，表现为血浆肌酐和BUN水平降低，肾组织学损伤、氧化应激以及中性粒细胞和巨噬细胞浸润减轻。值得注意的是，在p53 KO缺血性肾脏以及氧化剂损伤的p53缺陷型原发性PTC和pifithrin-α处理的PTC系中，坏死细胞死亡减弱。p53 KO缺血肾中氧化应激减少和PARP 1和Bax表达减少可能是坏死减少的原因。在p53 KO缺血性肾脏中，细胞凋亡和促凋亡p53靶点（包括Bid和Siva）的表达也显著减少，G2/M期细胞周期阻滞减弱。此外，在p53 KO小鼠中，IRI诱导的TGF-β活化以及炎症和间质纤维化的长期发展显著减少。总之，PTC中p53的特异性缺失通过减少坏死、凋亡和炎症保护肾脏免受IRI后的功能和组织学恶化，并通过防止间质纤维化来调节IRI的长期后遗症。
The contribution of p53 to kidney dysfunction, inflammation, and tubular cell death, hallmark features of ischemic renal injury (IRI), remains undefined. Here, we studied the role of proximal tubule cell (PTC)-specific p53 activation on the short- and long-term consequences of renal ischemia/reperfusion injury in mice. After IRI, mice with PTC-specific deletion of p53 (p53 knockout [KO]) had diminished whole-kidney expression levels of p53 and its target genes, improved renal function, which was shown by decreased plasma levels of creatinine and BUN, and attenuated renal histologic damage, oxidative stress, and infiltration of neutrophils and macrophages compared with wild-type mice. Notably, necrotic cell death was attenuated in p53 KO ischemic kidneys as well as oxidant-injured p53-deficient primary PTCs and pifithrin-α-treated PTC lines. Reduced oxidative stress and diminished expression of PARP1 and Bax in p53 KO ischemic kidneys may account for the decreased necrosis. Apoptosis and expression of proapoptotic p53 targets, including Bid and Siva, were also significantly reduced, and cell cycle arrest at the G2/M phase was attenuated in p53 KO ischemic kidneys. Furthermore, IRI-induced activation of TGF-β and the long-term development of inflammation and interstitial fibrosis were significantly reduced in p53 KO mice. In conclusion, specific deletion of p53 in the PTC protects kidneys from functional and histologic deterioration after IRI by decreasing necrosis, apoptosis, and inflammation and modulates the long-term sequelae of IRI by preventing interstitial fibrogenesis.