Kidney-specific Overexpression of Sirt1 Protects against Acute Kidney Injury by Retaining Peroxisome Function
Kidney-specific Overexpression of Sirt1 Protects against Acute Kidney Injury by Retaining Peroxisome Function
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DOI：
10.1074/jbc.m109.067728
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发表时间：
2010-04-23
影响因子：
4.8
通讯作者：
Itoh, Hiroshi
中科院分区：
文献类型：
--
作者：
Hasegawa, Kazuhiro;Wakino, Shu;Itoh, Hiroshi
Sirt 1是一种NAD依赖性蛋白脱乙酰酶，据报道可调节细胞内代谢并减弱活性氧化物质（ROS）诱导的细胞凋亡，从而导致长寿和急性应激抗性。我们使用近端小管中特异性驱动的启动子钠-磷酸盐协同转运蛋白IIa（Npt 2）创建了肾脏特异性过表达Sirt 1的转基因（TG）小鼠，并研究了Sirt 1在保护急性肾损伤（阿基）中的肾脏特异性作用。我们还阐明了过氧化物酶体和线粒体的数量或功能在介导Sirt 1在阿基中的肾脏保护作用机制中的作用。顺铂诱导的阿基降低了过氧化物酶体和线粒体的数量和功能，并导致局部ROS产生和肾小管凋亡细胞水平增加。用顺铂治疗的TG小鼠减轻了阿基、局部ROS和肾小管凋亡的肾小管细胞。与这些结果一致，用顺铂处理的TG小鼠也表现出过氧化物酶体数量和功能的恢复，以及挽救的线粒体功能;然而，线粒体数量没有恢复。免疫电镜结果一致表明，在野生型小鼠中顺铂的过氧化物酶体数量的减少在转基因小鼠中得到恢复。在HK-2细胞，培养的近曲小管细胞系，Sirt 1的过表达，通过恢复过氧化物酶体的数量挽救顺铂诱导的细胞凋亡，虽然线粒体的数量没有恢复。这些结果表明，近端小管中Sirt 1过表达通过维持过氧化物酶体的数量和功能、伴随的过氧化氢酶上调和肾ROS水平的消除来挽救顺铂诱导的阿基。肾脏Sirt 1可能成为阿基治疗的潜在靶点。
Sirt1, a NAD-dependent protein deacetylase, is reported to regulate intracellular metabolism and attenuate reactive oxidative species (ROS)-induced apoptosis leading to longevity and acute stress resistance. We created transgenic (TG) mice with kidney-specific overexpression of Sirt1 using the promoter sodium-phosphate cotransporter IIa (Npt2) driven specifically in proximal tubules and investigated the kidney-specific role of Sirt1 in the protection against acute kidney injury (AKI). We also elucidated the role of number or function of peroxisome and mitochondria in mediating the mechanisms for renal protective effects of Sirt1 in AKI. Cisplatin-induced AKI decreased the number and function of peroxisomes as well as mitochondria and led to increased local levels of ROS production and renal tubular apoptotic cells. TG mice treated with cisplatin mitigated AKI, local ROS, and renal tubular apoptotic tubular cells. Consistent with these results, TG mice treated with cisplatin also exhibited recovery of peroxisome number and function, as well as rescued mitochondrial function; however, mitochondrial number was not recovered. Immunoelectron microscopic findings consistently demonstrated that the decrease in peroxisome number by cisplatin in wild type mice was restored in transgenic mice. In HK-2 cells, a cultured proximal tubule cell line, overexpression of Sirt1 rescued the cisplatin-induced cell apoptosis through the restoration of peroxisome number, although the mitochondria number was not restored. These results indicate that Sirt1 overexpression in proximal tubules rescues cisplatin-induced AKI by maintaining peroxisomes number and function, concomitant up-regulation of catalase, and elimination of renal ROS levels. Renal Sirt1 can be a potential therapeutic target for the treatment of AKI.