Activation of the signal transducer and activator of transcription signaling pathway in renal proximal tubular cells by albumin
Activation of the signal transducer and activator of transcription signaling pathway in renal proximal tubular cells by albumin
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DOI：
10.1097/01.asn.0000109672.83594.02
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发表时间：
2004-02-01
影响因子：
13.6
通讯作者：
Imai, E
中科院分区：
文献类型：
--
作者：
Nakajima, H;Takenaka, M;Imai, E
被蛋白质重吸收激活的肾近端小管细胞被认为在肾脏疾病的进展中起重要作用。据推测，近端小管细胞中的信号传导和转录激活因子（STAT）蛋白可能被蛋白尿激活。为了验证这一假设，用白蛋白（30 mg/ml培养基）处理小鼠近端小管细胞不同时间长度。结果表明，白蛋白能在15分钟内激活近端小管细胞中的Stat1和Stat5。STATs的激活主要由Jak2介导，不需要蛋白质合成。此外，即使在ifn - γ中和后，Stat1也会激活。n -乙酰- l-半胱氨酸（谷胱甘肽的前体和活性氧（ROS）清除剂）抑制STATs的激活，荧光激活的细胞分选分析显示白蛋白超载后细胞内ROS上调，这表明白蛋白本身可以在近端小管细胞中产生ROS。STATs的激活是通过ROS生成系统发生的，特别是通过膜结合的NADPH氧化酶系统。谷胱甘肽过氧化物酶和过氧化氢酶活性的降低也可能是细胞内ROS积累的原因。因此，不仅ROS生成系统，而且ROS清除系统都可能参与白蛋白诱导ROS。这些发现支持了近端小管细胞被激活并产生ROS的假设，即通过肾小球毛细血管过滤的大量尿蛋白被重吸收，因此，各种ifn - γ诱导蛋白通过ifn - γ非依赖性STAT信号的激活合成。
Renal proximal tubular cells activated by reabsorption of protein are thought to play significant roles in the progression of kidney diseases. It was hypothesized that the signal transducer and activator of transcription (STAT) proteins may be activated by proteinuria in proximal tubular cells. To test this hypothesis, murine proximal tubular cells were treated with albumin (30 mg/ml medium) for various lengths of time. The results showed that albumin could activate Stat1 and Stat5 within 15 min in proximal tubular cells. The activation of STATs was mediated mostly by Jak2 and required no protein synthesis. In addition, activation of Stat1 occurred even after neutralization of IFN-gamma. The activation of STATs was inhibited by N-acetyl-L-cysteine, a precursor of glutathione and a reactive oxygen species (ROS) scavenger, and fluorescence-activated cell sorter analysis showed upregulation of intracellular ROS after albumin overloading, suggesting that albumin per se could generate ROS in proximal tubular cells. The activation of STATs occurred by way of the ROS generating system, and especially through the membrane-bound NADPH oxidase system. Reduced activities of glutathione peroxidase and catalase could also be responsible for the accumulation of intracellular ROS. Hence, not only the ROS generating system, but also the ROS scavenging system may contribute to the induction of ROS by albumin. These findings support the hypothesis that proximal tubular cells are activated and generate ROS by reabsorption of abundant urinary proteins filtered through the glomerular capillaries, and as a consequence, various IFN-gamma-inducible proteins are synthesized through IFN-gamma-independent activation of STAT signaling.