Impact of ER stress-regulated ATF4/p16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy
Impact of ER stress-regulated ATF4/p16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy
复制标题
内质网应激调节的ATF4/p16信号对糖尿病肾病肾小管上皮细胞早衰的影响
DOI：
10.1152/ajpcell.00096.2014
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发表时间：
2015-04-15
影响因子：
5.5
通讯作者：
He, Ya-Ni
中科院分区：
文献类型：
--
作者：
Liu, Jun;Yang, Ju-Rong;He, Ya-Ni
早衰是糖尿病肾病进展过程中的一个重要事件。在此，我们研究了内质网(ER)应激调节的转录因子4(ATF4)/p16信号在糖尿病肾病发生发展过程中肾小管上皮细胞(RTECs)早衰中的作用。在2型糖尿病肾病患者的肾组织中，我们检测到衰老细胞的数量增加，晚期糖基化终产物(AGEs)的沉积增加，ER应激标志葡萄糖调节蛋白78的表达上调，以及ATF4和p16的过度表达。类似地，在AGE处理后培养的小鼠RTEC中也观察到了这些现象。有趣的是，内质网应激抑制剂和ATF4基因沉默成功地缓解了AGE诱导的p16表达和早衰。此外，内质网应激诱导剂和ATF4的过度表达可模拟衰老诱导的衰老，而p16基因沉默可抑制衰老。此外，内质网应激诱导剂可增强ATF4的表达。因此，我们的结果表明，内质网应激调节的ATF4/p16通路参与了糖尿病肾病进展过程中RTECs的早衰。
Premature senescence is an important event during diabetic nephropathy (DN) progression. Here, we investigated the role of endoplasmic reticulum (ER) stress-regulated activation of transcription factor 4 (ATF4)/p16 signaling in the premature senescence of renal tubular epithelial cells (RTECs) during DN development. In the renal tissues of Type 2 DN patients, we detected an increased number of senescent cells; elevated deposition of advanced glycation end products (AGEs); upregulated expression of ER stress marker, glucose-regulated protein 78; as well as overexpression of ATF4 and p16. Similarly, these phenomena were also observed in cultured mouse RTECs following AGE treatment. Interestingly, AGE-induced p16 expression and premature senescence were successfully attenuated by ER stress inhibitor and ATF4 gene silencing. Moreover, AGE-induced premature senescence was mimicked by ER stress inducers and ATF4 overexpression, while suppressed by p16 gene silencing. In addition, ER stress inducers can augment ATF4 expression. Therefore, our results demonstrate that the ER stress-regulated ATF4/p16 pathway is involved in the premature senescence of RTECs during DN progression.