Receptor for advanced glycation end-products promotes premature senescence of proximal tubular epithelial cells via activation of endoplasmic reticulum stress-dependent p21 signaling
Receptor for advanced glycation end-products promotes premature senescence of proximal tubular epithelial cells via activation of endoplasmic reticulum stress-dependent p21 signaling
复制标题
晚期糖化终产物受体通过激活内质网应激依赖性 p21 信号传导促进近端肾小管上皮细胞过早衰老。
DOI：
10.1016/j.cellsig.2013.10.002
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发表时间：
2014-01-01
影响因子：
4.8
通讯作者：
He, Ya-Ni
中科院分区：
文献类型：
--
作者：
Liu, Jun;Huang, Kun;He, Ya-Ni
细胞过早衰老在糖尿病肾病（DN）进展中是一个关键过程。在本研究中，我们提出假设：在糖尿病肾病中，晚期糖基化终末产物受体（RAGE）介导内质网（ER）应激，通过激活p21信号通路诱导细胞过早衰老。在此，我们证实，在糖尿病肾病患者中，RAGE、内质网应激标志物葡萄糖调节蛋白78（GRP78）以及细胞周期调节因子p21的表达升高，均与衰老相关β - 半乳糖苷酶（SA - β - gal）活性增强呈正相关。此外，在培养的小鼠近端肾小管上皮细胞（PTECs）中，SA - β - gal阳性细胞比例或处于G₀G₁期的细胞增多，且晚期糖基化终末产物（AGEs）以剂量和时间依赖性方式上调RAGE、GRP78和p21的表达。有趣的是，内质网应激诱导剂或RAGE过表达可模拟AGEs诱导的细胞过早衰老，而p21基因沉默可显著抑制这种现象。然而，阻断RAGE能成功减轻AGEs诱导的内质网应激、p21表达以及细胞过早衰老。此外，内质网应激诱导剂可直接激活p21、引发细胞过早衰老，还通过正反馈增强RAGE表达。这些观察结果表明，RAGE通过激活内质网应激依赖性p21信号通路促进近端肾小管上皮细胞过早衰老。© 2013英国政府版权所有。由爱思唯尔公司出版。保留所有权利。
Premature senescence is a key process in the progression of diabetic nephropathy (DN). In our study, we hypothesized that receptors for advanced glycation end-products (RAGE) mediate endoplasmic reticulum (ER) stress to induce premature senescence via p21 signaling activation in diabetic nephropathy. Here, we demonstrated that elevated expression of RAGE, ER stress marker glucose-regulated protein 78 (GRP78), and cell-cycle regulator p21 was all positively correlated with enhanced senescence-associated-beta-galactosidase (SA-beta-gal) activity in DN patients. In addition, the fraction of SA-beta-gal or cells in the G(0)G(1) phase were enhanced in cultured mouse proximal tubular epithelial cells (FTECs) and the expression of RAGE, GRP78 and p21 was up-regulated by advanced glycation end-products (AGEs) in a dose- and time-dependent manner. Interestingly, ER stress inducers or RAGE overexpression mimicked AGEs induced-premature senescence, and this was significantly suppressed by p21 gene silencing. However, RAGE blocking successfully attenuated AGEs-induced ER stress and p21 expression, as well as premature senescence. Moreover, ER stress inducers directly caused p21 activation, premature senescence, and also enhanced RAGE expression by positive feedback. These observations suggest that RAGE promotes premature senescence of PTECs by activation of ER stress-dependent p21 signaling. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved.