Down-Regulation of PERK-ATF4-CHOP Pathway by Astragaloside IV is Associated with the Inhibition of Endoplasmic Reticulum Stress-Induced Podocyte Apoptosis in Diabetic Rats
Down-Regulation of PERK-ATF4-CHOP Pathway by Astragaloside IV is Associated with the Inhibition of Endoplasmic Reticulum Stress-Induced Podocyte Apoptosis in Diabetic Rats
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黄芪甲苷下调PERK-ATF4-CHOP通路与抑制糖尿病大鼠内质网应激诱导的足细胞凋亡相关
DOI：
10.1159/000362974
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发表时间：
2014-01-01
影响因子：
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通讯作者：
Wang, Niansong
中科院分区：
文献类型：
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作者：
Chen, Yifang;Gui, Dingkun;Wang, Niansong
背景：内质网（ER）应激诱导足细胞凋亡在糖尿病肾病（DN）的发生发展中起重要作用。在这里，我们测试的假设，抑制PERK-ATF 4-CHOP通路黄芪甲苷IV（AS-IV）与抑制ER应激诱导的足细胞凋亡链脲佐菌素（STZ）诱导的糖尿病大鼠。方法：糖尿病大鼠经口给予AS-IV治疗5和10 d，mg.kg 12周进行尿蛋白检测、苏木精-伊红染色及TUNEL分析。采用免疫组化、western blot和实时荧光定量PCR检测ER伴侣GRP 78和ER相关凋亡蛋白在肾组织中的表达。结果：AS-IV治疗可改善糖尿病大鼠的蛋白尿和肾脏组织病理学改变。糖尿病大鼠肾脏中足细胞凋亡以及磷酸化PERK和eIF 2 α显著增加，这些都被AS-IV治疗减弱。此外，发现糖尿病大鼠GRP 78和ER相关凋亡蛋白如ATF 4、CHOP和TRB 3的蛋白和mRNA表达增加，AS-IV治疗也减弱了这些蛋白和mRNA表达。糖尿病大鼠Bax表达增加，Bcl-2表达减少，这些变化被AS-IV治疗部分恢复。结论：AS-IV对ER应激诱导的足细胞凋亡具有保护作用，其机制可能与抑制PERK-ATF 4-CHOP通路有关。AS-IV下调PERK-ATF 4-CHOP通路可能是治疗DN的新策略。版权所有（C）2014 S. Karger AG，巴塞尔
Background: Endoplasmic reticulum (ER) stress-induced podocyte apoptosis plays a critical role in the development of diabetic nephropathy (DN). Here, we tested the hypothesis that suppression of PERK-ATF4-CHOP pathway by Astragaloside IV (AS-IV) is associated with inhibition of ER stress-induced podocyte apoptosis in streptozotocin (STZ)-induced diabetic rats. Methods: Diabetic rats were treated with AS-IV at 5 and 10 mg.kg(-1).d(-1), p.o., for 12 weeks. Albuminuria examination, hematoxylin & eosin staining and TUNEL analysis were performed. Immunohistochemistry, western blot, and real-time PCR were used to detect renal expression of ER chaperone GRP78 and ER-associated apoptosis proteins. Results: Treatment with AS-IV ameliorated albuminuria and renal histopathology in diabetic rats. Diabetic rats had significant increment in podocyte apoptosis as well as phosphorylated PERK and eIF2 alpha in the kidneys, which were attenuated by AS-IV treatment. Furthermore, diabetic rats were found to have increased protein and mRNA expressions of GRP78 and ER-associated apoptosis proteins, such as ATF4, CHOP and TRB3, which were also attenuated by AS-IV treatment. Increased Bax expression and decreased Bcl-2 expression were detected in diabetic rats, and these changes were partially restored by AS-IV treatment. Conclusion: The protective effect of AS-IV on ER stress-induced podocyte apoptosis is associated with inhibition of PERK-ATF4-CHOP pathway. Down-regulation of PERK- ATF4-CHOP pathway by AS-IV may be a novel strategy for the treatment of DN. Copyright (C) 2014 S. Karger AG, Basel