The Unfolded Protein Response Regulates an Angiogenic Response by the Kidney Epithelium during Ischemic Stress
The Unfolded Protein Response Regulates an Angiogenic Response by the Kidney Epithelium during Ischemic Stress
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DOI：
10.1074/jbc.m112.340570
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发表时间：
2012-04-27
影响因子：
4.8
通讯作者：
Pallet, Nicolas
中科院分区：
文献类型：
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作者：
Bouvier, Nicolas;Fougeray, Sophie;Pallet, Nicolas
缺血性损伤会永久影响肾脏组织并挑战细胞活力，促进炎症和纤维化。缺血导致营养缺乏，这触发内质网应激，最终导致未折叠蛋白反应（UPR）。本研究的目的是测试在人肾上皮缺血应激期间，UPR是否可以独立于HIF-1 α通路促进血管生成反应。葡萄糖剥夺诱导人肾上皮细胞分泌血管内皮生长因子A（VEGFA）、碱性成纤维细胞生长因子（bFGF）和血管生成素（ANG），这些分泌与HIF-1 α无关。葡萄糖剥夺，而不是缺氧，触发内质网应激和激活的UPR。RNA干扰介导的抑制编码激酶PERK的基因降低了VEGFA和bFGF的表达，但这两个基因都不受IRE 1 α或ATF 6抑制的影响。此外，我们表明，血管生成素的表达，抑制蛋白质的合成，是由IRE 1 α和PERK，这可能构成了一个互补的功能，在抑制翻译的UPR的调节。在大鼠急性缺血应激模型中，我们发现UPR与VEGFA、bFGF和ANG表达平行激活，且独立于HIF-1 α。
Ischemic injuries permanently affect kidney tissue and challenge cell viability, promoting inflammation and fibrogenesis. Ischemia results in nutrient deprivation, which triggers endoplasmic reticulum stress, ultimately resulting in the unfolded protein response (UPR). The aim of this study was to test whether the UPR could promote an angiogenic response independently of the HIF-1 alpha pathway during ischemic stress in the human kidney epithelium. Glucose deprivation induced the secretion of vascular endothelial growth factor A (VEGFA), basic fibroblast growth factor (bFGF) and angiogenin (ANG) in human kidney epithelial cells independently of HIF-1 alpha. Glucose deprivation, but not hypoxia, triggered endoplasmic reticulum stress and activated the UPR. RNA interference-mediated inhibition of the gene encoding the kinase PERK decreased VEGFA and bFGF expression, but neither gene was affected by the inhibition of IRE1 alpha or ATF6. Furthermore, we show that the expression of angiogenin, which inhibits protein synthesis, is regulated by both IRE1 alpha and PERK, which could constitute a complementary function of the UPR in the repression of translation. In a rat model of acute ischemic stress, we show that the UPR is activated in parallel with VEGFA, bFGF, and ANG expression and independently of HIF-1 alpha.