Kinin B1R Activation Induces Endoplasmic Reticulum Stress in Primary Hypothalamic Neurons.
Kinin B1R Activation Induces Endoplasmic Reticulum Stress in Primary Hypothalamic Neurons.
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DOI：
10.3389/fphar.2022.841068
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发表时间：
2022
影响因子：
5.6
通讯作者：
Sriramula S
中科院分区：
文献类型：
--
作者：
White A;Parekh RU;Theobald D;Pakala P;Myers AL;Van Dross R;Sriramula S
内质网（ER）是一种重要的细胞器，参与蛋白质的合成和运输，以及游离钙的储存等稳态功能。内质网应激增强神经炎症和神经变性，是神经源性高血压发病机制的关键因素。最近，我们发现激肽B1受体（B1 R）的激活在调节神经炎症和高血压中起着至关重要的作用。然而，B1 R激活是否导致ER应激的进展和增强尚未研究。在这份简短的研究报告中，我们测试了神经元中B1 R激活有助于未折叠蛋白反应（UPR）和ER应激发展的假设。为了验证这一假设，我们用B1受体特异性激动剂Lys-Des-Arg 9-缓激肽（LDABK）处理原代下丘脑神经元培养物，并测量UPR和ER应激的组分。我们的数据表明，通过LDABK刺激B1 R，诱导内质网应激的分子伴侣GRP 78的上调。B1 R刺激与跨膜ER应激传感器ATF 6、IRE 1 α和PERK（UPR的关键组分）的表达和激活增加相关。在存在压倒性的ER应激时，激活的ER应激传感器可导致氧化应激、自噬或凋亡。为了确定B1 R激活是否诱导细胞凋亡，我们测量了细胞内Ca 2+和细胞外ATP水平，半胱天冬酶3/7活性和细胞活力。我们的数据表明，LDABK治疗确实增加了Ca 2+和ATP水平，但不改变半胱天冬酶活性或细胞活力。这些发现表明，B1 R激活启动UPR，是ER应激途径中的关键因素。
The endoplasmic reticulum (ER) is a key organelle involved in homeostatic functions including protein synthesis and transport, and the storage of free calcium. ER stress potentiates neuroinflammation and neurodegeneration and is a key contributor to the pathogenesis of neurogenic hypertension. Recently, we showed that kinin B1 receptor (B1R) activation plays a vital role in modulating neuroinflammation and hypertension. However, whether B1R activation results in the progression and enhancement of ER stress has not yet been studied. In this brief research report, we tested the hypothesis that B1R activation in neurons contributes to unfolded protein response (UPR) and the development of ER stress. To test this hypothesis, we treated primary hypothalamic neuronal cultures with B1R specific agonist Lys-Des-Arg9-Bradykinin (LDABK) and measured the components of UPR and ER stress. Our data show that B1R stimulation via LDABK, induced the upregulation of GRP78, a molecular chaperone of ER stress. B1R stimulation was associated with an increased expression and activation of transmembrane ER stress sensors, ATF6, IRE1α, and PERK, the critical components of UPR. In the presence of overwhelming ER stress, activated ER stress sensors can lead to oxidative stress, autophagy, or apoptosis. To determine whether B1R activation induces apoptosis we measured intracellular Ca2+ and extracellular ATP levels, caspases 3/7 activity, and cell viability. Our data show that LDABK treatment does increase Ca2+ and ATP levels but does not alter caspase activity or cell viability. These findings suggest that B1R activation initiates the UPR and is a key factor in the ER stress pathway.
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DOI：
10.1164/rccm.201504-0657oc
发表时间：
2015-12-01
影响因子：
24.7
作者：
Lubamba, Bob A.;Jones, Lisa C.;Ribeiro, Carla M. P.
通讯作者：
Ribeiro, Carla M. P.
影响因子：
6.3
作者：
Dai, S. -Y.;Fan, J.;Peng, W.
通讯作者：
Peng, W.
影响因子：
4.3
作者：
Casas C
通讯作者：
Casas C
影响因子：
5.6
作者：
Bahar E;Kim H;Yoon H
通讯作者：
Yoon H
影响因子：
5.6
作者：
Parekh RU;Sriramula S
通讯作者：
Sriramula S