Activation of Kinin B1R Upregulates ADAM17 and Results in ACE2 Shedding in Neurons.
Activation of Kinin B1R Upregulates ADAM17 and Results in ACE2 Shedding in Neurons.
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DOI：
10.3390/ijms22010145
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发表时间：
2020-12-25
影响因子：
5.6
通讯作者：
Sriramula S
中科院分区：
文献类型：
--
作者：
Parekh RU;Sriramula S
血管紧张素转换酶2（ACE 2）是肾素血管紧张素系统代偿轴的关键组分。ACE 2基因和蛋白质表达的改变，以及由"A去整合素和金属蛋白酶"（ADAM）家族的成员A去整合素和金属蛋白酶17（ADAM 17）介导的活性涉及若干心血管和神经退行性疾病。我们以前报道，在大脑中的激肽B1受体（B1R）的激活增加神经炎症，氧化应激和交感神经兴奋，导致神经源性高血压的发展。我们还发现了神经元中ADAM17介导的ACE2脱落的证据。然而，激肽B1受体（B1R）激活是否在改变ADAM 17活性中起任何作用，以及它对神经元中ACE 2脱落的影响尚不清楚。在这项研究中，我们测试的假设，激活B1 R上调ADAM17，并导致ACE2脱落的神经元。为了验证这一假设，我们刺激野生型和B1 R基因缺失的小鼠新生儿原代下丘脑神经元培养与B1 R特异性激动剂，并测量神经元中的ADAM 17和ACE 2的活性。B1R刺激显著增加野生型神经元中的ADAM17活性并降低ACE2活性，而用B1R特异性拮抗剂R715预处理可逆转这些变化。用特异性B1R激动剂Lys-Des-Arg9-缓激肽（LDABK）刺激B1R基因缺失的神经元，对ADAM17或ACE2活性没有任何影响。这些数据表明，B1 R激活导致原代下丘脑神经元中ADAM17介导的ACE2脱落。此外，高浓度谷氨酸刺激显著增加B1 R基因和蛋白表达，沿着野生型神经元中ADAM 17活性增加和ACE 2活性降低。用B1R特异性拮抗剂R715预处理逆转了这些谷氨酸诱导的作用，表明B1R确实参与谷氨酸介导的ADAM 17活性上调和ACE 2脱落。
Angiotensin converting enzyme 2 (ACE2) is a critical component of the compensatory axis of the renin angiotensin system. Alterations in ACE2 gene and protein expression, and activity mediated by A Disintegrin And Metalloprotease 17 (ADAM17), a member of the “A Disintegrin And Metalloprotease” (ADAM) family are implicated in several cardiovascular and neurodegenerative diseases. We previously reported that activation of kinin B1 receptor (B1R) in the brain increases neuroinflammation, oxidative stress and sympathoexcitation, leading to the development of neurogenic hypertension. We also showed evidence for ADAM17-mediated ACE2 shedding in neurons. However, whether kinin B1 receptor (B1R) activation has any role in altering ADAM17 activity and its effect on ACE2 shedding in neurons is not known. In this study, we tested the hypothesis that activation of B1R upregulates ADAM17 and results in ACE2 shedding in neurons. To test this hypothesis, we stimulated wild-type and B1R gene-deleted mouse neonatal primary hypothalamic neuronal cultures with a B1R-specific agonist and measured the activities of ADAM17 and ACE2 in neurons. B1R stimulation significantly increased ADAM17 activity and decreased ACE2 activity in wild-type neurons, while pretreatment with a B1R-specific antagonist, R715, reversed these changes. Stimulation with specific B1R agonist Lys-Des-Arg9-Bradykinin (LDABK) did not show any effect on ADAM17 or ACE2 activities in neurons with B1R gene deletion. These data suggest that B1R activation results in ADAM17-mediated ACE2 shedding in primary hypothalamic neurons. In addition, stimulation with high concentration of glutamate significantly increased B1R gene and protein expression, along with increased ADAM17 and decreased ACE2 activities in wild-type neurons. Pretreatment with B1R-specific antagonist R715 reversed these glutamate-induced effects suggesting that indeed B1R is involved in glutamate-mediated upregulation of ADAM17 activity and ACE2 shedding.
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ACE2小鼠模型：用于心血管和肺部研究的工具箱。
影响因子：
16.6
作者：
Jia H;Yue X;Lazartigues E
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影响因子：
8.3
作者：
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影响因子：
3.3
作者：
Chaparro-Huerta, V;Rivera-Cervantes, MC;Beas-Zárate, C
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Beas-Zárate, C
DOI：
10.1074/jbc.m505111200
发表时间：
2005-08-26
期刊：
The Journal of biological chemistry
影响因子：
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作者：
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影响因子：
20.1
作者：
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