Excessive Glutamate Stimulation Impairs ACE2 Activity Through ADAM17-Mediated Shedding in Cultured Cortical Neurons.

Cellular and Molecular Neurobiology
Jiaxi XuEric Lazartigues

Abstract

The excitotoxicity of glutamate plays an important role in the progression of various neurological disorders via participating in inflammation and neuronal damage. In this study, we identified the role of excessive glutamate stimulation in the modulation of angiotensin-converting enzyme type 2 (ACE2), a critical component in the compensatory axis of the renin-angiotensin system (RAS). In primary cultured cortical neurons, high concentration of glutamate (100 µM) significantly reduced the enzymatic activity of ACE2. The elevated activity of ADAM17, a member of the 'A Disintegrin And Metalloprotease' (ADAM) family, was found to contribute to this glutamate-induced ACE2 down-regulation. The decrease of ACE2 activity could be prevented by pre-treatment with antagonists targeting ionotropic glutamate receptors. In addition, the glutamate-induced decrease in ACE2 activity was significantly attenuated when the neurons were co-treated with MitoTEMPOL or blockers that target oxidative stress-mediated signaling pathway. In summary, our study reveals a strong relationship between excessive glutamate stimulation and ADAM17-mediated impairment in ACE2 activity, suggesting a possible cross-talk between glutamate-induced excitotoxicity and dy...Continue Reading

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Citations

Nov 18, 2018·Neurochemical Research·Natalia Alenina, Michael Bader
Jun 27, 2019·Cellular and Molecular Life Sciences : CMLS·Hung-En HsiaStefan F Lichtenthaler
Dec 23, 2019·Cellular and Molecular Neurobiology·Rohan Umesh ParekhSrinivas Sriramula
Sep 5, 2020·NPJ Parkinson's Disease·David SulzerK Ray Chaudhuri
Dec 31, 2020·International Journal of Molecular Sciences·Rohan Umesh Parekh, Srinivas Sriramula
Feb 13, 2021·NPJ Parkinson's Disease·David SulzerK Ray Chaudhuri
Apr 6, 2021·Current Opinion in Toxicology·Ayse Basak EnginAtilla Engin

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