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

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 dysregulated RAS.

• Authors: Jiaxi Xu, Srinivas Sriramula, Eric Lazartigues
• Journal: Cellular and molecular neurobiology (Cell Mol Neurobiol) Vol. 38 Issue 6 Pg. 1235-1243 (Aug 2018) ISSN: 1573-6830 [Electronic] United States
• PMID: 29766392 (Publication Type: Journal Article)

Chemical References

• Reactive Oxygen Species
• Glutamic Acid
• Nitric Oxide Synthase Type II
• Peptidyl-Dipeptidase A
• Ace2 protein, mouse
• Angiotensin-Converting Enzyme 2
• ADAM17 Protein

Topics

• ADAM17 Protein (metabolism)
• Angiotensin-Converting Enzyme 2
• Animals
• Cells, Cultured
• Cerebral Cortex (cytology)
• Glutamic Acid (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Mice, Inbred C57BL
• Mitochondria (drug effects, metabolism)
• Neurons (drug effects, metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Peptidyl-Dipeptidase A (metabolism)
• Reactive Oxygen Species (metabolism)