Abstract

Decrease of Angiotensin‐converting enzyme 2 (ACE2) expression and activity in the brain has been shown to be associated with neurogenic hypertension. We recently reported that up‐regulation of the matrix metalloprotease A Disintegrin And Metalloprotease 17 (ADAM17) expression in hypertension mediates ACE2 shedding in neurons. To study the contribution of Ang II Type 1 Receptor (AT1R) and oxidative stress on ACE2 shedding, Neuro2A (neuronal cell line) were first transfected with human ACE2 (hACE2) then pretreated with AT1R blocker Losartan (10 µM) or the reactive oxygen species scavenger Tempol (10 µM), 30 min prior to treatment with AngII (100 and 300 nM). Western blotting revealed that ACE2 expression was decreased (12 and 40%, respectively), while ADAM17 expression was increased (30 and 36%, respectively) in Neuro2A cells after Ang II treatment. Pretreatment with losartan or tempol attenuated the effect of Ang II on ADAM17 expression (18 and 19%, respectively). To further study the involvement of oxidative stress in Ang II‐induced ADAM17 expression, another set of Neuro2A cells were studied without transfection with hACE2. In these cells treated with Ang II (100 nM), ADAM17 expression was similarly decreased by tempol. These data suggest that ADAM17 expression is increased by an AT1R‐dependent, as well as oxidative stress‐dependent mechanism, leading to enhanced ACE2 shedding in neurons.Grant Funding Source: Supported by AHA 12EIA8030004, CNPq

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