Clinical Relevance and Role of Neuronal AT1 Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension
Rationale: Neurogenic hypertension is characterized by an increase in sympathetic activity and often resistance to drug treatments. We previously reported that it is also associated with a reduction of Angiotensin Converting Enzyme 2 (ACE2) and an increase in A Disintegrin And Metalloprotease 17 (ADAM17) activity in experimental hypertension. In addition, while multiple cells within the central nervous system have been involved in the development of neurogenic hypertension, the contribution of ADAM17 has not been investigated.
Objective: To assess the clinical relevance of this ADAM17-mediated ACE2 shedding in hypertensive patients and further identify the cell types and signaling pathways involved in this process.
Methods and Results: Using a mass spectrometry-based assay, we identified ACE2 as the main enzyme converting Ang II into Ang-(1-7) in human cerebrospinal fluid (CSF). We also observed an increase in ACE2 activity in the CSF of hypertensive patients, which was correlated with systolic blood pressure. Moreover, the increased level of tumor necrosis factor (TNF)-α in those CSF samples confirmed that ADAM17 was up-regulated in the hypertensive patients' brain. To further assess the interaction between brain renin-angiotensin system and ADAM17, we generated mice lacking Angiotensin II type 1 receptors (AT1R) specifically on neurons. Our data reveal that despite expression on astrocytes and other cells types in the brain, ADAM17 up-regulation during DOCA-salt hypertension occurs selectively on neurons and neuronal AT1R are indispensable to this process. Mechanistically, reactive oxygen species (ROS) and extracellular signal-regulated kinase (ERK) were found to mediate ADAM17 activation.
Conclusions: Our data demonstrate that AT1R promote ADAM17-mediated ACE2 shedding in the brain of hypertensive patients, leading to a loss in compensatory activity during neurogenic hypertension.
- TNF-alpha convertase enzyme
- hypertension, high blood pressure
- central nervous system
- renin angiotensin system
- Received December 19, 2016.
- Revision received May 11, 2017.
- Accepted May 16, 2017.