Brain ACE2 Shedding Contributes to the Development of Neurogenic Hypertension
Rationale: Over-activity of the brain Renin Angiotensin System (RAS) is a major contributor to neurogenic hypertension. While over-expression of Angiotensin-Converting Enzyme type 2 (ACE2) has been shown to be beneficial in reducing hypertension by transforming Angiotensin (Ang)-II into Ang-(1-7), several groups have reported decreased brain ACE2 expression and activity during the development of hypertension.
Objective: We hypothesized that ADAM17-mediated ACE2 shedding results in decreased membrane-bound ACE2 in the brain, thus promoting the development of neurogenic hypertension.
Methods and Results: To test this hypothesis, we used the DOCA-salt model of neurogenic hypertension in non-transgenic (NT) and syn-hACE2 mice over-expressing ACE2 in neurons. DOCA-salt treatment in NT mice led to significant increases in blood pressure, hypothalamic Ang-II levels, inflammation, impaired baroreflex sensitivity, autonomic dysfunction, as well as decreased hypothalamic ACE2 activity and expression, while these changes were blunted or prevented in syn-hACE2 mice. In addition, reduction of ACE2 expression and activity in the brain paralleled a rise in ACE2 activity in the cerebrospinal fluid of NT mice following DOCA-salt treatment and was accompanied by enhanced ADAM17 expression and activity in the hypothalamus. Chronic knockdown of ADAM17 in the brain blunted the development of hypertension and restored ACE2 activity and baroreflex function.
Conclusions: Our data provide the first evidence that ADAM17-mediated shedding impairs brain ACE2 compensatory activity, thus contributing to the development of neurogenic hypertension.
- autonomic function
- hypertension, high blood pressure
- renin angiotensin system
- central nervous system
- baroreflex control
- Received May 16, 2013.
- Revision received September 4, 2013.
- Accepted September 6, 2013.