Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

Abstract

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.

Increased urinary angiotensin converting enzyme 2 and neprilysin in patients with type 2 diabetes

“…ADAM17 is abundant in different organs and cleaves several cell surface enzymes, including ACE2 and NEP (8,16,23,36,38,41,54). We detected increased urinary ADAM17 in all patients with diabetes, including Dnormo.…”

“…We have also reported that physical exercise training and/or metformin treatment of type 2 diabetic mice attenuated renal ADAM17 expression and shedding of urinary ACE2 (44). Recently, it was demonstrated that Ang II type 1 receptors promote ADAM17 mediated ACE2 shedding in hypertensive patients (54). In addition, in vitro studies showed that the release of ACE2 into the culture media of human proximal tubular cells was inhibited by treatment with the ADAM17 inhibitor TNF-␣ protease inhibitor-1 (41).…”

Nicotine and the renin-angiotensin system

“…In primary cultures of neurons and glial cells isolated from brainstem and hypothalamus of 1-day-old rats, nicotine treatment resulted in increased expression of AT 1 R but decreased expression of ACE2, and these nicotine effects were greater in cells isolated from spontaneously hypertensive rats compared with Wistar-Kyoto rats (43,44). The above findings provide strong evidence that interaction between nicotine and the brain RAS may contribute to the sympatho-mimetic actions of nicotine as well as AT 1 R-mediated neurogenic hypertension (144).…”

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…ACE2 is a known substrate of ADAM17 (534). The importance of neuronal AT 1 Rs in mediating upregulation of ADAM17 and downregulation of ACE2 in humans and in DOCA-salt hypertension highlights the importance of neuronal AT 1 R clinically and in experimental hypertension (1168,1177).…”