ACE2 and ADAM17 Interaction Regulates the Activity of Presympathetic Neurons

Abstract

Brain renin angiotensin system within the paraventricular nucleus plays a critical role in balancing excitatory and inhibitory inputs to modulate sympathetic output and blood pressure regulation. We previously identified ACE2 and ADAM17 as a compensatory enzyme and a sheddase, respectively, involved in brain renin angiotensin system regulation. Here, we investigated the opposing contribution of ACE2 and ADAM17 to hypothalamic presympathetic activity and ultimately neurogenic hypertension. New mouse models were generated where ACE2 and ADAM17 were selectively knocked down from all neurons (AC-N) or Sim1 neurons (SAT), respectively. Neuronal ACE2 deletion revealed a reduction of inhibitory inputs to AC-N presympathetic neurons relevant to blood pressure regulation. Primary neuron cultures confirmed ACE2 expression on GABAergic neurons synapsing onto excitatory neurons within the hypothalamus but not on glutamatergic neurons. ADAM17 expression was shown to colocalize with angiotensin-II type 1 receptors on Sim1 neurons, and the pressor relevance of this neuronal population was demonstrated by photoactivation. Selective knockdown of ADAM17 was associated with a reduction of FosB gene expression, increased vagal tone, and prevented the acute pressor response to centrally administered angiotensin-II. Chronically, SAT mice exhibited a blunted blood pressure elevation and preserved ACE2 activity during development of salt-sensitive hypertension. Bicuculline injection in those models confirmed the supporting role of ACE2 on GABAergic tone to the paraventricular nucleus. Together, our study demonstrates the contrasting impact of ACE2 and ADAM17 on neuronal excitability of presympathetic neurons within the paraventricular nucleus and the consequences of this mutual regulation in the context of neurogenic hypertension.

Massive transient damage of the olfactory epithelium associated with infection of sustentacular cells by SARS-CoV-2 in golden Syrian hamsters

“…where OSNs projects and in the piriform cortex where the olfactory signal is integrated. We also focused on the hypothalamus which contains ACE2 expressing neurons (Mukerjee et al, 2019) as well as on the respiratory centres of the brainstem as the latter are suspected to be infected in COVID-19 patients suffering from heavy respiratory disorders (Gandhi et al, 2020). Our lack of virus detection in the central nervous system may be due to the low number of animal examined but, nevertheless, we can rule out a systematic and important infection of the brain following SARS-CoV-2 infection in hamster.…”

Comparative ACE2 variation and primate COVID-19 risk

“…Sites showing evidence of positive selection within catarrhine ACE2 sequences were not in or near known CoV binding sites (Table 2,Figure 1). Two (residues 653, 658) fall within the cleavage site (residues 652-659) utilized by the sheddase ADAM17, known to interact with ACE262 . However, neither of the residues under selection are the amino acids targeted by ADAM1763 leaving the functional significance of evolution at these sites uncertain.…”

Comparative ACE2 variation and primate COVID-19 risk

“…1 ). Two (residues 653, 658) fall within the cleavage site (residues 652-659) utilized by the sheddase ADAM17, known to interact with ACE2 44 . However, neither of the residues under selection are the amino acids targeted by ADAM17 45 leaving the functional significance of evolution at these sites uncertain.…”