Increased ADAM17 Expression in ACE2 Knockout Mice is Associated with Increased Excitability of Paraventricular Nucleus Pre‐sympathetic Neurons

Abstract

We previously reported that ACE2 knockout (KO) mice, like humans, develop age‐dependent hypertension. In addition, a disintegrin and metalloprotease 17 (ADAM17) was recently shown to contribute to neurogenic hypertension. Accordingly, we hypothesized that ADAM17 in the paraventricular nucleus (PVN) of hypothalamus contributes to enhanced sympathetic tone in mice lacking ACE2. Adult 10‐12 week‐old wildtype (WT) and ACE2 KO male mice (n=2‐4/group) were injected in the kidney with a pseudorabies virus encoding a green fluorescent protein, for retrograde labeling of sympathetic neurons. After 4 days, whole‐cell patch‐clamp recordings were conducted from labeled pre‐sympathetic PVN neurons. The resting membrane potential of these PVN neurons in WT mice was ‐59.7 ±1.06 mV, while ‐52.7 ±1.6 mV in ACE2 KO mice, which may suggest an increase threshold for excitability in pre‐sympathetic PVN neurons. In another set of mice, the hypothalamus was dissected from WT and KO animals (n=4/group) for western blot analysis. ADAM17 expression showed a 2‐fold increase in KO compared to WT (P<0.05). Finally, using immunohistochemistry, ADAM17 expression was confirmed in parvocellular neurons. Taken together, our data suggest that enhanced expression of ADAM17 in the parvocellular PVN could be associated with increased excitability of pre‐sympathetic neurons in ACE2 KO mice. This dysregulation in neuronal activity might alter the intricate pressor homeostasis leading to increased blood pressure. These results suggest that ADAM17 could be a potential new target for the reduction of enhanced sympathetic activity in neurogenic hypertension.Support: NIH HL093178