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ACE2 Deletion is Associated with Increased ADAM17 and Reduced Inhibitory Currents to Pre‐sympathetic Hypothalamic Neurons
Author(s) -
Mukerjee Snigdha,
Xu Jiaxi,
Sriramula Srinivas,
Gao Hong,
Zsombok Andrea,
Lazartigues Eric
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.964.16
Subject(s) - medicine , endocrinology , hypothalamus , knockout mouse , inhibitory postsynaptic potential , angiotensin ii , western blot , sympathetic nervous system , biology , chemistry , blood pressure , receptor , gene , biochemistry
Deletion of the Angiotensin Converting Enzyme type 2 (ACE2) leads to a genetic background‐dependent increase in baseline blood pressure in mice, which can reach hypertensive levels with age. Recently, we identified a disintegrin and metalloprotease 17 (ADAM17) as a new member of a signaling pathway leading to the development of neurogenic hypertension. In an attempt to pinpoint the origin of developing hypertension in ACE2 knockout mice, we hypothesized that enhanced sympathetic drive could originate from elevated ADAM17 in pre‐sympathetic neurons of the paraventricular nucleus (PVN) of hypothalamus. Adult (10–12 week‐old) wildtype (WT) and ACE2 knockout male mice were used to assess ADAM17 protein expression (immunohistochemistry, Western blot and qPCR) in the PVN while another group was 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 pre‐sympathetic PVN neurons in WT mice was −49.01 ± 2.09 mV, while −48.9 ± 0.2 mV in ACE2 knockout mice, which may suggest an increased threshold for excitability in pre‐sympathetic PVN neurons. Interestingly, when the inhibitory inputs were analyzed, miniature IPSC frequency was reduced in ACE2 KO compared to WT (0.68 ± 0.29 vs. 1.56 ± 0.28 Hz; P <0.05) suggesting that the ACE2 knockout mice might be more susceptible to excitation, thus contributing to a sympathetic overdrive. Within the hypothalamus, ADAM17 expression showed a 2‐fold increase in ACE2 knockout compared to WT mice ( P <0.05). Using immunohistochemistry, increased ADAM17 expression was confirmed in parvocellular neurons of the PVN. Taken together, our data suggest that enhanced expression of ADAM17 in the parvocellular region of the PVN could be associated with increased excitability of pre‐sympathetic neurons in ACE2 knockout 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 or Funding Information NIH/NHLBI (HL093178) COBRE (P30GM106392)