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Increasing Angiotensin Converting Enzyme 2 Activity in the Brain Is Anxiolytic and Dampens Activation of Hypothalamic‐Pituitary‐Adrenal Axis in Male Mice
Author(s) -
Wang Lei,
Kloet Annette,
Pati Dipanwita,
Hiller Helmut,
Smith Justin,
Pioquinto David,
Oh S.,
Katovich Michael,
Raizada Mohan,
Frazier Charles,
Krause Eric
Publication year - 2015
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.29.1_supplement.931.11
Subject(s) - medicine , endocrinology , anxiogenic , stria terminalis , anxiolytic , chemistry , elevated plus maze , corticosterone , corticotropin releasing hormone , receptor , amygdala , hypothalamus , biology , hormone , anxiety , psychiatry
This study evaluates whether driving the counter‐regulatory limb of the renin‐angiotensin‐system influences anxiety and activation of the hypothalamic‐pituitary‐adrenal (HPA) axis. Using the Cre/Lox system, we generated male mice overexpressing angiotensin converting enzyme 2 (ACE2 KI) and wild‐type littermate controls (WT). Relative to WT, ACE2 KI mice had reduced anxiety‐like behavior and decreased stress‐induced HPA activation. These effects were abolished by central antagonism of the Mas receptor (MasR) but delivery of an ACE2 activator into the brains of WT mice was anxiolytic. To investigate underlying mechanisms we examined Fos expression subsequent to an anxiogenic stimulus. Relative to WT, ACE2 KI mice had increased Fos in the basolateral amygdala (BLA) but decreased Fos in the bed nucleus of the stria terminalis. Anatomical studies determined that GABA neurons in the BLA robustly express the MasR and electrophysiological studies revealed that ACE2 overexpression increased the frequency of spontaneous inhibitory postsynaptic currents in BLA principal neurons, an effect abolished by MasR blockade. To determine whether ACE2 attenuates HPA activation through interactions with corticotropin‐releasing‐hormone (CRH) we generated mice with ACE2 expression driven by the CRH gene. Indeed, ACE2 overexpression in CRH cells decreased activation of HPA axis. Collectively, the results suggest that ACE2 acts in the brain to decrease anxiety and HPA activation, in part, by stimulating the MasR.