Angiotensin-(1-7) Activates POMC Neurons in the Arcuate Nucleus of the Hypothalamus Through a<i>M as</i>Receptor-Mediated Mechanism

Angiotensin-(1-7) is a protective hormone of the renin-angiotensin system that is well recognized to lower blood pressure and improve metabolic function in animal models of cardiovascular-related diseases; however, the precise mechanisms involved remain incompletely understood. Recent data from our laboratory suggests that the blood pressure lowering effects of angiotensin-(1-7) could occur through a central mechanism of action by inhibiting sympathetic activity to cardiovascular end organs. We have shown that angiotensin-(1-7) mas receptors highly colocalize to proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC), making these neurons a potential target for angiotensin-(1-7) cardiometabolic actions. In this study, we hypothesized that angiotensin-(1-7) activates POMC neurons in the ARC in a ma s receptor-dependent manner. To test this, we used male and female POMC-GFP mice to selectively target POMC neurons in the ARC. We assessed action potential firing of ARC POMC neurons following bath application of 100 nM angiotensin-(1-7) using cell attached patch clamp electrophysiology (n=7-10 cells per group). Angiotensin-(1-7) increased action potential firing of POMC neurons from baseline with no difference in angiotensin-(1-7) responsiveness between sexes (174±26% change in males vs. 133±12% change in females; one-sample t-test p=0.028 males vs. p=0.024 females; unpaired t-test p=0.127). To assess whether this increase in action potential firing occurred through a mas receptor mediated mechanism, we pretreated ARC slices with the selective mas receptor antagonist A779 (1 uM) for at least 30 minutes. Pretreatment with A779 prevented the increase in action potential firing following 100nM angiotensin-(1-7) bath application (106±13% change in males vs. 99±9% change in females; one-sample t-test p=0.549 males vs. p=0.884 females; unpaired t-test p=0.534). We also explored the neurotransmitter identity of ARC POMC neurons that express mas receptor using RNAscope in situ hybridization. We found that nearly 75% of POMC neurons in the ARC co-express mas receptor and mRNA for the vesicular GABA transporter (Vgat). Based on these data, we propose that angiotensin-(1-7) activates GABAergic subpopulations of POMC neurons in the ARC through a mas receptor-mediated mechanism, which may lead to a downstream inhibition of cardiovascular sympathetic activity. Additional studies are ongoing to further test this mechanism of action as well as to examine the impact of angiotensin-(1-7) on activity of ARC POMC neurons in the context of diet-induced obesity. Overall, these data provide new insight into central circuits engaged by angiotensin-(1-7). Funding: NIH F31 HL170693, NIH R01 HL156986 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.