A novel protective role for hypothalamic AgRP neurons in hypertension

In addition to their role in energy and glucose homeostasis, agouti-related protein (AgRP) neurons located in the hypothalamic arcuate nucleus (ARC) project to multiple hypothalamic nuclei involved in autonomic and cardiovascular control and are implicated in blood pressure (BP) regulation. To investigate their role in the pathogenesis of hypertension, we employed a designer receptors exclusively activated by designer drugs (DREADD) approach. We report that in AgRP-hM3Dq mice, chemogenic activation of AgRP neurons (induced by intraperitoneal (I.P.) DREADD agonist (JHU37160, 0.2 mg/kg)) lowered BP (-53.4 ± 8.2 vs. 9.5 ± 3.4 mmHg) and heart rate (HR: -214.5 ± 33.6 vs. 110.9 ± 28.3 bpm) compared with vehicle (saline, I.P.) (n = 4-7). Thus, AgRP neuron activation exerts a depressor effect in otherwise normal mice. These observations led us to hypothesize that loss of AgRP neuron activity contributes to the pathogenesis of hypertension. To test this hypothesis, we selectively silenced AgRP neurons by bilaterally injection of a Cre-dependent adeno-associated virus (AAV2) encoding tetanus toxin light chain (TeLC-eYFP) into the ARC of AgRP-IRES-Cre mice (n = 5). Control littermates received a Cre-dependent AAV2-eGFP (n = 3). After stereotaxic surgery, mice were implanted with telemetry probes for continuous BP and HR monitoring. After a two-week recovery and baseline recordings, hypertension was induced using a two-week DOCA-salt administration protocol (50 mg DOCA; 0.9% saline as drinking water). Vasomotor sympathetic tone was evaluated as the depressor response following ganglionic blockade with chlorisondamine (6 mg/kg, I.P.). To verify the efficacy of AgRP neuron silencing, we injected AAV2-TeLC-eYFP into AgRP-hM3Dq mice and assessed food intake 15 min following administration of the JHU37160 (0.2 mg/kg). As expected, the robust stimulation of food intake induced by activating these neurons (15.2 ± 2.7 vs. 2 ± 0.4 mg, p < 0.0001 vs. vehicle) was markedly blunted in mice expressing AAV2-TeLC-eYFP (8 ± 1.6 mg, p < 0.0001), confirming effective functional silencing of AgRP neurons. AgRP neuron inactivation did not alter baseline BP, HR, or cardiovascular autonomic indices. As expected, two weeks of DOCA-salt increased mean arterial pressure (MAP: 145.0 ± 9.2 vs. 124.9 ± 1.9 mmHg, p < 0.05) and vasomotor sympathetic tone (delta MAP: -64.2 ± 6.5 vs. -29.7 ± 6.2 mmHg, p < 0.05) while having no impact on HR in otherwise normal mice. This hypertensive phenotype was exacerbated in mice with silenced AgRP neurons, however. Specifically, we observed increases of both MAP (159.7 ± 1.9 vs. 145.0 ± 9.2 mmHg, p < 0.05 TeLC vs. Control) and chlorisondamine-induced MAP decrease (delta MAP: -88.9 ± 4.5 vs. -64.2 ± 6.5 mmHg, p < 0.05 TeLC vs. Control) compared to mice with intact AgRP neuron function. Since AgRP neuron silencing had no effect on food intake, body weight gain, or saline intake compared with controls, the observed cardiovascular phenotype was not secondary to changes in these variables. Together, these findings demonstrate that AgRP neuron silencing exacerbates DOCA-salt-induced hypertension, likely by enhancing neurogenic vasomotor sympathetic tone. This abstract was presented at the American Physiology Summit 2026 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.