Abstract Body: Agouti-related protein (AgRP) neurons, a key neuronal population within the arcuate nucleus (ARC), are known for their pivotal roles in regulating energy- and glucose homeostasis. However, their involvement in cardiovascular regulation remains poorly understood. Using RNAscope in situ hybridization, we found that 95.4% of the ARC^AgRP neurons express the (pro)renin receptor (PRR), a component of the brain renin-angiotensin system that is crucial for blood pressure (BP) regulation. We therefore hypothesized that PRR signaling in the ARC^AgRP neurons plays a regulatory role in the development of hypertension. To test this hypothesis, we selectively deleted PRR in ARC^AgRP neurons by crossing AgRP-IRES-Cre mice with PRR^fl/fl mice. Using RNAscope, as expected, AgRP^Cre+PRR^fl/y mice displayed a significantly lower PRR mRNA in the ARC^AgRP neurons than WT mice (76.3 ± 6.1 vs. 127.7 ± 2.9 AFU, p < 0.05), indicating efficient ablation of PRR in ARC^AgRP neurons. To examine the impact of PRR deletion in the ARC^AgRP neurons on BP, the AgRP^Cre+PRR^fl/y and control mice were implanted with telemetry probes to monitor BP continuously. After baseline recording, mice received DOCA-salt treatment (50 mg DOCA + saline as drinking water) for two weeks. BP variability and standard time domain heart rate variability (HRV) parameters, including overall HRV (SDNN) and short-term HRV (rMSSD), were analyzed from beat-to-beat intervals (n = 2-7 mice/group). At baseline, there was no difference between the two groups in BP, BP variability, and HRV. Two weeks of DOCA-salt induced a significantly higher BP in AgRP^Cre+PRR^fl/y mice than the controls (156.2 ± 6 vs. 119.4 ± 3 mmHg, p < 0.05), while BP variability did not differ between the two groups. Noteworthy, AgRP^Cre+PRR^fl/y mice exhibited lower SDNN than the controls (13.3 ± 4 vs. 19.4 ± 4 ms), indicating increased sympathetic and/or reduced parasympathetic nervous activity. This lower SDNN suggests impaired cardiac autonomic function and adaptability to physiological demands in AgRP^Cre+PRR^fl/y mice. Concurrently, AgRP^Cre+PRR^fl/y mice showed a lower rMSSD (4.7 ± 0.5 vs. 10.8 ± 3.5 ms), implying reduced parasympathetic activity. In conclusion, deletion of PRR in the ARC^AgRP neurons results in compromised cardiac autonomic function associated with the development of hypertension. Our findings underscore a novel protective role of PRR signaling in the ARC^AgRP neurons in BP regulation.