Abstract Body: The arcuate nucleus of the hypothalamus (ARC) serves as a key regulator of the cardiovascular and sympathetic regulating center. While neurons in the ARC expressing agouti-related peptide (AgRP) are implicated in the regulation of energy- and glucose homeostasis, our recent findings show that acute chemogenic activation of ARC^AgRP neurons reduces blood pressure (BP), whereas inhibition of these neurons has the opposite effect. Together, these observations indicate ARC^AgRP neuronal activity as a determinant of basal BP and suggest that tonic activity of these neurons may be required to maintain BP in the normal range. Importantly, most AgRP neurons express the (pro)renin receptor (PRR), a pivotal component of the brain renin-angiotensin system critical for BP regulation. Accordingly, we hypothesized that prorenin may regulate AgRP neuron activity through PRR, and thereby contributing to the autonomic regulation of BP. This study employed whole-cell patch clamp methodology in brain slices of ARC to investigate the effect of prorenin on AgRP neuron firing activity and understand mechanisms. Male and female mice expressing tdTomato in the AgRP neurons were used. Prorenin (2.5 nM) depolarized the resting membrane potential (-41.9 ± 8.7 mV vs. -47.2 ± 7.8 mV, P < 0.001) and increased the frequency of action potential (AP) (2.3 ± 1.3 Hz vs. 1.2 ± 0.8 Hz, P < 0.001) compared with the control (artificial cerebrospinal fluid (aCSF), n=10 neurons from 7mice). Analysis of AP waveforms revealed that prorenin decreased the amplitude of AP (61.0 ± 14.4 mV vs. 70.2 ± 14.3 mV, P < 0.001) and threshold potential (-31.8 ± 6.0 mV vs. -35.5 ± 4.8 mV, P < 0.001), and increased the rise time (2.3 ± 0.7 ms vs. 1.9 ± 0.6 ms, P < 0.001), decay time (2.6 ± 1.1 ms vs. 2.0 ± 0.9 ms, P < 0.01) and half-width (2.2 ± 0.7 ms vs. 1.8 ± 0.6 ms, P <0.01) compared with the control. These changes suggest that alterations in the intrinsic conductance underlying the AP waveform likely coincide with the observed decrease in resting membrane potentials, while the ion channels involved remained to be determined. In summary, prorenin increases the firing activity of the ARC^AgRP neurons by depolarizing the resting membrane potential, implicating that activation of PRR in the ARC^AgRP neurons may reduce BP and protect against hypertension development.