The hypothalamus activates the SNS and other pathways contributing to the pathogenesis of hypertension. Dysregulated AVP neurons in the SON and PVN produce excess AVP, which activates hypothalamic V1a, brain V2, and peripheral V1a receptors, thus activating the SNS, RAS, or endothelial cells, respectively. Circulating cortisol activates MRs in the hypothalamus to simultaneous stimulate the SNS and RAS. Leptin binds to the LepR to activate AMPK and the SNS. The ARC produces α-MSH, which binds to the MC4 in the hypothalamus to increase SNS outflow. Dysregulated clock gene expression promotes aldosterone production leading to salt-sensitive hypertension.