A clinical and experimental investigation of liraglutide effects on the brain-kidney axis

Glucagon-like peptide-1 receptor agonists elicit diuresis and natriuresis in humans and rodents. However, little is known about their interactions with the bodies hormonal systems that control fluid homeostasis. We performed a single center, open-label, before-and-after study and discovered that liraglutide reduces plasma arginine vasopressin (AVP) levels in healthy humans. By quantitative proteomic and phosphoproteomic investigation of the rat pituitary gland, we detail time- and sex-dependent modifications to synaptic proteins mediated by liraglutide. We developed an in vitro AVP luciferase assay to assess the impact of synaptic protein phosphorylation on AVP secretion. We used this assay to identify synaptic protein phosphosites that influence AVP release and liraglutide-mediated sex differences in AVP release. Investigation of AVP downstream signaling pathways in the kidney revealed posttranslational changes to the crucial AVP-regulated water channel aquaporin 2. Thus, glucagon-like peptide-1 receptor agonist modulation of AVP release may be responsible for cardiovascular and renal changes observed in patients.