Salt-sensitive hypertension is a critical component of essential hypertension (the leading global non-communicable cause of mortality), but the exact role of sodium in the pathogenesis of hypertension remains unclear. In normotensive, salt-resistant subjects, endogenous neural and renal water- and sodium-retaining mechanisms are suppressed to counter the influence of salt intake on blood pressure regulation. At present, there exists no clear understanding of the integrated sodium-sensitive signal transduction mechanisms that operate between the brain and the kidney to facilitate sodium homeostasis and normotension. The brain pathways that mediate salt-resistant responses to high salt-intake involve activation of G-protein coupled receptors (GPCR) and signal transduction via Gα-subunit proteins. Our laboratory has demonstrated that endogenous brain Gαi2-subunit protein-gated signal transduction pathways mediate the acute renal sympathoinhibitory and natriuretic responses to GPCR activation evoked by both pharmacological and physiological stimuli (volume expansion, acute sodium loading). Significantly, we have observed endogenous up-regulation of PVN Gαi2 proteins in salt-resistant animal models in response to increased salt-intake, a response that is required to potentiate endogenous renal-nerve dependent sodium excreting mechanisms to counter the development of salt-sensitive hypertension. Further, we have identified that failure to up-regulate PVN Gαi2 proteins in response to salt-intake contributes to the pathophysiology of salt-sensitive hypertension via renal nerve dependent mechanisms to impact the activity and expression of the sodium chloride co-transporter (NCC). Our recent advances in this area have identified a requirement of PVN Gαi2 protein signal transduction in mediating neuronal activation, in response to both acute and chronic sodium challenge, within the parvocellular neurons of the PVN to facilitate sympathoinhibition, sodium homeostasis and normotension. Collectively, our studies provide the first direct evidence of a central molecular signal transduction mechanism, PVN Gαi2 protein-gated pathways, that influences central sympathetic outflow to the kidney to impact sodium homeostasis and long-term blood pressure regulation.