Using DOCA salt, a model that induces elevations in brain RAS activity and Ang-II signaling, the same group has also shown that neuron-specific knockout of the (pro) renin receptor attenuates DOCA salt–induced hypertension and sympathetic activation, concomitant with a reduction in brain Ang-II production. 11 Furthermore, a recently developed (pro) renin antagonist has been shown to attenuate DOCA salt–mediated increases in blood pressure and brain Ang-II, highlighting the therapeutic potential in targeting brain pro (renin)-mediated Ang-II production in hypertensive conditions. 16 Whether centrally or peripherally generated, the hypertensive actions of brain Ang-II occur primarily via AT1R. Indeed, Cre-LoxP–mediated removal of AT1R from catecholaminergic cells blunts Ang-II–dependent hypertension and sympathetic modulation of blood pressure. 17 These data suggest that AT1R in this cell population, presumably within sympathetic premotor neurons, the adrenal medulla, and sympathetic ganglia, is involved in the hypertensive actions of Ang-II, although a role of AT1R in peripheral cell populations, such as T lymphocytes, cannot be excluded from these findings. Additional support for brain AT1R signaling has also been demonstrated in a murine DOCA salt model. Hilzendeger et al18showed that selective knockdown of AT1R in the SFO blunted elevations in arterial blood pressure, reduced sympathetic cardiac modulation and urine vasopression markers (copeptin), and positively affected fluid and salt homeostasis. Collectively, these recent findings build on existing evidence and provide additional insight into specific CNS nuclei and cell populations involved in the development of hypertension due to brain Ang-II–AT1R signaling.

Although the primary actions of AT1R are prohypertensive, as highlighted by the aforementioned studies, it is important to consider the neural region in which Ang-II–induced signaling occurs. The nTS, located in the dorsomedial aspect of the brain stem, is a key example. Stimulation of excitatory nTS projections activate inhibitory neurons in the caudal ventrolateral medulla, in turn inhibiting sympathoexcitatory neurons in the RVLM, resulting in decreases in arterial blood pressure. Indeed, recent observations indicate that AT1R expression is elevated in the nTS of SHR and small hairpin RNA knockdown