Increased (Pro)renin Receptor Expression in the Hypertensive Human Brain.

Overactivation of the renin-angiotensin system (RAS) - a central physiological pathway involved in controlling blood pressure (BP) - leads to hypertension. It is now well-recognized that the central nervous system (CNS) has its own local RAS, and the majority of its components are known to be expressed in the brain. In physiological and pathological states, the (pro)renin receptor (PRR), a novel component of the brain RAS, plays a key role in the formation of angiotensin II (Ang II) and also mediates Ang II-independent PRR signaling. A recent study reported that neuronal PRR activation is a novel mechanism for cardiovascular and metabolic regulation in obesity and diabetes. Expression of the PRR is increased in cardiovascular regulatory nuclei in hypertensive (HTN) animal models and plays an important role in BP regulation in the CNS. To determine the clinical significance of the brain PRR in human hypertension, we investigated whether the PRR is expressed and regulated in the paraventricular nucleus of the hypothalamus (PVN) and rostral ventrolateral medulla (RVLM) - two key cardiovascular regulatory nuclei - in postmortem brain samples of normotensive (NTN) and HTN humans. Here, we report that the PRR is expressed in neurons, but not astrocytes, of the human PVN and RVLM. Notably, PRR immunoreactivity was significantly increased in both the PVN and RVLM of HTN subjects. In addition, PVN-PRR immunoreactivity was positively correlated with systolic BP (sBP) and showed a tendency toward correlation with age but not body mass index (BMI). Collectively, our data provide clinical evidence that the PRR in the PVN and RVLM may be a key molecular player in the neural regulation of BP and cardiovascular and metabolic function in humans.

The neuronal (pro)renin receptor and astrocyte inflammation in the central regulation of blood pressure and blood glucose in mice fed a high-fat diet.

We report here that the neuronal (pro)renin receptor (PRR), a key component of the brain renin-angiotensin system (RAS), plays a critical role in the central regulation of high-fat-diet (HFD)-induced metabolic pathophysiology. The neuronal PRR is known to mediate formation of the majority of angiotensin (ANG) II, a key bioactive peptide of the RAS, in the central nervous system and to regulate blood pressure and cardiovascular function. However, little is known about neuronal PRR function in overnutrition-related metabolic physiology. Here, we show that PRR deletion in neurons reduces blood pressure, neurogenic pressor activity, and fasting blood glucose and improves glucose tolerance without affecting food intake or body weight following a 16-wk HFD. Mechanistically, we found that a HFD increases levels of the PRR ligand (pro)renin in the circulation and hypothalamus and of ANG II in the hypothalamus, indicating activation of the brain RAS. Importantly, PRR deletion in neurons reduced astrogliosis and activation of the astrocytic NF-κB p65 (RelA) in the arcuate nucleus and the ventromedial nucleus of the hypothalamus. Collectively, our findings indicate that the neuronal PRR plays essential roles in overnutrition-related metabolic pathophysiology.