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

Abstract

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.

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

“…PRR expression is also upregulated in the hypothalamus of HTN mice (Li et al, 2015a). Pan-neuronal PRR knockdown or PVN-specific neuronal PRR knockdown attenuates hypertension development and high-fat diet-induced type II diabetes in mice (Souza et al, 2019;Worker et al, 2020). These studies indicate the physiological and pathological importance of the PRR in cardiovascular and metabolic regulation in rodents.…”

“…In rodents, the PRR is expressed in many BP-regulatory brain regions, including the SFO, SON, PVN, RVLM, and NTS (Contrepas et al, 2009;Shan et al, 2010;Li et al, 2012). In humans, PRR expression was reported in the SFO, PVN, and the pituitary (Takahashi et al, 2010;Cooper et al, 2018). PRR is colocalized with arginine vasopressin in the PVN and pituitary and with oxytocin in the hypothalamus (Takahashi et al, 2010).…”

“…In humans, PRR expression was reported in the SFO, PVN, and the pituitary (Takahashi et al, 2010;Cooper et al, 2018). PRR is colocalized with arginine vasopressin in the PVN and pituitary and with oxytocin in the hypothalamus (Takahashi et al, 2010). In the current study, we showed that the PRR is expressed in the PVN and RVLM in humans.…”

“…The PRR is highly expressed in mouse brain regions, including cardiovascular regulatory nuclei, such as the subfornical organ (SFO), paraventricular nucleus of the hypothalamus (PVN), supraoptic nucleus (SON), rostral ventrolateral medulla (RVLM), and nucleus tractus solitarius (NTS; Contrepas et al, 2009;Li et al, 2012;Xu et al, 2016). In the human brain, the PRR is reported to be expressed in the hypothalamus and pituitary (Takahashi et al, 2010). Recently, our research group also reported that PRR expression in the SFO is elevated in hypertensive (HTN) humans (Cooper et al, 2018).…”

“…These observations suggest that (pro)renin acts through the PRR in the PVN to play a role in regulating splanchnic sympathetic nerve activity and, potentially, downstream metabolic organs. A recent study reported that neuronal PRR activation is a novel mechanism for cardiovascular and metabolic regulation in obesity and diabetes (Worker et al, 2020). Despite evidence from preclinical studies suggesting a pivotal role for the PRR in cardiovascular diseases (Shan et al, 2010;Li et al, 2012;Huber et al, 2015;Souza et al, 2019), the clinical importance of the PRR in the PVN and RVLM has yet to be defined.…”