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

Abstract

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. Keywords: (pro)renin receptor/(P)RR, human hypertension, paraventricular nucleus of the hypothalamus, rostral ventrolateral medulla, renin-angiotensin system

NADPH-Oxidase, Rho-Kinase and Autophagy Mediate the (Pro)renin-Induced Pro-Inflammatory Microglial Response and Enhancement of Dopaminergic Neuron Death

“…The results were consistent with previous studies in several peripheral tissues showing pro-oxidative and pro-inflammatory effects after PRR activation [ 45 , 46 , 47 ]. In the brain, PRR was observed in neurons and microglial cells [ 17 , 18 , 19 ], and at low levels [ 18 , 19 ] or undetectable [ 17 , 48 , 49 ] in astrocytes. To investigate if the increase in PRR expression in the pro-inflammatory state was related to neurons or microglial cells, we isolated microglial cells, using anti-CD11 microbeads and neurons, using laser microdissection, from brains of adult AT2 KO mice, and we detected a significant increase in PRR expression in microglial cells but not in neurons.…”

PLIN2 Mediates Neuroinflammation and Oxidative/Nitrosative Stress via Downregulating Phosphatidylethanolamine in the Rostral Ventrolateral Medulla of Stressed Hypertensive Rats

“…Overactive brain local renin-angiotensin system (RAS), oxidative/nitrosative stress, and neuroinflammation in concert play a pivotal role in triggering augmenting sympathetic activity in the centers. [8][9][10][11][12] We previously reported that stress induced mitochondrial damage in the microglia of RVLM. 13,14 Microglial mitophagy-lysosome dysfunction mediates the activation of intracellular NLRP3 inflammasome in stress hypertension mice, thus promoting the release of proinflammatory factors.…”

Cardiovascular aspects of the (pro)renin receptor: Function and significance

“…The expression of PRR in neurons of the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) was significantly increased in hypertensive humans and positively correlated with systolic BP, 146 implying a key role of the PRR in the PVN and RVLM in the neural regulation of BP in humans. Along with this line, increasing evidence from animal models has shown that PRR plays an essential role in brain AngII formation independently of circulating signals that control BP.…”