Interactions of the Brain Renin-Angiotensin-System (RAS) and Inflammation in the Sensitization of Hypertension

Abstract

Mounting evidence indicates that the renin-angiotensin (RAS) and immune systems interact with one another in the central nervous system (CNS) and that they are importantly involved in the pathogenesis of hypertension. Components comprising the classic RAS were first identified in the periphery, and subsequently, similar factors were found to be generated de novo in many different organs including the brain. There is humoral-neural coupling between the systemic and brain RASs, which is important for controlling sympathetic tone and the release of endocrine factors that collectively determine blood pressure (BP). Similar to the interactions between the systemic and brain RASs is the communication between the peripheral and brain immune systems. Systemic inflammation activates the brain’s immune response. Importantly, the RAS and inflammatory factors act synergistically in brain regions involved in the regulation of BP. This review presents evidence of how such interactions between the brain RAS and central immune mechanisms contribute to the pathogenesis of hypertension. Emphasis focuses on the role of these interactions to induce neuroplastic changes in a central neural network resulting in hypertensive response sensitization (HTRS). Neuroplasticity and HTRS can be induced by challenges (stressors) presented earlier in life such as a low-dose of angiotensin II or high fat diet (HFD) feeding in adults. Similarly, the offspring of mothers with gestational hypertension or of mothers ingesting a HFD during pregnancy are reprogrammed and manifest HTRS when exposed to new stressors as adults. Consideration of the actions and interactions of the brain RAS and inflammatory mediators in the context of the induction and expression of HTRS will provide insights into the etiology of high BP that may lead to new strategies for the prevention and treatment of hypertension.

Maternal Angiotensin II–Induced Hypertension Sensitizes Postweaning High‐Fat Diet–Elicited Hypertensive Response Through Increased Brain Reactivity in Rat Offspring

“…In obese humans and in animal models of diet‐induced obesity, increased sympathetic nervous system activity and BP have been demonstrated to be associated with RAS activation, elevation of inflammation, and increased leptin peripherally and centrally. 13 , 16 , 19 , 32 , 33 Consistent with this, we found that HFD‐fed offspring exhibited increased BP, elevated levels of angiotensin II, interleukin‐6, and leptin in the plasma and increased centrally driven sympathetic activity. The increased BP and central sympathetic tone were greater in HFD‐fed offspring of hypertensive dams when compared with HFD‐fed offspring of normotensive dams.…”

“… 38 , 39 In the central neural network, RAS components, inflammatory factors and leptin act on these structures to alter neural processing and storage information to establish a new level of sympathetic nervous system basal activity and reactivity to stressors, such as seen with obesity‐related hypertension. 16 , 19 , 32 , 40 To explore the central mechanisms underlying maternal hypertension sensitization of postweaning HFD‐induced increase in BP, we determined the pressor effects of intracerebroventricular application of angiotensin II, TNF‐α, or leptin in offspring. We found that although LFD‐fed offspring of hypertensive dam had a normal baseline BP, they exhibited increased pressor responses to intracerebroventricular angiotensin II and to TNF‐α.…”

“… 14 , 15 Evidence indicates that the cause of obesity‐related hypertension is mediated primarily through neurogenic mechanisms, in which activation of renin‐angiotensin system (RAS), inflammation, and elevated levels of leptin result in reprograming the central nervous system to produce a state of enhanced sympathetic reactivity. 16 , 17 , 18 , 19 , 20 , 21 , 22 We and others have demonstrated that maternal HFD feeding induces markedly elevated renal sympathetic nerve activity and pressor responses to central angiotensin II, tumor necrosis factor (TNF)‐α, or leptin in male adult offspring. 23 , 24 Conversely, postnatal HFD feeding in offspring previously subjected to several types of experimental prenatal insults exacerbates prenatal insult‐induced metabolic‐like syndrome, impaired renal function, and the developmental programming of increased BP.…”

“…Either renal denervation or systemic antagonism of the RAS blocked hypertensive response sensitization and reversed the changes in brain RAS and PIC mRNA expression of the offspring of hypertensive dams. 19 , 28 , 29 Pladys and colleagues 30 reported that in fetal protein‐restricted offspring, there was increased expression of the angiotensin II receptor type 1 (AT1‐R) in the subfornical organ and the vascular organ of the LT, and that intracerebroventricular injection of an angiotensin‐converting enzyme inhibitor or an AT1‐R antagonist significantly reduced BP in these offspring. These data implicate the brain RAS and inflammation in hypertension associated with prenatal insults.…”

μ-Opioid Receptor-Mediated AT1R–TLR4 Crosstalk Promotes Microglial Activation to Modulate Blood Pressure Control in the Central Nervous System

“…As previously noted, the regulation of Ang II and TLR4 involves the body–brain communication between afferent neural and humoral pathways that activate the central neural network to control cardiovascular function [ 36 ]. Neither RAS nor inflammatory mediators can contribute individually to the pathogenesis of hypertension; thus, the interactions between RAS components and inflammation mediators are likely synergistic [ 37 ]. Our findings concluded that the downregulation of AT1R-induced superoxide generation is associated with the activation of microglia and the expression of TLR4 in the NTS of SHR.…”