Angiotensin II–Induced Hypertension Is Modulated by Nuclear Factor-κB in the Paraventricular Nucleus

Abstract

Hypertension is considered a low-grade inflammatory condition and understanding the role of transcription factors in guiding this response is pertinent. A prominent transcription factor that governs inflammatory responses and has become a focal point in hypertensive research is Nuclear Factor-kappaB (NFκB). Within the hypothalamic paraventricular nucleus (PVN), a known brain cardio-regulatory center, NFκB becomes potentially even more important in ultimately coordinating the systemic hypertensive response. To definitively demonstrate the role of NFκB in the neurogenic hypertensive response, we hypothesized that PVN NFκB blockade would attenuate angiotensin II (AngII)-induced hypertension. Twelve-week old Sprague-Dawley rats were implanted with radio-telemetry probes for blood pressure measurement and allowed a 7-day recovery. Following baseline blood pressure recordings, rats were administered either continuous NFκB decoy oligodeoxynucleotide infusion or microinjection of a serine mutated Adenoviral Inhibitory-kappaB (AdIκB) vector, or their respective controls, bilaterally into the PVN to inhibit NFκB at two levels of its activation pathway. Simultaneously, rats were implanted subcutaneously with an AngII or saline-filled 14-day osmotic minipump. Following the 2-week treatments, rats were sacrificed and brain tissues collected for PVN analysis. Bilaterally inhibited NFκB rats had a decreased blood pressure, NFκB p65 subunit activity, proinflammatory cytokines and reactive oxygen species, including the AngII type-1 receptor, ACE, TNF and superoxide, in AngII-treated rats. Moreover, following NFκB blockade, key protective anti-hypertensive renin-angiotensin system components were up-regulated. This demonstrates the important role that transcription factor NFκB plays within the PVN in modulating and perpetuating the hypertensive response via renin-angiotensin system modulation.

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

“…PVN was isolated from frozen brain sections using a Stoelting brain punch (Stoelting) and, then, the tissue was homogenized with RIPA lysis buffer, as previously described (2,7,18,39). The protein concentration was measured using a bicinchoninic acid (BCA) protein assay kit (Pierce).…”

“…In addition, it was demonstrated that acute microinjection of proinflammatory molecules into the PVN of normotensive rats causes elevation of both arterial pressure and renal sympathetic nerve activity (38). On the other hand, chronic inhibition of proinflammatory signaling in the brain decreased arterial pressure and renal sympathetic nerve activity, and reversed the deleterious cardiac remodeling in hypertensive rats (7,13,18,39). Therefore, brain inflammation emerges as a central factor that contributes to autonomic and cardiovascular abnormalities in hypertension.…”

Heart Failure as a Disruption of Dynamic Circulatory Homeostasis Mediated by the Brain

“…HEART FAILURE AS CIRCULATORY HOMEOSTASIS FAILURE pro-inflammatory cytokines, [65][66][67][68][69] perivascular macrophages, 70,71) transcription factor nuclear factor kappa B, 72) and microglial cytokines 73,74) have been reported as being important factors of sympathoexcitation.…”

Using optogenetics to translate the “inflammatory dialogue” between heart and brain in the context of stress

“…More recently, experiments suggested that cytokines as neuromodulators exert their action on cardiovascular control through interaction with the brain angiotensin system: pretreatment with either IL-1β or TNF-α enhances the pressor response to the central infusion of angiotensin II [73] ; the pressor and dipsogenic effects of angiotensin II in mice require the presence of TNF-α [74] ; blockade of NF-κB in brain ameliorates the development of AngII-induced hypertension, and reduces the expression of angiotensin II type 1 receptors in the heart and the PVN [75] .…”