Inhibition of TNF in the Brain Reverses Alterations in RAS Components and Attenuates Angiotensin II-Induced Hypertension

Dysfunction of brain renin-angiotensin system (RAS) components is implicated in the development of hypertension. We previously showed that angiotensin (Ang) II-induced hypertension is mediated by increased production of proinflammatory cytokines (PIC), including tumor necrosis factor (TNF), in brain cardiovascular regulatory centers such as the paraventricular nucleus (PVN). Presently, we tested the hypothesis that central TNF blockade prevents dysregulation of brain RAS components and attenuates Ang II-induced hypertension. Male Sprague-Dawley rats were implanted with radio-telemetry transmitters to measure mean arterial pressure (MAP) and subjected to intracerebroventricular (ICV) infusion of etanercept (10 µg/kg/day) with/without concurrent subcutaneous 4-week Ang II (200 ng/kg/min) infusion. Chronic Ang II infusion resulted in a significant increase in MAP and cardiac hypertrophy, which was attenuated by inhibition of brain TNF with etanercept. Etanercept treatment also attenuated Ang II-induced increases in PIC and decreases in IL-10 expression in the PVN. Additionally, Ang II infusion increased expression of pro-hypertensive RAS components (ACE and AT(1)R), while decreasing anti-hypertensive RAS components (ACE2, Mas, and AT(2) receptors), within the PVN. ICV etanercept treatment reversed these changes. Ang II-infusion was associated with increased oxidative stress as indicated by increased NAD(P)H oxidase activity and super oxide production in the PVN, which was prevented by inhibition of TNF. Moreover, brain targeted TNF blockade significantly reduced Ang II-induced NOX-2 and NOX-4 mRNA and protein expression in the PVN. These findings suggest that chronic TNF blockade in the brain protects rats against Ang II-dependent hypertension and cardiac hypertrophy by restoring the balance between pro- and anti-hypertensive RAS axes and inhibiting PIC and oxidative stress genes and proteins in the PVN.