Neuronal (pro)renin receptor stimulation of proinflammatory cytokines involves NF‐kappa B signaling

Our previous studies have demonstrated that brain proinflammatory cytokines (PIC) play an important role in neurogenic hypertension. This, coupled with the observation that (pro)renin receptor (PRR) expression is increased in the brain of spontaneously hypertensive rats (SHR), led us to hypothesize that brain PRR may, in part, be responsible for regulation of PIC production. To test this hypothesis, neuronal cells in primary culture from the SHR hypothalamus and brainstem, which express increased PRR levels, were incubated with 100 nM of human prorenin for 6 hours. Real time PCR was performed to analyze PIC mRNA expression. The results indicated that prorenin treatment resulted in respective 200 fold, 1000 fold, and 25 fold increases in TNFα, IL1β and IL6 mRNA levels. This stimulation was blocked (>95%) by treatment with quinazoline (15 μM), an NF‐kappa B activation inhibitor, indicating a novel PRR mediated activation of the NF‐kappa B pathway. This PRR regulation of neuronal PIC was not affected by co‐incubation of cultures with prorenin in the presence of the AT1 receptor antagonist losartan, demonstrating that the effect is not mediated by PRR‐induced AngII generation. Our studies suggest that PRR plays a central role in the establishment of PIC‐dependent neurogenic hypertension.