Orexin A increases sympathetic nerve activity through promoting expression of proinflammatory cytokines in Sprague Dawley rats

Abstract

Aim: Accumulating evidence suggests that orexin signalling is involved in the regulation of blood pressure and cardiovascular function. However, the underlying mechanisms are not clear. Here, we test the hypothesis that upregulated orexin A signalling in the paraventricular nucleus (PVN) increases sympathetic nerve activity (SNA) through stimulating expression of proinflammatory cytokines (PICs). Methods: In vivo sympathetic nerve recordings were performed to test the impact of PVN orexin signalling on sympathetic outflow in Sprague Dawley (SD) rats. Real-time PCR was carried out to assess effects of central administration of orexin A on PVN PICs expression in SD rats. To test whether orexin A-induced increases in PICs were exclusively mediated by orexin receptor 1 (OX1R), OX1R-expressing PC12 (PC12-OX1R) cells were incubated with different dose of orexin A, and then, PICs mRNA and immunoreactivity were measured. Results: Orexin A microinjection (25 pmol) into the PVN significantly increased splanchnic SNA (93.5%) and renal SNA (83.3%) in SD rats, and these increases were attenuated by OX1R antagonist SB408124. Intracerebroventricular injection of orexin A (0.2 nmol) into SD rats increased mRNA levels of PICs including IL-1-β (2.7-fold), IL-6 (1.7-fold) and TNF-α (1.5-fold), as well as Fra1 (1.6-fold) in the PVN. Orexin A treatment in PC12-OX1R cells resulted in a dose- and time-dependent increase in the expression of PICs and Fra1, a subunit of AP1 transcriptional factor. The increase in the PICs was blocked by AP1 blocker curcumin. Conclusion: Paraventricular nucleus orexin system activation is involved in SNA regulation maybe through triggering AP1-PICs pathway.

Expression of Proinflammatory Cytokines Is Upregulated in the Hypothalamic Paraventricular Nucleus of Dahl Salt-Sensitive Hypertensive Rats

“…This evidence coupled with the evidence that PICs such as IL-1β and IL-6 can stimulate AVP secretion (Yasin et al, 1994 ; Chikanza et al, 2000 ) suggest that HS diet may increase plasma AVP through increasing PVN PICs expression. It is important to take into account that the neurons in the LM is not exclusively involved in neurohormones production and secretion, some neurons in this brain region also project to the RVLM and are probably involved in controlling SNA outflow (Fan et al, 2018 ). In addition, HS diet intake Dahl S rats and SD rats that received ICV infusion of hypertonic salt also presented increased IL-6 and Fra1 expression in the VM subnucleus, a key area concentrated with pre-autonomic neurons.…”

“…mRNA levels of PICs and Fra1 in the PVN and cultured hypothalamic neurons were assessed using real time PCR as detailed previously (Huber et al, 2017 ; Fan et al, 2018 ). Briefly, PVN tissues were punched from rat brains.…”

“…The ICV infusion was performed as detailed in our recent publications (Huber et al, 2017 ; Fan et al, 2018 ). In brief, adult male SD rats (350–400 g) were anesthetized with isoflurane (3% in O 2 ) and were placed in a stereotaxic head frame.…”

Inflammation—Dysregulated inflammatory response and strategies for treatment

“…Fan et al hypothesize that upregulated orexin A signalling in the paraventricular nucleus (PVN) increases sympathetic nerve activity (SNA) through stimulating the expression of proinflammatory cytokines. This results in an excessive production of proinflammatory cytokines, which in turn increases sympathetic outflow and leads to high blood pressure . Fan et al found out that the activation of Orexin A‐orexin 1 receptor signalling results in increased levels of the proinflammatory cytokines interleukin‐6 (IL‐6) and TNFα.…”

Recent advances in hypertension research

“…Sympathetic nerve activity modulates arterial blood pressure. In an interesting experimental study by Fan et al, the authors investigate the role of the neuropeptide orexin A in the signalling of the paraventricular nucleus (PVN) in the brain with respect to sympathetic activity. The authors find that after microinjection of orexin into the PVN the sympathetic activity is increased as determined by nerve activity measurements.…”