Targeting Interleukin-1 beta to Suppress Sympathoexcitation in Hypothalamic Paraventricular Nucleus in Dahl Salt-Sensitive Hypertensive Rats

Abstract

Findings from our laboratory indicate that expressions of some proinflammatory cytokines such as tumor necrosis factor, interleukin-6 and oxidative stress responses are increased in the hypothalamic paraventricular nucleus (PVN) and contribute to the progression of salt-sensitive hypertension. In this study, we determined whether interleukin-1 beta (IL-1β) activation within the PVN contributes to sympathoexcitation during development of salt-dependent hypertension. Eight-week-old male Dahl salt-sensitive (S) rats received a high-salt diet (HS, 8 % NaCl) or a normal-salt diet (NS, 0.3 % NaCl) for 6 weeks, and all rats were treated with bilateral PVN injection of gevokizumab (IL-1β inhibitor, 1 μL of 10 μg) or vehicle once a week. The mean arterial pressure (MAP), heart rate (HR) and plasma norepinephrine (NE) were significantly increased in high-salt-fed rats. In addition, rats with high-salt diet had higher levels of NOX-2, NOX-4 [subunits of NAD (P) H oxidase], IL-1β, NLRP3 (NOD-like receptor family pyrin domain containing 3), Fra-LI (an indicator of chronic neuronal activation) and lower levels of IL-10 in the PVN than normal-diet rats. Bilateral PVN injection of gevokizumab decreased MAP, HR and NE, attenuated the levels of oxidative stress and restored the balance of cytokines. These findings suggest that IL-1β activation in the PVN plays a role in salt-sensitive hypertension.

Microglial Mincle receptor in the PVN contributes to sympathetic hyperactivity in acute myocardial infarction rat

“…On the other hand, Syk, the downstream protein of Mincle, regulates NLRP3 activity via the production of reactive oxygen species . Qi et al observed increased NLRP3 expression within the PVN in salt‐sensitive hypertension rats compared with the normal rats and chronic antagonism of IL‐1β in the PVN decreased the levels of NLRP3. However, we did not found that NLRP3 expression was decreased following administration of IL‐1β inhibitor.…”

“…112 rats were randomly divided into six groups: (a) naïve, n = 14; (b) scramble siRNA, n = 16; (c) LPS (Sigma‐Aldrich, St. Louis, MO, USA, 12.5 μg of LPS dissolved in 50 nL of saline), n = 17; (d) LPS+rSAP130 (Abnova, Taiwan, China, 25 ng in 50 nL of saline), n = 21; (e) LPS+rSAP130 + NLRP3 siRNA (Thermo Fisher, 250 pmol/50 nL), n = 22; (f) LPS+rSAP130 + gevokizumab (XOMA 052; XOMA Corporation, Emeryville, CA, USA, 50 nL of saline solution containing 10 μg of gevokizumab), n = 22. The doses of reagents were referred according to previous studies . Animals in naïve group did not receive any procedure except anesthesia until RSNA measurement.…”

Inflammasomes—A Molecular Link for Altered Immunoregulation and Inflammation Mediated Vascular Dysfunction in Preeclampsia

“…Numerous studies have detailed the pathogenesis of hypertensive disorders and reported that the molecular inflammasome platform represents a central pathogenic mechanism in initiating and promoting organ damage attributed to hypertension. Eight-week-old male Dahl salt-sensitive rats fed with a high-salt diet (8% NaCl) for six weeks were found to have higher levels of NLRP3 and IL-1β in the hypothalamic paraventricular nucleus when compared to rats fed a normal diet (0.3% NaCl) [84]. Similarly, bilateral hypothalamic paraventricular nucleus injection of an IL-1β inhibitor, gevokizumab (1 µL of 10 µg), reduced the mean arterial pressure, heart rate, and levels of plasma norepinephrine, as well as, attenuated the levels of oxidative stress (NOX-2 and NOX-4) and restored the levels of NLRP3, IL-1β, and IL-10 [84].…”

“…Eight-week-old male Dahl salt-sensitive rats fed with a high-salt diet (8% NaCl) for six weeks were found to have higher levels of NLRP3 and IL-1β in the hypothalamic paraventricular nucleus when compared to rats fed a normal diet (0.3% NaCl) [84]. Similarly, bilateral hypothalamic paraventricular nucleus injection of an IL-1β inhibitor, gevokizumab (1 µL of 10 µg), reduced the mean arterial pressure, heart rate, and levels of plasma norepinephrine, as well as, attenuated the levels of oxidative stress (NOX-2 and NOX-4) and restored the levels of NLRP3, IL-1β, and IL-10 [84]. Additionally, via inhibiting NLRP3-induced inflammation and idiopathic pulmonary fibrosis, the clinically used TGF-β blocker, pirfenidone protected against thoracic aortic constriction (TAC)-induced hypertension and left ventricular hypertrophy, collectively contributing to myocardial fibrosis, via blocking NLRP3-mediated inflammation and fibrosis [85].…”

Autoimmunity in the Pathogenesis of Hypertension

“…22,23 Several elements in the hypertension-induced tissue injury are capable of acting as danger-associated molecular patterns that activate the innate immunity. In the deoxycorticosterone acetate-salt hypertension model 47 and in the Dahl SS rat, 48 the elements of the inflammasome are overexpressed. In the spontaneously hypertensive rat, the priming signals for inflammasome activation, including overexpression of Toll-like receptors 2 and 4 49 and nuclear factor kappa B activation, 50 have been demonstrated, and mRNA stimulation with overexpression of all the components of the canonical nod-like receptor pyrin 3 inflammasone are present (unpublished).…”