NF-κB Blockade in Hypothalamic Paraventricular Nucleus Inhibits High-Salt-Induced Hypertension Through NLRP3 and Caspase-1

Abstract

High-salt-induced inflammation and oxidative stress in the hypothalamic paraventricular nucleus (PVN) contribute to the pathogenesis of salt-sensitive hypertension. In this study, we hypothesized that chronic inhibition of nuclear factor-κB (NF-κB) activity in the PVN delays the progression of hypertension by upregulating anti-inflammatory cytokines, reducing NLRP3 (NOD-like receptor family pyrin domain containing 3) and IL-1β and attenuating p-IKKβ, NF-κB p65 activity and NAD(P)H oxidase in the PVN of salt-sensitive hypertensive rats. Dahl salt-sensitive rats received a high-salt diet (HS, 8 % NaCl) or a normal-salt diet (NS, 0.3 % NaCl) for 6 weeks and were treated with bilateral PVN infusion with either vehicle or pyrrolidine dithiocarbamate (PDTC, 5 μg/h), a NF-κB inhibitor via osmotic minipump. The mean arterial pressure and plasma levels of norepinephrine (NE) and epinephrine (EPI) were significantly increased in high-salt-fed rats. In addition, rats with high-salt diet had higher levels of p-IKKβ, NF-κB p65 activity, Fra-like (Fra-LI) activity (an indicator of chronic neuronal activation), NOX-4 (subunits of NAD(P)H oxidase), NLRP3 and IL-1β, and lower levels of IL-10 in the PVN than normal diet rats. Bilateral PVN infusions of PDTC attenuated these high-salt-induced changes. These findings suggest that high-salt-induced NF-κB activation in the PVN caused hypertension via sympathoexcitation, which are associated with the increases of NLRP3, IL-1β and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates NLRP3, IL-1β and oxidative stress in the PVN and thereby attenuates hypertension.

Vildagliptin inhibits high free fatty acid (FFA)-induced NLRP3 inflammasome activation in endothelial cells

“…NOX-4 is an important mitochondrial enzyme, which mediates ROS production. Importantly, increased NOX-4 expression is associated with NLRP3 activation and IL-1b maturation in endothelial cells [16]. Importantly, blockage of NOX-4 activation with its specific inhibitor can prevent NLRP3 inflammasome activation and reduce caspase-1 cleavage as well as the production of IL-1b and IL-18 [17].…”

Age‐dependent alterations to paraventricular nucleus insulin‐like growth factor 1 receptor as a possible link between sympathoexcitation and inflammation

“…Furthermore, hypertension has been described as an inflammatory disorder associated with elevated levels of circulating angiotensin II (Ang II) and pro‐inflammatory cytokines that alters synaptic activity (Qi et al . ,b; Hay ; Takesue et al . ).…”

“…; Qi et al . ,b). Synergistically, Ang II and HMGB1 facilitate the depletion of nNOS and adversely alter synaptic activity (Reis et al .…”

Novel adaptive and innate immunity targets in hypertension

“…Furthermore, ASC −/− mice or mice treated with NLRP3 inhibitor MCC950 were protected from 1K/DOCA/salt-induced HTN, inflammation, and fibrosis 65 . NLRP3 inflammasome involvement has also been established in animal models of SSHTN and was first shown by Qi et al where Dahl SS rats fed a high salt diet resulted in elevated NLRP3 and IL-1β in the hypothalamic paraventricular nucleus (PVN), which was inhibited by NFκB blockade, indicating the importance of localized PVN NFκB activation in the sympathoexcitation that leads to HTN in response to high salt 66 . More recently NLRP3 inflammasome upregulation has also been demonstrated in the renal medulla of Dahl SS rats fed high salt and administration of caspase-1 inhibitor Ac-YVAD-cmk prevented SSHTN 67 .…”