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

Cardiovasc Toxicol. 2016 Oct;16(4):345-54. doi: 10.1007/s12012-015-9344-9.

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.

Keywords: Hypothalamic paraventricular nucleus; NF-κB; NLRP3; Oxidative stress; Salt-sensitive hypertension.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Antihypertensive Agents / administration & dosage*
  • Antioxidants / administration & dosage
  • Arterial Pressure / drug effects*
  • Biomarkers / blood
  • Caspase 1 / metabolism*
  • Disease Models, Animal
  • Epinephrine / blood
  • Hypertension / enzymology
  • Hypertension / physiopathology
  • Hypertension / prevention & control*
  • I-kappa B Kinase / metabolism
  • Infusions, Parenteral
  • Interleukin-1beta / metabolism
  • Male
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Norepinephrine / blood
  • Oxidative Stress / drug effects
  • Paraventricular Hypothalamic Nucleus / drug effects*
  • Paraventricular Hypothalamic Nucleus / enzymology
  • Paraventricular Hypothalamic Nucleus / physiopathology
  • Phosphorylation
  • Pyrrolidines / administration & dosage*
  • Rats, Inbred Dahl
  • Signal Transduction
  • Sodium Chloride, Dietary*
  • Sympathetic Nervous System / drug effects
  • Sympathetic Nervous System / metabolism
  • Sympathetic Nervous System / physiopathology
  • Thiocarbamates / administration & dosage*
  • Transcription Factor RelA / antagonists & inhibitors*
  • Transcription Factor RelA / metabolism

Substances

  • Anti-Inflammatory Agents
  • Antihypertensive Agents
  • Antioxidants
  • Biomarkers
  • IL1B protein, rat
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, rat
  • Pyrrolidines
  • Rela protein, rat
  • Sodium Chloride, Dietary
  • Thiocarbamates
  • Transcription Factor RelA
  • pyrrolidine dithiocarbamic acid
  • I-kappa B Kinase
  • Caspase 1
  • Norepinephrine
  • Epinephrine