Central blockade of NLRP3 reduces blood pressure via regulating inflammation microenvironment and neurohormonal excitation in salt-induced prehypertensive rats

Abstract

BackgroundInflammation has been implicated in the development of cardiovascular disease. We determined whether nod-like receptor with pyrin domain containing 3 (NLRP3) involved in the process of prehypertension, central blockade of NLRP3 decreased inflammation reaction, regulated neurohormonal excitation, and delayed the progression of prehypertension.MethodsPrehypertensive rats were induced by 8% salt diet. The rats on high-salt diet for 1 month were administered a specific NLRP3 blocker in the hypothalamic paraventricular nucleus (PVN) for 4 weeks. ELISA, western blotting, immunohistochemistry, and flow cytometry were used to measure NLRP3 cascade proteins, pro-inflammation cytokines (PICs), chemokine ligand 2 (CCL2), C-X-C chemokine receptor type 3 (CXCR3), vascular cell adhesion molecule 1 (VCAM-1), neurotransmitters, and leukocytes count detection, respectively.ResultsNLRP3 expression in PVN was increased significantly in prehypertensive rats, accompanied by increased number of microglia, CD4+, CD8+ T cell, and CD8+ microglia. Expressions of PICs, CCL2, CXCR3, and VCAM-1 significantly increased. The balance between 67-kDa isoform of glutamate decarboxylase (GAD67) and tyrosine hydroxylase (TH) was damaged. Plasma norepinephrine (NE) in prehypertensive rats was increased and gamma-aminobutyric acid (GABA) was reduced. NLRP3 blockade significantly decreased blood pressure, reduced PICs, CCL2, VCAM-1 expression in PVN, and restored neurotransmitters. Blood pressure and inflammatory markers were upregulated after termination of central blockage NLRP3.ConclusionsSalt-induced prehypertension is partly due to the role of NLRP3 in PVN. Blockade of brain NLRP3 attenuates prehypertensive response, possibly via downregulating the cascade reaction triggered by inflammation and restoring the balance of neurotransmitters.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1131-7) contains supplementary material, which is available to authorized users.

Role of the NLRP3 Inflammasome in Preeclampsia

“…A murine experimental hypertension model (uninephrectomy and treatment with deoxycorticosterone acetate and 0.9% NaCl in the drinking water) induced activation of the NLRP3 inflammasome in kidney and specific NLRP3 inhibitor, MCC950, inhibited the NLRP3 inflammasome and inflammation, resulting in improvement of hypertension in mice (78). In rats, salt-induced hypertension occurs partly due to the role of NLRP3 inflammasome activation in the hypothalamic paraventricular nucleus, while blockade of brain NLRP3 attenuates the hypertensive response (79). An absence of ASC also reduces pulmonary hypertension induced by hypoxia (80).…”

Microglia-Derived NLRP3 Activation Mediates the Pressor Effect of Prorenin in the Rostral Ventrolateral Medulla of Stress-Induced Hypertensive Rats

“…In chronic inflammation, NLRP3 acts as the primary activator of inflammation, which can trigger the cascade production of other pro-inflammatory cytokines [50,51]. In salt-induced pre-hypertensive rats, NLRP3 inflammasome activation is associated with hypertension in the PVN [36,52]. We found that prorenin increased ROS production and triggered microglial M1 phenotype-switching and NLRP3 activation in primary cultured microglia.…”

Study on the Antihypertensive Mechanism of Astragalus membranaceus and Salvia miltiorrhiza Based on Intestinal Flora-Host Metabolism

“…4-pyridic acid was a metabolite of vitamin B6, and the low level of vitamin B6 was closely related to inflammatory status and cardiovascular mortality [50]. Gamma-aminobutyric acid, as an inhibitory neurotransmitter, has been found to be decreased in salt-sensitive hypertensive rats, and its increase decreased SHRs' blood pressure [51, 52]. Sphingosine 1-phosphate was catalyzed by sphingosine kinase (SPK) through the S1P receptor.…”