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

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          Abstract

          Increased microglial activation and neuroinflammation within autonomic brain regions such as the rostral ventrolateral medulla (RVLM) have been implicated in stress-induced hypertension (SIH). Prorenin, a member of the brain renin-angiotensin system (RAS), can directly activate microglia. The present study aimed to investigate the effects of prorenin on microglial activation in the RVLM of SIH rats. Rats were subjected to intermittent electric foot-shocks plus noise, this stress was administered for 2 h twice daily for 15 consecutive days, and mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) were monitored. The results showed that MAP and RSNA were augmented, and this paralleled increased pro-inflammatory phenotype (M1) switching. Prorenin and its receptor (PRR) expression and the NLR family pyrin domain containing 3 (NLRP3) activation were increased in RVLM of SIH rats. In addition, PLX5622 (a microglial depletion agent), MCC950 (a NLRP3 inhibitor), and/or PRO20 (a (Pro)renin receptor antagonist) had antihypertensive effects in the rats. The NLRP3 expression in the RVLM was decreased in SIH rats treated with PLX5622. Mito-tracker staining showed translocation of NLRP3 from mitochondria to the cytoplasm in prorenin-stimulated microglia. Prorenin increased the ROS-triggering M1 phenotype-switching and NLRP3 activation, while MCC950 decreased the M1 polarization. In conclusion, upregulated prorenin in the RVLM may be involved in the pathogenesis of SIH, mediated by activation of the microglia-derived NLRP3 inflammasome. The link between prorenin and NLRP3 in microglia provides insights for the treatment of stress-related hypertension.

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          The online version of this article (10.1007/s12264-020-00484-9) contains supplementary material, which is available to authorized users.

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          Inflammation, immunity, and hypertension.

          David G. Harrison, Tomasz J. Guzik, Heinrich E. Lob … (2011)
          Article 0 comments Cited 235 times – based on 0 reviews     Review now
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            Role of the Immune System in Hypertension

            Richard J. Johnson, Héctor Pons, Bernardo Rodriguez-Iturbe (2017)
            High blood pressure is present in more than one billion adults worldwide and is the most important modifiable risk factor of death resulting from cardiovascular disease. While many factors contribute to the pathogenesis of hypertension, a role of the immune system has been firmly established by a large number of investigations from many laboratories around the world. Immunosuppressive drugs and inhibition of individual cytokines prevent or ameliorate experimental hypertension, and studies in genetically-modified mouse strains have demonstrated that lymphocytes are necessary participants in the development of hypertension and in hypertensive organ injury. Furthermore, immune reactivity may be the driving force of hypertension in autoimmune diseases. Infiltration of immune cells, oxidative stress, and stimulation of the intrarenal angiotensin system are induced by activation of the innate and adaptive immunity. High blood pressure results from the combined effects of inflammation-induced impairment in the pressure natriuresis relationship, dysfunctional vascular relaxation, and overactivity of the sympathetic nervous system. Imbalances between proinflammatory effector responses and anti-inflammatory responses of regulatory T cells to a large extent determine the severity of inflammation. Experimental and human studies have uncovered autoantigens (isoketal-modified proteins and heat shock protein 70) of potential clinical relevance. Further investigations on the immune reactivity in hypertension may result in the identification of new strategies for the treatment of the disease.
            Article 0 comments Cited 143 times – based on 0 reviews     Review now
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              AChE-stained horizontal sections of the rat brain in stereotaxic coordinates.

              George Paxinos, Charles R.R. Watson, Piers C Emson (1980)
              This paper presents an atlas of the rat brain based on horizontal sections stained for acetylcholinesterase (AChE). Fourteen labeled photographs from sections at 0.5 mm intervals are presented. The atlas is intended for use with male rats 250-300 g in weight. It was constructed using the flat-skull position (lambda and bregma in same horizontal plane). Either the interaural midline or bregma can serve as the reference zero point. We have found the stain for AChE to be a useful general purpose stain for identifying brain nuclei and tracts.
              Article 0 comments Cited 120 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Fuxue Chen: chenfuxue@staff.shu.edu.cn
                Chunmei Xia: cmxia@fudan.edu.cn
                Journal
                Journal ID (nlm-ta): Neurosci Bull
                Journal ID (iso-abbrev): Neurosci Bull
                Title: Neuroscience Bulletin
                Publisher: Springer Singapore (Singapore )
                ISSN (Print): 1673-7067
                ISSN (Electronic): 1995-8218
                Publication date (Electronic): 3 April 2020
                Publication date PMC-release: 3 April 2020
                Publication date Collection: May 2020
                Volume: 36
                Issue: 5
                Pages: 475-492
                Affiliations
                [1 ]GRID grid.39436.3b, ISNI 0000 0001 2323 5732, Laboratory of Neuropharmacology and Neurotoxicology, Shanghai Key Laboratory of Bio-Energy Crops, College of Life Science, , Shanghai University, ; Shanghai, 200444 China
                [2 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Department of Physiology and Pathophysiology, Basic Medicine College, , Fudan University, ; Shanghai, 200032 China
                [3 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Department of Neurosurgery, Huashan Hospital, , Fudan University, ; Shanghai, 200040 China
                [4 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, Department of Neurology, Renji Hospital, , Shanghai Jiaotong University, ; Shanghai, 200240 China
                [5 ]GRID grid.412987.1, ISNI 0000 0004 0630 1330, Department of Cardiovascular Diseases, , Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, ; Shanghai, 200025 China
                Article
                Publisher ID: 484
                DOI: 10.1007/s12264-020-00484-9
                PMC ID: 7186257
                PubMed ID: 32242284
                SO-VID: 488c4e66-dbc5-4f82-bd5d-bb20fe953f9f
                Copyright © © The Author(s) 2020
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 11 June 2019
                Date accepted : 14 December 2019
                Categories
                Subject: Original Article
                Custom metadata
                issue-copyright-statement © Shanghai Institutes for Biological Sciences, CAS 2020

                Keywords: stress,nlrp3,prorenin,microglia,hypertension
                Data availability:
                Keywords: stress, nlrp3, prorenin, microglia, hypertension

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