Direct Pro-Inflammatory Effects of Prorenin on Microglia

Shi, Peng; Grobe, Justin L; Desland, Fiona; Zhou, Guannan; Shen, Xiao Z.; Shan, Zhiying; Li, Meng; Raizada, Mohan K.; Sumners, Colin

doi:10.1371/journal.pone.0092937

Cited by 74 publications

(68 citation statements)

References 37 publications

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“…Specific blockage of the RVLM iNOS normalized the ABP in the SHR (18), while chronic overexpression of iNOS in the RVLM elicits hypertension by activating the sympathetic nervous system (19). Previous studies from others and ours have demonstrated that PRR expression is significantly increased in the PVN of some hypertensive animal models (22,39). This evidence coupled with our observation that PRR activation in cultured PVN neurons dramatically increase mRNA levels of iNOS suggests that increased PVN PRR expression may result in excessive NO production through upregulating iNOS expression.…”

Section: Discussionmentioning

confidence: 70%

“…In addition, we focused on the signaling pathway of neuronal PRR. It should be mentioned that PRR is also expressed in microglia in the brain (39). Our recently published data showed that PRR activation in PVN microglia induced proinflammatory cytokines expression and secretion (39), while cytokines are also neuronal activity modulators (40).…”

Section: Discussionmentioning

confidence: 98%

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Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats

Huber

Basu

Cecchettini

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats. Am J Physiol Heart Circ Physiol 309: H880 -H887, 2015. First published June 26, 2015 doi:10.1152/ajpheart.00095.2015.-Previous studies have indicated that hyperactivity of brain prorenin receptors (PRR) is implicated in neurogenic hypertension. However, the role of brain PRR in regulating arterial blood pressure (ABP) is not well understood. Here, we test the hypothesis that PRR activation in the hypothalamic paraventricular nucleus (PVN) contributes to increased sympathetic nerve activity (SNA). In anaesthetized adult Sprague-Dawley (SD) rats, bilateral PVN microinjection of human prorenin (2 pmol/side) significantly increased splanchnic SNA (SSNA; 71 Ϯ 15%, n ϭ 7). Preinjection of either prorenin handle region peptide, the PRR binding blocker (PRRB), or tiron (2 nmol/side), the scavenger of reactive oxygen species (ROS), significantly attenuated the increase in SSNA (PRRB: 32 Ϯ 5% vs. control, n ϭ 6; tiron: 8 Ϯ 10% vs. control, n ϭ 5; P Ͻ 0.05) evoked by prorenin injection. We further investigated the effects of PRR activation on ROS production as well as downstream gene expression using cultured hypothalamus neurons from newborn SD rats. Incubation of brain neurons with human prorenin (100 nM) dramatically enhanced ROS production and induced a time-dependent increase in mRNA levels of inducible nitric oxide synthase (iNOS), NAPDH oxidase 2 subunit cybb, and FOS-like antigen 1 (fosl1), a marker for neuronal activation and a component of transcription factor activator protein-1 (AP-1). The maximum mRNA increase in these genes occurred 6 h following incubation (iNOS: 201-fold; cybb: 2 -fold; Ffosl1: 11-fold). The increases in iNOS and cybb mRNA were not attenuated by the AT 1 receptor antagonist losartan but abolished by the AP-1 blocker curcumin. Our results suggest that PVN PRR activation induces sympathoexcitation possibly through stimulation of an ANG II-independent, ROS-AP-1-iNOS signaling pathway. paraventricular nucleus; (pro)renin receptor; reactive oxygen species; sympathetic nerve activity NEW & NOTEWORTHY To our best knowledge, this study is the first to investigate PVN PRR-mediated ANG II-independent signaling transduction on the control of sympathetic outflow and blood pressure. Our results suggest that PVN PRR-induced sympathoexcitation is possibly mediated by ROS-AP-1-iNOS signal transduction pathways.ACCUMULATING EVIDENCE INDICATES that alteration of central (pro)renin receptor (PRR) is involved in the development of cardiovascular diseases including neurogenic hypertension (32,46). The importance of the brain PRR in cardiovascular control is further strengthened by the observation that increased PRR expression in brain cardiovascular control areas altered body fluid homeostasis (38) and genetic knockdown of the PRR induced long-term depressor effects in hypertensive animals (21,22,38). However, the detailed mechanism underlying the role of brain PRR on blood pressure regulati...

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 98%

Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats

Huber

Basu

Cecchettini

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

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“…30 Recent studies have revealed that HFD feeding increases hypothalamic PIC expression including IL-1β, IL-6 and TNF-α, and several components of the RAS such as AT1-R. 14,31 The increased gene expression for the RAS and for PICs is accompanied by increased microglial activation in the hypothalamus including the arcuate nucleus (ARC), SFO and PVN. 13,32,33 Some of these responses were reversed upon deletion of AT1a specially within the PVN. 31 …”

Section: Discussionmentioning

confidence: 99%

Central Renin–Angiotensin System Activation and Inflammation Induced by High-Fat Diet Sensitize Angiotensin II–Elicited Hypertension

Xue

Thunhorst

et al. 2016

Hypertension

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Obesity has been shown to promote renin-angiotensin system (RAS) activity and inflammation in the brain and to be accompanied by increased sympathetic activity and blood pressure (BP). Our previous studies demonstrated that administration of a subpressor dose of angiotensin (Ang) II sensitizes subsequent Ang II-elicited hypertension. The present study tested whether high fat diet (HFD) feeding also sensitizes the Ang II-elicited hypertensive response and whether HFD-induced sensitization is mediated by an increase in RAS activity and inflammatory mechanisms in the brain. HFD did not increase baseline BP, but enhanced the hypertensive response to Ang II compared to a normal fat diet. The sensitization produced by the HFD was abolished by concomitant central infusions of either a tumor necrosis factor α (TNF-α) synthesis inhibitor, pentoxifylline, an Ang II type 1 receptor (AT1-R) blocker, irbesartan or an inhibitor of microglial activation, minocycline. Furthermore, central pretreatment with TNF-α mimicked the sensitizing action of a central subpressor dose of Ang II, whereas central pentoxifylline or minocycline abolished this Ang II-induced sensitization. RT-PCR analysis of lamina terminalis tissue indicated that HFD feeding, central TNF-α or a central subpressor dose of Ang II upregulated mRNA expression of several components of the RAS and proinflammatory cytokines, whereas inhibition of AT1-R and of inflammation reversed these changes. The results suggest that HFD-induced sensitization of Ang II-elicited hypertension is mediated by upregulation of the brain RAS and of central proinflammatory cytokines.

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“…Increased proinflammatory cytokines (PIC) expression in autonomic control areas, as the RVLM, has been identified as a major central molecular mechanism to decrease increase pressure variability and renal sympathetic nerve activity, thus contributing to the development/maintenance of hypertension [5,36]. Nuclear factor-kappa B (NF-κB) is one of the most important downstream transcription factors responsible for the transcription of PIC, and thereby regulates BP [20,21].…”

Section: Discussionmentioning

confidence: 99%

Exercise Training Attenuates Proinflammatory Cytokines, Oxidative Stress and Modulates Neurotransmitters in the Rostral Ventrolateral Medulla of Salt-Induced Hypertensive Rats

Huo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Exercise training (ExT) was associated with cardiovascular diseases including hypertension. The rostral ventrolateral medulla (RVLM) is a key region for central control of blood pressure and sympathetic nerve activity. Therefore, this study aimed to investigate the mechanisms within RVLM that can influence exercise training induced effects in salt-induced hypertension. Methods: Male Wistar rats were fed with a normal salt (0.3%) (NS) or a high salt (8%) (HS) diet for 12 weeks to induce hypertension. Then these rats were given moderate-intensity ExT for a period of 12 weeks. RVLM was used to determine glutamate and gamma-aminobutyric acid (HPLC), phosphorylated IKKβ, Fra-LI, 67-kDa isoform of glutamate decarboxylase (GAD67), proinflammatory cytokines (PIC) and NADPH-oxidase (NOX) subunits expression (Immunohistochemistry and Immunofluorescence, Western blotting). PIC and NF-κB p65 activity in the plasma were evaluated by ELISA studies. Renal sympathetic nerve activity (RSNA) was recorded and analyzed using the PowerLab system. Results: High salt diet resulted in increased mean arterial pressure and cardiac hypertrophy. These high salt diet rats had higher RVLM levels of glutamate, PIC, phosphorylated IKKβ, NF-κB p65 activity, Fra-LI, superoxide, NOX-2 (gp91^phox) and 4, and lower RVLM levels of gamma-aminobutyric acid and GAD67, and higher plasma levels of PIC, norepinephrine, and higher RSNA. ExT attenuated these changes in salt-induced hypertensive rats. Conclusions: These findings suggest that high salt diet increases the activity of NF-κB and the levels of PIC and oxidative stress, and induces an imbalance between excitatory and inhibitory neurotransmitters in the RVLM. ExT attenuates hypertension and cardiac hypertrophy partially mediated by attenuating oxidative stress and modulating neurotransmitters in the RVLM.

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Direct Pro-Inflammatory Effects of Prorenin on Microglia

Cited by 74 publications

References 37 publications

Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats

Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats

Central Renin–Angiotensin System Activation and Inflammation Induced by High-Fat Diet Sensitize Angiotensin II–Elicited Hypertension

Exercise Training Attenuates Proinflammatory Cytokines, Oxidative Stress and Modulates Neurotransmitters in the Rostral Ventrolateral Medulla of Salt-Induced Hypertensive Rats

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