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Journal ArticleDOI

Histamine receptor agonist alleviates severe cardiorenal damages by eliciting anti-inflammatory programming.

TL;DR: It is found that histamine is elevated in the plasma of a preclinical mouse model with severe cardiac dysfunction and showed that it acts protectively rather than harmfully on heart and kidney damages in this model, and that a histamine H3 agonist, Imm, prevents the cardiorenal damages.
Abstract: Heart failure and chronic kidney disease are major causes of morbidity and mortality internationally. Although these dysfunctions are common and frequently coexist, the factors involved in their relationship in cardiorenal regulation are still largely unknown, mainly due to a lack of detailed molecular targets. Here, we found the increased plasma histamine in a preclinical mouse model of severe cardiac dysfunction, that had been cotreated with angiotensin II (Ang II), nephrectomy, and salt (ANS). The ANS mice exhibited impaired renal function accompanied with heart failure, and histamine depletion, by the genetic inactivation of histidine decarboxylase in mice, exacerbated the ANS-induced cardiac and renal abnormalities, including the reduction of left ventricular fractional shortening and renal glomerular and tubular injuries. Interestingly, while the pharmacological inhibition of the histamine receptor H3 facilitated heart failure and kidney injury in ANS mice, administration of the H3 agonist immethridine (Imm) was protective against cardiorenal damages. Transcriptome analysis of the kidney and biochemical examinations using blood samples illustrated that the increased inflammation in ANS mice was alleviated by Imm. Our results extend the pharmacological use of H3 agonists beyond the initial purposes of its drug development for neurogenerative diseases and have implications for therapeutic potential of H3 agonists that invoke the anti-inflammatory gene expression programming against cardiorenal damages.
Citations
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Journal ArticleDOI
TL;DR: A newly developed histaminergic cell‐monitoring transgenic mouse line (Hdc‐BAC‐GFP) is introduced that serves as a valuable experimental tool to identify the source of histamine and dissect upstream regulatory signals.
Abstract: Histamine is a bioactive monoamine that is synthesized by the enzymatic activity of histidine decarboxylase (HDC) in basophils, mast cells, gastric enterochromaffin-like (ECL) cells and histaminergic neuronal cells. Upon a series of cellular stimuli, these cells release stored histamine, which elicits allergies, inflammation, and gastric acid secretion and regulates neuronal activity. Recent studies have shown that certain other types of myeloid lineage cells also produce histamine with HDC induction under various pathogenic stimuli. Histamine has been shown to play a series of pathophysiological roles by modulating immune and inflammatory responses in a number of disease conditions, whereas the mechanistic aspects underlying induced HDC expression remain elusive. In the present review, we summarize the current understanding of the regulatory mechanism of Hdc gene expression and the roles played by histamine in physiological contexts as well as pathogenic processes. We also introduce a newly developed histaminergic cell-monitoring transgenic mouse line (Hdc-BAC-GFP) that serves as a valuable experimental tool to identify the source of histamine and dissect upstream regulatory signals.

20 citations


Cites background from "Histamine receptor agonist alleviat..."

  • ...This study showed that an H3R agonist (immethridine) had a preventive efficacy toward chronic heart and kidney diseases (Noguchi et al., 2020)....

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  • ...More recently, an interesting study showed that histamine plays an anti-inflammatory role by suppressing inflammatory cytokine gene expression through the histamine H3 receptor (H3R) in cardiorenal syndrome animal model (Figure 4) (Noguchi et al., 2020)....

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Journal ArticleDOI
TL;DR: In this article, the authors identify the common mechanism underlying SGAs-induced cardiotoxicity using dual-omics analyses and conclude that the spliceosome signaling was a common pathway driving SGAs cardio-toxicity.

12 citations

Journal ArticleDOI
TL;DR: It is found that vDAO is more potent than commercial anti-histamine drugs at inhibiting histamine-induced contraction of murine distal colon muscles and pyridoxal 5′-phosphate (the biologically active form of vitamin B6) as an effective enhancer of vDAo antispasmodic activity.
Abstract: Excess of histamine in gut lumen generates a pronounced gastrointestinal discomfort, which may include diarrhea and peristalsis dysfunctions. Deleterious effects of histamine can be alleviated with antihistamine drugs targeting histamine receptors. However, many antihistamine agents come with various undesirable side effects. Vegetal diamine oxidase (vDAO) might be a relevant alternative owing to its histaminase activity. Mammalian intestinal mucosa contains an endogenous DAO, yet possessing lower activity compared to that of vDAO preparation. Moreover, in several pathological conditions such as inflammatory bowel disease and irritable bowel syndrome, this endogenous DAO enzyme can be lost or inactivated. Here, we tested the therapeutic potential of vDAO by focusing on the well-known effect of histamine on gut motility. Using ex vivo and in vitro assays, we found that vDAO is more potent than commercial anti-histamine drugs at inhibiting histamine-induced contraction of murine distal colon muscles. We also identified pyridoxal 5'-phosphate (the biologically active form of vitamin B6) as an effective enhancer of vDAO antispasmodic activity. Furthermore, we discovered that rectally administered vDAO can be retained on gut mucosa and remain active. These observations make administration of vDAO in the gut lumen a valid alternative treatment for histamine-induced intestinal dysfunctions.

8 citations

Journal ArticleDOI
TL;DR: An overview of the current knowledge regarding the role of histamine and its metabolism in the kidney can be found in this paper, where the authors provide an overview of existing knowledge regarding histamine signaling for kidney function.
Abstract: Inflammation is an essential part of the immune response; it has been found to be central to the disruption of kidney function in acute kidney injury, diabetic nephropathy, hypertension, and other renal conditions. One of the well-known mediators of the inflammatory response is histamine. Histamine receptors are expressed throughout different tissues, including the kidney, and their inhibition has proven to be a viable strategy for the treatment of many inflammation-associated diseases. Here, we provide an overview of the current knowledge regarding the role of histamine and its metabolism in the kidney. Establishing the importance of histamine signaling for kidney function will enable new approaches for the treatment of kidney diseases associated with inflammation.

6 citations

Journal ArticleDOI
TL;DR: Clinical and epidemiological studies support a causal relationship between CKD, cardiovascular risk, and heart failure and a moderate elevation in serum creatinine levels will significantly increase cardiovascular mortality in patients with congestive heart failure.
Abstract: Cardiac and renal dysfunction frequently go hand in hand in hospitalized patients, and epidemiological studies have suggested an inverse correlation between renal function and cardiovascular morbidity and mortality. This relationship exists regardless of what organ is first affected (1). It reflects upon a complex interplay between heart and kidneys, with dysfunction of one organ often impairing the function of the other. The causal association between chronic kidney disease (CKD) and cardiovascular risk was initially discussed by Bright in 1836. The notion of passive renal congestion arising from cardiac dysfunction was coined “rein cardiaque” by French pathologist Frederic Justin Collet in 1903, while “cardiorenal syndrome” (CRS) was introduced in the 1940s to describe the bidirectional interactions between heart and kidneys (2). Kidney injury will stress both the heart and the circulatory system and cardiac dysfunction can, reciprocally, inflict injury on the kidney. Determinants of CRS include hemodynamic parameters such as central venous pressure, extracellular fluid volume, cardiac output, arterial pressure, pulmonary hypertension, and edema. Reduced cardiac performance ultimately limits blood perfusion of all organs including the kidneys and thereby contributes to renal injury. Altered tissue perfusion with disproportionate effects on the kidney leads to overactivation of both the sympathetic nervous and renin–angiotensin systems (RAS) reported in CRS. Inadequate renal extracellular fluid handling may have deleterious effects on the heart with an ensuing increase in volume preload and afterload and thus myocardial oxygen demand and vasoconstriction—including of coronary vessels—and an increase in inflammation, reactive oxygen species, and fibrosis (3). Clinical and epidemiological studies support a causal relationship between CKD, cardiovascular risk, and heart failure (4, 5). In patients with congestive heart failure, a moderate elevation in serum creatinine levels (e.g., by 26.5 µmol/L [0.3 mg/dL]) will significantly increase cardiovascular mortality (6). Thus, even subtle alterations in renal function may … [↵][1]1Email: pierre-louis.tharaux{at}inserm.fr. [1]: #xref-corresp-1-1

6 citations

References
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Journal ArticleDOI
TL;DR: The utility of ToppGene Suite is demonstrated using 20 recently reported GWAS-based gene–disease associations (including novel disease genes) representing five diseases.
Abstract: ToppGene Suite (http://toppgene.cchmc.org; this web site is free and open to all users and does not require a login to access) is a one-stop portal for (i) gene list functional enrichment, (ii) candidate gene prioritization using either functional annotations or network analysis and (iii) identification and prioritization of novel disease candidate genes in the interactome. Functional annotation-based disease candidate gene prioritization uses a fuzzy-based similarity measure to compute the similarity between any two genes based on semantic annotations. The similarity scores from individual features are combined into an overall score using statistical meta-analysis. A P-value of each annotation of a test gene is derived by random sampling of the whole genome. The protein-protein interaction network (PPIN)-based disease candidate gene prioritization uses social and Web networks analysis algorithms (extended versions of the PageRank and HITS algorithms, and the K-Step Markov method). We demonstrate the utility of ToppGene Suite using 20 recently reported GWAS-based gene-disease associations (including novel disease genes) representing five diseases. ToppGene ranked 19 of 20 (95%) candidate genes within the top 20%, while ToppNet ranked 12 of 16 (75%) candidate genes among the top 20%.

2,435 citations


"Histamine receptor agonist alleviat..." refers methods in this paper

  • ...Gene ontology (GO) enrichment analysis in biological processes and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway using the ToppGene Suite (20) analyses of these differentially expressed 150 transcripts revealed gene sets with significantly down-regulated responses to proinflammatory signals in the Imm-treated ANS group versus the ANS group....

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Journal ArticleDOI
TL;DR: KDIGO has convened a workgroup to develop a global clinical practice guideline for the definition, classification, and prognosis of chronic kidney disease.

1,912 citations


"Histamine receptor agonist alleviat..." refers background in this paper

  • ...In recent years, many investigators have become interested in this relationship with respect to cardiorenal syndrome and in the role that chronic kidney disease plays in being a strong risk factor for heart failure (2, 3)....

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Journal ArticleDOI
TL;DR: A new classification of the CRS with 5 subtypes that reflect the pathophysiology, the time-frame, and the nature of concomitant cardiac and renal dysfunction is presented to help physicians characterize groups of patients, provides the rationale for specific management strategies, and allows the design of future clinical trials with more accurate selection and stratification of the population under investigation.

1,233 citations

Journal ArticleDOI
TL;DR: In this review, some of the functions of heterotrimeric G proteins in defined cells and tissues are described.
Abstract: Heterotrimeric G proteins are key players in transmembrane signaling by coupling a huge variety of receptors to channel proteins, enzymes, and other effector molecules. Multiple subforms of G proteins together with receptors, effectors, and various regulatory proteins represent the components of a highly versatile signal transduction system. G protein-mediated signaling is employed by virtually all cells in the mammalian organism and is centrally involved in diverse physiological functions such as perception of sensory information, modulation of synaptic transmission, hormone release and actions, regulation of cell contraction and migration, or cell growth and differentiation. In this review, some of the functions of heterotrimeric G proteins in defined cells and tissues are described.

1,074 citations


"Histamine receptor agonist alleviat..." refers background in this paper

  • ...Regarding the association of histamine with renal injury, it has been previously demonstrated that a bolus injection of the platelet activating factor causes histological damages in the proximal tubule and significant histamine release in isolated perfused rat kidneys (30)....

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Journal ArticleDOI
TL;DR: Most evidence indicates that the actions of ANG to enhance sympathetic activity do not contribute significantly to the pressor response to exogenous ANG II, but there is considerable evidence that theactions of endogenous ANG II on the sympathetic nervous system enhance the cardiovascular responses elicited by activation of the sympathetic nerve endings.
Abstract: The renin-angiotensin system plays an important role in the regulation of arterial blood pressure and in the development of some forms of clinical and experimental hypertension. It is an important blood pressure control system in its own right but also interacts extensively with other blood pressure control systems, including the sympathetic nervous system and the baroreceptor reflexes. Angiotensin (ANG) II exerts several actions on the sympathetic nervous system. These include a central action to increase sympathetic outflow, stimulatory effects on sympathetic ganglia and the adrenal medulla, and actions at sympathetic nerve endings that serve to facilitate sympathetic neurotransmission. ANG II also interacts with baroreceptor reflexes. For example, it acts centrally to modulate the baroreflex control of heart rate, and this accounts for its ability to increase blood pressure without causing a reflex bradycardia. The physiological significance of these actions of ANG II is not fully understood. Most evidence indicates that the actions of ANG to enhance sympathetic activity do not contribute significantly to the pressor response to exogenous ANG II. On the other hand, there is considerable evidence that the actions of endogenous ANG II on the sympathetic nervous system enhance the cardiovascular responses elicited by activation of the sympathetic nervous system.

565 citations


"Histamine receptor agonist alleviat..." refers background in this paper

  • ...Specifically, Ang II is a vasoconstrictive hormone in RAS that plays an essential role in the regulation of blood pressure, electrolyte, and volume homeostasis (6)....

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