Critical role of high-mobility-group proteins in kidney development/cross-talk Wnt/β-catenin signaling pathway

2021 ◽  
Vol 9 (1) ◽  
pp. 123-134
Author(s):  
Mary Ann S. Arndt ◽  
William D. Wheaton
Keyword(s):  
Signaling Pathway ◽  
Kidney Development ◽  
Critical Role ◽  
High Mobility ◽  
Kidney Injury ◽  
High Mobility Group ◽  
Loss Of Function ◽  
Hmg Proteins ◽  
Associated Proteins

The treatment of severe acute kidney injury with dialytic support for renal replacement therapy can be life sustaining and permit recovery from critical illness. The high-mobility-group (HMG) proteins are the most abundant non-histone chromatin-associated proteins. HMG proteins are present at high levels in various undifferentiated tissues during embryonic development and reduced in the corresponding adult tissues. We used used in study C57BL/6, HMG+/− and HMG−/− mice and found that HMG is expressed in the mouse embryonic kidney at the cortex area. HMG knockout led to enhanced Wnt/β-catenin signaling pathway. Analysis of siRNA-mediated loss-of-function experiments in embryonic kidney culture confirmed the role of HMG as a key regulator of cortex epithelium differentiation.

Critical role of high-mobility-group proteins in kidney development/cross-talk Wnt/β-catenin signaling pathway

2021 ◽  
Vol 9 (1) ◽  
pp. 135-144
Keyword(s):  
Signaling Pathway ◽  
Kidney Development ◽  
Critical Role ◽  
High Mobility ◽  
High Mobility Group ◽  
Loss Of Function ◽  
Hmg Proteins ◽  
Cortex Area ◽  
Associated Proteins

recovery from critical illness.The high-mobility-group (HMG) proteins are the most abundant non-histone chromatin-associated proteins. HMG proteins are present at high levels in various undifferentiated tissues during embryonic development and reduced in the corresponding adult tissues. We used used in study C57BL/6, HMG+/− and HMG−/−  mice and found that HMG is expressed in the mouse embryonic kidney at the cortex area. HMG knockout led to enhanced Wnt/β-catenin signaling pathway. Analysis of siRNA-mediated loss-of-function experiments in embryonic kidney culture confirmed the role of HMG as a key regulator of cortex epithelium differentiation.

scholarly journals Role of High-Mobility Group Box-1 in Liver Pathogenesis

2019 ◽  
Vol 20 (21) ◽  
pp. 5314 ◽  
Author(s):  
Bilon Khambu ◽  
Shengmin Yan ◽  
Nazmul Huda ◽  
Xiao-Ming Yin
Keyword(s):  
Liver Disease ◽  
Critical Role ◽  
High Mobility ◽  
High Mobility Group ◽  
Sterile Inflammation ◽  
Contributing Factors ◽  
Drug Induced ◽  
Ductular Reaction ◽  
Alcoholic Fatty Liver

High-mobility group box 1 (HMGB1) is a highly abundant DNA-binding protein that can relocate to the cytosol or undergo extracellular release during cellular stress or death. HMGB1 has a functional versatility depending on its cellular location. While intracellular HMGB1 is important for DNA structure maintenance, gene expression, and autophagy induction, extracellular HMGB1 acts as a damage-associated molecular pattern (DAMP) molecule to alert the host of damage by triggering immune responses. The biological function of HMGB1 is mediated by multiple receptors, including the receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs), which are expressed in different hepatic cells. Activation of HMGB1 and downstream signaling pathways are contributing factors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and drug-induced liver injury (DILI), each of which involves sterile inflammation, liver fibrosis, ductular reaction, and hepatic tumorigenesis. In this review, we will discuss the critical role of HMGB1 in these pathogenic contexts and propose HMGB1 as a bona fide and targetable DAMP in the setting of common liver diseases.

α-Chemokine receptor blockade reduces high mobility group box 1 protein-induced lung inflammation and injury and improves survival in sepsis

2005 ◽  
Vol 289 (4) ◽  
pp. L583-L590 ◽  
Author(s):  
Xinchun Lin ◽  
Huan Yang ◽  
Tohru Sakuragi ◽  
Maowen Hu ◽  
Lin L. Mantell ◽  
...  
Keyword(s):  
Lung Injury ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Critical Role ◽  
High Mobility ◽  
High Mobility Group ◽  
Receptor Blockade ◽  
Inflammatory Injury ◽  
Receptor Inhibition

High mobility group box 1 (HMGB1) protein, a late mediator of lethality in sepsis, can induce acute inflammatory lung injury. Here, we identify the critical role of α-chemokine receptors in the HMGB1-induced inflammatory injury and show that α-chemokine receptor inhibition increases survival in sepsis, in a clinically relevant time frame. Intratracheal instillation of recombinant HMGB1 induces a neutrophilic leukocytosis, preceded by alveolar accumulation of the α-chemokine macrophage inflammatory protein-2 and accompanied by injury and increased inflammatory potential within the air spaces. To investigate the role of α-chemokine receptors in the injury, we instilled recombinant HMGB1 (0.5 μg) directly into the lungs and administered a subcutaneous α-chemokine receptor inhibitor, Antileukinate (200 μg). α-Chemokine receptor blockade reduced HMGB1-induced inflammatory injury (neutrophils: 2.9 ± 3.2 vs. 8.1 ± 2.4 × 104cells; total protein: 120 ± 48 vs. 311 ± 129 μg/ml; reactive nitrogen species: 2.3 ± 0.3 vs. 3.5 ± 1.3 μM; and macrophage migration inhibitory factor: 6.4 ± 4.2 vs. 37.4 ± 15.9 ng/ml) within the bronchoalveolar lavage fluid, indicating that HMGB1-induced inflammation and injury are α-chemokine mediated. Because HMGB1 can mediate late septic lethality, we administered Antileukinate to septic mice and observed increased survival (from 58% in controls to 89%) even when the inhibitor treatment was initiated 24 h after the induction of sepsis. These data demonstrate that α-chemokine receptor inhibition can reduce HMGB1-induced lung injury and lethality in established sepsis and may provide a novel treatment in this devastating disease.

scholarly journals Involvement of high mobility group box 1 in the pathogenesis of severe hemolytic uremic syndrome in a murine model

2019 ◽  
Vol 317 (6) ◽  
pp. F1420-F1429 ◽  
Author(s):  
Ryo Maeda ◽  
Yukihiko Kawasaki ◽  
Yohei Kume ◽  
Hayato Go ◽  
Kazuhide Suyama ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Murine Model ◽  
Severe Disease ◽  
High Mobility ◽  
Kidney Injury ◽  
Saline Group ◽  
High Mobility Group ◽  
Uremic Syndrome ◽  
Group D

Typical hemolytic uremic syndrome is caused by Shiga toxin (Stx2) and lipopolysaccharide (LPS) of Escherichia coli and leads to acute kidney injury. The role of innate immunity in this pathogenesis is unclear. We analyzed the role of high mobility group box 1 (HMGB1) at the onset of disease in a murine model. C57BL/6 mice were intraperitoneally administered saline ( group A), anti-HMGB1 monoclonal antibody ( group B), Stx2 and LPS to elicit severe disease ( group C), or Stx2, LPS, and anti-HMGB1 antibody ( group D). While all mice in group C died by day 5 of the experiment, all mice in group D survived. Anemia and thrombocytopenia were pronounced and plasma creatinine levels were significantly elevated in group C only at 72 h. While at 72 h after toxin administration the glomerulus tissue in group C showed pathology similar to that of humans, mesangial cell proliferation was seen in group D. Plasma HMGB1 levels in group C peaked 3 h after administration and were higher than those in other groups. Expression of the receptor of advanced glycation end products and NF-κB, involved in HMGB1 signaling, was significantly elevated in group C but not in group D. Administration of anti-HMGB1 antibody in a murine model of severe disease inhibited plasma HMGB1 and promoted amelioration of tissue damage. HMGB1 was found to be involved in the disease pathology; therefore, controlling HMGB1 activity might inhibit disease progression.

scholarly journals Deficiency of the novel high mobility group protein HMGXB4 protects against systemic inflammation-induced endotoxemia in mice

2021 ◽  
Vol 118 (7) ◽  
pp. e2021862118
Author(s):  
Xiangqin He ◽  
Kunzhe Dong ◽  
Jian Shen ◽  
Guoqing Hu ◽  
Jinhua Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Critical Role ◽  
Cecal Ligation ◽  
High Mobility ◽  
High Mobility Group ◽  
No Production ◽  
High Mobility Group Protein ◽  
Pulmonary Vascular Permeability ◽  
Proinflammatory Gene

Sepsis is a major cause of mortality in intensive care units, which results from a severely dysregulated inflammatory response that ultimately leads to organ failure. While antibiotics can help in the early stages, effective strategies to curtail inflammation remain limited. The high mobility group (HMG) proteins are chromosomal proteins with important roles in regulating gene transcription. While HMGB1 has been shown to play a role in sepsis, the role of other family members including HMGXB4 remains unknown. We found that expression of HMGXB4 is strongly induced in response to lipopolysaccharide (LPS)-elicited inflammation in murine peritoneal macrophages. Genetic deletion of Hmgxb4 protected against LPS-induced lung injury and lethality and cecal ligation and puncture (CLP)-induced lethality in mice, and attenuated LPS-induced proinflammatory gene expression in cultured macrophages. By integrating genome-wide transcriptome profiling and a publicly available ChIP-seq dataset, we identified HMGXB4 as a transcriptional activator that regulates the expression of the proinflammatory gene, Nos2 (inducible nitric oxide synthase 2) by binding to its promoter region, leading to NOS2 induction and excessive NO production and tissue damage. Similar to Hmgxb4 ablation in mice, administration of a pharmacological inhibitor of NOS2 robustly decreased LPS-induced pulmonary vascular permeability and lethality in mice. Additionally, we identified the cell adhesion molecule, ICAM1, as a target of HMGXB4 in endothelial cells that facilitates inflammation by promoting monocyte attachment. In summary, our study reveals a critical role of HMGXB4 in exacerbating endotoxemia via transcriptional induction of Nos2 and Icam1 gene expression and thus targeting HMGXB4 may be an effective therapeutic strategy for the treatment of sepsis.

High Mobility Group Box-1 (HMGB1): A Potential Target in Therapeutics

2019 ◽  
Vol 20 (14) ◽  
pp. 1474-1485 ◽  
Author(s):  
Eyaldeva C. Vijayakumar ◽  
Lokesh Kumar Bhatt ◽  
Kedar S. Prabhavalkar
Keyword(s):  
Myocardial Infarction ◽  
Vagus Nerve Stimulation ◽  
Nuclear Protein ◽  
Therapeutic Potential ◽  
High Mobility ◽  
Dna Binding Protein ◽  
High Mobility Group ◽  
Eukaryotic Cells ◽  
Hmgb1 Protein

High mobility group box-1 (HMGB1) mainly belongs to the non-histone DNA-binding protein. It has been studied as a nuclear protein that is present in eukaryotic cells. From the HMG family, HMGB1 protein has been focused particularly for its pivotal role in several pathologies. HMGB-1 is considered as an essential facilitator in diseases such as sepsis, collagen disease, atherosclerosis, cancers, arthritis, acute lung injury, epilepsy, myocardial infarction, and local and systemic inflammation. Modulation of HMGB1 levels in the human body provides a way in the management of these diseases. Various strategies, such as HMGB1-receptor antagonists, inhibitors of its signalling pathway, antibodies, RNA inhibitors, vagus nerve stimulation etc. have been used to inhibit expression, release or activity of HMGB1. This review encompasses the role of HMGB1 in various pathologies and discusses its therapeutic potential in these pathologies.

scholarly journals Association of plasma level of high-mobility group box-1 with necroptosis and sepsis outcomes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hongseok Yoo ◽  
Yunjoo Im ◽  
Ryoung-Eun Ko ◽  
Jin Young Lee ◽  
Junseon Park ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Validation Cohort ◽  
High Mobility ◽  
Kinase Domain ◽  
High Mobility Group ◽  
Rank Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Derivation Cohort ◽  
The Difference

AbstractThe role of high-mobility group box-1 (HMGB1) in outcome prediction in sepsis is controversial. Furthermore, its association with necroptosis, a programmed cell necrosis mechanism, is still unclear. The purpose of this study is to identify the association between the plasma levels of HMGB1 and the severity and clinical outcomes of sepsis, and to examine the correlation between HMGB1 and key executors of necroptosis including receptor-interacting kinase 3 (RIPK3) and mixed lineage kinase domain-like- (MLKL) proteins. Plasma HMGB1, RIPK3, and MLKL levels were measured with the enzyme-linked immunosorbent assay from the derivation cohort of 188 prospectively enrolled, critically-ill patients between April 2014 and December 2016, and from the validation cohort of 77 patients with sepsis between January 2017 and January 2019. In the derivation cohort, the plasma HMGB1 levels of the control (n = 46, 24.5%), sepsis (n = 58, 30.9%), and septic shock (n = 84, 44.7%) groups were significantly increased (P < 0.001). A difference in mortality between high (≥ 5.9 ng/mL) and low (< 5.9 ng/mL) HMGB1 levels was observed up to 90 days (Log-rank test, P = 0.009). There were positive linear correlations of plasma HMGB1 with RIPK3 (R2 = 0.61, P < 0.001) and MLKL (R2 = 0.7890, P < 0.001). The difference in mortality and correlation of HMGB1 levels with RIPK3 and MLKL were confirmed in the validation cohort. Plasma levels of HMGB1 were associated with the severity and mortality attributed to sepsis. They were correlated with RIPK3 and MLKL, thus suggesting an association of HMGB1 with necroptosis.

scholarly journals LPS Primes Brain Responsiveness to High Mobility Group Box-1 Protein

2021 ◽  
Vol 14 (6) ◽  
pp. 558
Author(s):  
Verena Peek ◽  
Lois M. Harden ◽  
Jelena Damm ◽  
Ferial Aslani ◽  
Stephan Leisengang ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Area Postrema ◽  
High Mobility ◽  
High Mobility Group ◽  
Direct Access ◽  
Significant Release ◽  
Factor Α ◽  
Culture Supernatants

High mobility group box (HMGB)1 action contributes to late phases of sepsis, but the effects of increased endogenous plasma HMGB1 levels on brain cells during inflammation are unclear. Here, we aimed to further investigate the role of HMGB1 in the brain during septic-like lipopolysaccharide-induced inflammation in rats (LPS, 10 mg/kg, i.p.). HMGB-1 mRNA expression and release were measured in the periphery/brain by RT-PCR, immunohistochemistry and ELISA. In vitro experiments with disulfide-HMGB1 in primary neuro-glial cell cultures of the area postrema (AP), a circumventricular organ with a leaky blood–brain barrier and direct access to circulating mediators like HMGB1 and LPS, were performed to determine the direct influence of HMGB1 on this pivotal brain structure for immune-to-brain communication. Indeed, HMGB1 plasma levels stayed elevated after LPS injection. Immunohistochemistry of brains and AP cultures confirmed LPS-stimulated cytoplasmatic translocation of HMGB1 indicative of local HMGB1 release. Moreover, disulfide-HMGB1 stimulation induced nuclear factor (NF)-κB activation and a significant release of interleukin-6, but not tumor necrosis factor α, into AP culture supernatants. However, only a few AP cells directly responded to HMGB1 with increased intracellular calcium concentration. Interestingly, priming with LPS induced a seven-fold higher percentage of responsive cells to HMGB1. We conclude that, as a humoral and local mediator, HMGB1 enhances brain inflammatory responses, after LPS priming, linked to sustained sepsis symptoms.

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