bims-heshmo Biomed News
on Trauma hemorrhagic shock — molecular basis
Issue of 2021–08–01
twelve papers selected by
Andreia Luís, Ludwig Boltzmann Institute
  1. Antibody-Free Mass Spectrometry Identification of Vascular Integrity Markers in Major Trauma.
  2. Suppressing Syndecan-1 Shedding to Protect Against Renal Ischemia/Reperfusion Injury by Maintaining Polarity of Tubular Epithelial Cells.
  3. Treprostinil reduces mitochondrial injury during rat renal ischemia-reperfusion injury.
  4. Inhibiting miR-205 Alleviates Cardiac Ischemia/Reperfusion Injury by Regulating Oxidative Stress, Mitochondrial Function, and Apoptosis.
  5. Hippo-YAP/MCP-1 mediated tubular maladaptive repair promote inflammation in renal failed recovery after ischemic AKI.
  6. Plasmacytoid Dendritic Cells Mediate Myocardial Ischemia/Reperfusion Injury by Secreting Type I Interferons.
  7. The secreted tyrosine kinase VLK is essential for normal platelet activation and thrombus formation.
  8. Selective activation of PFKL suppresses the phagocytic oxidative burst.
  9. Ethyl pyruvate: A newly discovered compound against ischemia-reperfusion injury in multiple organs.
  10. Non-occlusive mesenteric ischemia: Diagnostic challenges and perspectives in the era of artificial intelligence.
  11. Glucocorticoid and mineralocorticoid receptor expression in critical illness: A narrative review.
  12. NLRP3 Inflammasome in Metabolic-Associated Kidney Diseases: An Update.
  1. Neurotrauma Rep. 2021 ;2(1): 322-329
    Antibody-Free Mass Spectrometry Identification of Vascular Integrity Markers in Major Trauma.
    H E Hinson, Jon Jacobs, Shannon McWeeney, Ann Wachana, Tujin Shi, Kendall Martin, Karin Rodland.
      Antibody mediated strategies for protein biomarker detection are common, but may limit discovery. We hypothesized that the use of antibody-free proteomics is feasible for detecting protein biomarkers in plasma of patients sustaining major trauma. A subset of subjects with major trauma from a prospective observational trial were analyzed. Patients were assigned to one of four groups based on their presenting Abbreviated Injury Severity Score (AIS). Sensitive, antibody-free selective reaction monitoring (SRM) mass spectrometry (MS), with spiked-in isotopically labeled synthetic peptides, was used for targeted protein quantification of a panel of 10 prospective targets. An overall tiered sensitivity analytical approach was used for peptide detection and quantification based upon plasma immunoaffinity depletion and PRISM fractionation. Forty-four patients were included in the analysis, of which 82% were men with a mean age of 50 (±19) years. Half had isolated head injury (n = 22), with the remaining patients experiencing multiple injuries or polytrauma (n = 14), isolated body injury (n = 2), or minor injury (n = 6). Peptides from 3 proteins (vascular adhesion molecule 1 [VCAM1], intercellular adhesion molecule 1 [ICAM1], and matrix metalloproteinase 9 [MMP9]) were detected and quantified in non-depleted processed plasma. Peptides from 2 proteins (angiopoietin 2 [Ang2] and plasminogen activator inhibitor-1 [PAI1]) were detected and quantification in depleted plasma, whereas the remaining 5 of the 10 prospective targets were undetected. VCAM1 (p = 0.02) and MMP9 (p = 0.03) were significantly upregulated in in the major trauma groups (1-3) versus mild injury group (4), whereas the others were not. There were no differences in protein expression between patients with traumatic brain injury (TBI; groups 1 and 2) versus those without TBI (groups 3 and 4). We detected non-specific upregulation of proteins reflecting blood-brain barrier breakdown in severely injured patients, indicating label-free MS techniques are feasible and may be informative.
    Keywords:  biomarkers; blood–brain barrier dysfunction; endothelial activation; mass spectrometry; proteomics
    DOI:  https://doi.org/10.1089/neur.2021.0007
  2. Shock. 2021 Jul 26.
    Suppressing Syndecan-1 Shedding to Protect Against Renal Ischemia/Reperfusion Injury by Maintaining Polarity of Tubular Epithelial Cells.
    Man Guo, Jiarui Xu, Shuan Zhao, Daoqi Shen, Wuhua Jiang, Lin Zhang, Xiaoqiang Ding, Xialian Xu.
       ABSTRACT: Syndecan-1 (SDC-1), a type of heparan sulfate proteoglycan on the surface of epithelial cells, is involved in maintaining cell morphology. Loss of cell polarity constitutes the early stage of ischemic acute kidney injury (AKI). This study investigated the role of SDC-1 shedding in ischemia/reperfusion (I/R)-induced AKI and the underlying mechanisms. Levels of the shed SDC-1 in the serum were measured with ELISA 12 h and 24 h after reperfusion in renal I/R model mice. Na+/K+-ATPase-α1 expression was evaluated using western blotting in vivo and immunofluorescence in hypoxia/reoxygenation (H/R) cysts. Renal tubular epithelial cell apoptosis was measured using TUNEL and flow cytometry in vitro. Furthermore, plasma syndecan-1(pSDC-1) levels were measured in patients at the time of anesthesia resuscitation after cardiac surgery. We found that shed SDC-1 levels increased and Na+/k+-ATPase-α1 expression decreased after H/R in the three-dimensional (3D) tubular model, and this state was exacerbated with extended period of hypoxia. After the inhibition of SDC-1 shedding by GM6001, SDC-1 and Na+/k+-ATPase-α1 expression was restored, while H/R-induced apoptosis was decreased. In vivo, SDC-1 shedding was induced by renal I/R and was accompanied with a loss of renal tubular epithelial cell polarity and increased apoptosis. GM6001 pretreatment protected against I/R injury by alleviating the disruption of cell polarity and apoptosis. pSDC-1 levels were significantly higher in AKI patients than in non-AKI patients. ROC curve showed that the accuracy of pSDC-1 for AKI prediction was 0.769. In conclusion, inhibition of I/R-induced SDC-1 shedding could contribute to renal protection by restoring the loss of cell polarity and alleviating apoptosis in tubular epithelial cells.
    DOI:  https://doi.org/10.1097/SHK.0000000000001838
  3. Biomed Pharmacother. 2021 Jul 15. pii: S0753-3322(21)00694-6. [Epub ahead of print]141 111912
    Treprostinil reduces mitochondrial injury during rat renal ischemia-reperfusion injury.
    Meiwen Ding, Evelyn Tolbert, Mark Birkenbach, Reginald Gohh, Fatemeh Akhlaghi, Nisanne S Ghonem.
       BACKGROUND: Renal ischemia-reperfusion injury (IRI) is a major factor contributing to acute kidney injury and it is associated with a high morbidity and mortality if untreated. Renal IRI depletes cellular and tissue adenosine triphosphate (ATP), which compromises mitochondrial function, further exacerbating renal tubular injury. Currently, no treatment for IRI is available. This study investigates the protective role of treprostinil in improving mitochondria biogenesis and recovery during rat renal IRI.
    METHODS: Male Sprague Dawley rats were randomly assigned to groups: control, sham, IRI-placebo or IRI-treprostinil and subjected to 45 min of bilateral renal ischemia followed by 1-72 h reperfusion. Placebo or treprostinil (100 ng/kg/min) was administered subcutaneously via an osmotic minipump.
    RESULTS: Treprostinil significantly reduced peak elevated serum creatinine (SCr) levels and accelerated normalization relative to IRI-placebo (p < 0.0001). Treatment with treprostinil also inhibited IRI-mediated renal apoptosis, mitochondrial oxidative injury (p < 0.05), and the release of cytochrome c (p < 0.01) vs. IRI-placebo. In addition, treprostinil preserved renal mitochondrial DNA copy number (p < 0.0001) and renal ATP levels (p < 0.05) to nearly those of sham-operated animals. Non-targeted semi-quantitative proteomics showed reduced levels of ATP synthase subunits in the IRI-placebo group which were restored to sham levels by treprostinil treatment (p < 0.05). Furthermore, treprostinil reduced renal IRI-induced upregulated Drp1 and pErk protein levels, and restored Sirt3 and Pgc-1α levels to baseline (p < 0.05).
    CONCLUSIONS: Treprostinil reduces mitochondrial-mediated renal apoptosis, inhibits mitochondria fission, and promotes mitochondria fusion, thereby accelerating mitochondrial recovery and protecting renal proximal tubules from renal IRI. These results support the clinical investigation of treprostinil as a viable therapy to reduce renal IRI.
    Keywords:  Acute kidney injury; Apoptosis; Mitochondria; Prostacyclin
    DOI:  https://doi.org/10.1016/j.biopha.2021.111912
  4. Oxid Med Cell Longev. 2021 ;2021 9986506
    Inhibiting miR-205 Alleviates Cardiac Ischemia/Reperfusion Injury by Regulating Oxidative Stress, Mitochondrial Function, and Apoptosis.
    Yuerong Xu, Wangang Guo, Di Zeng, Yexian Fang, Runze Wang, Dong Guo, Bingchao Qi, Yugang Xue, Feng Xue, Zuolin Jin, Yan Li, Mingming Zhang.
       Background: miR-205 is important for oxidative stress, mitochondrial dysfunction, and apoptosis. The roles of miR-205 in cardiac ischemia/reperfusion (I/R) injury remain unknown. The aim of this research is to reveal whether miR-205 could regulate cardiac I/R injury by focusing upon the oxidative stress, mitochondrial function, and apoptosis.
    Methods: Levels of miR-205 and Rnd3 were examined in the hearts with I/R injury. Myocardial infarct size, cardiac function, oxidative stress, mitochondria function, and cardiomyocyte apoptosis were detected in mice with myocardial ischemia/reperfusion (MI/R) injury. The primary neonatal cardiomyocytes underwent hypoxia/reoxygenation (H/R) to simulate MI/R injury.
    Results: miR-205 levels were significantly elevated in cardiac tissues from I/R in comparison with those from Sham. In comparison with controls, levels of Rnd3 were significantly decreased in the hearts from mice with MI/R injury. Furthermore, inhibiting miR-205 alleviated MI/R-induced apoptosis, reduced infarct size, prevented oxidative stress increase and mitochondrial fragmentation, and improved mitochondrial functional capacity and cardiac function. Consistently, overexpression of miR-205 increased infarct size and promoted apoptosis, oxidative stress, and mitochondrial dysfunction in mice with MI/R injury. In cultured mouse neonatal cardiomyocytes, downregulation of miR-205 reduced oxidative stress in H/R-treated cardiomyocytes. Finally, inhibiting Rnd3 ablated the cardioprotective effects of miR-205 inhibitor in MI/R injury.
    Conclusions: We conclude that inhibiting miR-205 reduces infarct size, improves cardiac function, and suppresses oxidative stress, mitochondrial dysfunction, and apoptosis by promoting Rnd3 in MI/R injury. miR-205 inhibitor-induced Rnd3 activation is a valid target to treat MI/R injury.
    DOI:  https://doi.org/10.1155/2021/9986506
  5. Cell Death Dis. 2021 Jul 30. 12(8): 754
    Hippo-YAP/MCP-1 mediated tubular maladaptive repair promote inflammation in renal failed recovery after ischemic AKI.
    Zhihuang Zheng, Chuanlei Li, Guangze Shao, Jinqing Li, Kexin Xu, Zhonghua Zhao, Zhigang Zhang, Jun Liu, Huijuan Wu.
      Acute kidney injury (AKI) is associated with significant morbidity and its chronic inflammation contributes to subsequent chronic kidney disease (CKD) development. Yes-associated protein (YAP), the major transcriptional coactivator of the Hippo pathway, has been shown associated with chronic inflammation, but its role and mechanism in AKI-CKD transition remain unclear. Here we aimed to investigate the role of YAP in AKI-induced chronic inflammation. Renal ischemia/reperfusion (I/R) was used to induce a mouse model of AKI-CKD transition. We used verteporfin (VP), a pharmacological inhibitor of YAP, to treat post-IRI mice for a period, and evaluated the influence of YAP inhibition on long-term outcomes of AKI. In our results, severe IRI led to maladaptive tubular repair, macrophages infiltration, and progressive fibrosis. Following AKI, the Hippo pathway was found significantly altered with YAP persistent activation. Besides, tubular YAP activation was associated with the maladaptive repair, also correlated with interstitial macrophage infiltration. Monocyte chemoattractant protein 1 (MCP-1) was found notably upregulated with YAP activation. Of note, pharmacological inhibition of YAP in vivo attenuated renal inflammation, including macrophage infiltration and MCP-1 overexpression. Consistently, in vitro oxygen-glucose deprivation and reoxygenation (OGD/R) induced YAP activation and MCP-1 overproduction whereas these could be inhibited by VP. In addition, we modulated YAP activity by RNA interference, which further confirmed YAP activation enhances MCP-1 expression. Together, we concluded tubular YAP activation with maladaptive repair exacerbates renal inflammation probably via promoting MCP-1 production, which contributes to AKI-CKD transition.
    DOI:  https://doi.org/10.1038/s41419-021-04041-8
  6. J Am Heart Assoc. 2021 Jul 30. e020754
    Plasmacytoid Dendritic Cells Mediate Myocardial Ischemia/Reperfusion Injury by Secreting Type I Interferons.
    Lina Lai, Aimee Zhang, Boris Yang, Eric J Charles, Irving L Kron, Zequan Yang.
      Background We previously demonstrated that ischemically injured cardiomyocytes release cell-free DNA and HMGB1 (high mobility group box 1 protein) into circulation during reperfusion, activating proinflammatory responses and ultimately exacerbating reperfusion injury. We hypothesize that cell-free DNA and HMGB1 mediate myocardial ischemia-reperfusion injury by stimulating plasmacytoid dendritic cells (pDCs) to secrete type I interferon (IFN-I). Methods and Results C57BL/6 and interferon alpha receptor-1 knockout mice underwent 40 minutes of left coronary artery occlusion followed by 60 minutes of reperfusion (40'/60' IR) before infarct size was evaluated by 2,3,5-Triphenyltetrazolium chloride-Blue staining. Cardiac perfusate was acquired in ischemic hearts without reperfusion by antegrade perfusion of the isolated heart. Flow cytometry in pDC-depleted mice treated with multiple doses of plasmacytoid dendritic cell antigen-1 antibody via intraperitoneal injection demonstrated plasmacytoid dendritic cell antigen-1 antibody treatment had no effect on conventional splenic dendritic cells but significantly reduced splenic pDCs by 60%. pDC-depleted mice had significantly smaller infarct size and decreased plasma interferon-α and interferon-β compared with control. Blockade of the type I interferon signaling pathway with cyclic GMP-AMP synthase inhibitor, stimulator of interferon genes antibody, or interferon regulatory factor 3 antibody upon reperfusion similarly significantly attenuated infarct size by 45%. Plasma levels of interferon-α and interferon-β were significantly reduced in cyclic GMP-AMP synthase inhibitor-treated mice. Infarct size was significantly reduced by >30% in type I interferon receptor monoclonal antibody-treated mice and interferon alpha receptor-1 knockout mice. In splenocyte culture, 40'/0' cardiac perfusate treatment stimulated interferon-α and interferon-β production; however, this effect disappeared in the presence of cyclic GMP-AMP synthase inhibitor. Conclusions Type I interferon production is stimulated following myocardial ischemia by cardiogenic cell-free DNA/HMGB1 in a pDC-dependent manner, and subsequently activates type I interferon receptors to exacerbate reperfusion injury. These results identify new potential therapeutic targets to attenuate myocardial ischemia-reperfusion injury.
    Keywords:  cell signaling; infarct size; ischemia reperfusion injury
    DOI:  https://doi.org/10.1161/JAHA.121.020754
  7. Blood. 2021 Jul 30. pii: blood.2020010342. [Epub ahead of print]
    The secreted tyrosine kinase VLK is essential for normal platelet activation and thrombus formation.
    Leila Denise Revollo, Glenn Merrill-Skoloff, Karen De Ceunynck, James R Dilks, Shihui Guo, Mattia Renato Bordoli, Christian G Peters, Leila Noetzli, Andreia Marina Ionescu, Vicki Rosen, Joseph E Italiano, Malcolm Whitman, Robert Flaumenhaft.
      Tyrosine phosphorylation of extracellular proteins is observed in cell cultures and in vivo, but little is known about the functional roles of tyrosine phosphorylation of extracellular proteins. Vertebrate Lonesome Kinase (VLK) is a broadly expressed secretory pathway tyrosine kinase present in platelet ɑ-granules. It is released from platelets upon activation and phosphorylates substrates extracellularly. Its role in platelet function, however, has not been previously studied. In human platelets, we identified phosphorylated tyrosines mapped to luminal or extracellular domains of transmembrane and secreted proteins implicated in the regulation of platelet activation. To determine the role of VLK in extracellular tyrosine phosphorylation and platelet function, we generated mice with a megakaryocyte/platelet-specific deficiency of VLK. Platelets from these mice are normal in abundance and morphology, but have significant changes in function both in vitro and in vivo. Resting and thrombin-stimulated VLK-deficient platelets demonstrate a significant decrease of several tyrosine phosphobands. Functional testing of VLK-deficient platelets shows decreased PAR4- and collagen-mediated platelet aggregation, but normal responses to ADP. Dense granule and a-granule release are reduced in these platelets. Furthermore, VLK-deficient platelets exhibit decreased PAR4-mediated Akt (S473) and Erk1/2 (T202/Y204) phosphorylation, indicating altered proximal signaling. In vivo, mice lacking VLK in megakaryocytes/platelets demonstrate strongly reduced platelet accumulation and fibrin formation following laser-injury of cremaster arterioles compared to controls, but normal bleeding times. These studies demonstrate that the secretory pathway tyrosine kinase VLK is critical for stimulus-dependent platelet activation and thrombus formation, providing the first evidence that a secreted protein kinase is required for normal platelet function.
    DOI:  https://doi.org/10.1182/blood.2020010342
  8. Cell. 2021 Jul 17. pii: S0092-8674(21)00830-8. [Epub ahead of print]
    Selective activation of PFKL suppresses the phagocytic oxidative burst.
    Neri Amara, Madison P Cooper, Maria A Voronkova, Bradley A Webb, Eric M Lynch, Justin M Kollman, Taylur Ma, Kebing Yu, Zijuan Lai, Dewakar Sangaraju, Nobuhiko Kayagaki, Kim Newton, Matthew Bogyo, Steven T Staben, Vishva M Dixit.
      In neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) generated via the pentose phosphate pathway fuels NADPH oxidase NOX2 to produce reactive oxygen species for killing invading pathogens. However, excessive NOX2 activity can exacerbate inflammation, as in acute respiratory distress syndrome (ARDS). Here, we use two unbiased chemical proteomic strategies to show that small-molecule LDC7559, or a more potent designed analog NA-11, inhibits the NOX2-dependent oxidative burst in neutrophils by activating the glycolytic enzyme phosphofructokinase-1 liver type (PFKL) and dampening flux through the pentose phosphate pathway. Accordingly, neutrophils treated with NA-11 had reduced NOX2-dependent outputs, including neutrophil cell death (NETosis) and tissue damage. A high-resolution structure of PFKL confirmed binding of NA-11 to the AMP/ADP allosteric activation site and explained why NA-11 failed to agonize phosphofructokinase-1 platelet type (PFKP) or muscle type (PFKM). Thus, NA-11 represents a tool for selective activation of PFKL, the main phosphofructokinase-1 isoform expressed in immune cells.
    Keywords:  LDC7559; NA-11; NADPH; NETosis; NOX2; PFKL; ROS; neutrophils
    DOI:  https://doi.org/10.1016/j.cell.2021.07.004
  9. Pharmacol Res. 2021 Jul 21. pii: S1043-6618(21)00341-8. [Epub ahead of print] 105757
    Ethyl pyruvate: A newly discovered compound against ischemia-reperfusion injury in multiple organs.
    Chenxi Lu, Changyu Wang, Haoxiang Xiao, Mengfan Chen, Zhi Yang, Zhenxing Liang, Haiying Wang, Yonglin Liu, Yang Yang, Qiang Wang.
      Ischemia-reperfusion injury (IRI) is a process whereby an initial ischemia injury and subsequent recovery of blood flow, which leads to the propagation of an innate immune response and the changes of structural and functional of multiple organs. Therefore, IRI is considered to be a great challenge in clinical treatment such as organ transplantation or coronary angioplasty. In recent years, ethyl pyruvate (EP), a derivative of pyruvate, has received great attention because of its stability and low toxicity. Previous studies have proved that EP has various pharmacological activities, including anti-inflammation, anti-oxidative stress, anti-apoptosis, and anti-fibrosis. Compelling evidence has indicated EP plays a beneficial role in a variety of acute injury models, such as brain IRI, myocardial IRI, renal IRI, and hepatic IRI. Moreover, EP can not only effectively inhibit multiple IRI-induced pathological processes, but also improve the structural and functional lesion of tissues and organs. In this study, we review the recent progress in the research on EP and discuss their implications for a better understanding of multiple organ IRI, and the prospects of targeting the EP for therapeutic intervention.
    Keywords:  Ethyl pyruvate; Ischemia-reperfusion injury; Mechanism; Organ
    DOI:  https://doi.org/10.1016/j.phrs.2021.105757
  10. World J Gastroenterol. 2021 Jul 14. 27(26): 4088-4103
    Non-occlusive mesenteric ischemia: Diagnostic challenges and perspectives in the era of artificial intelligence.
    Simon Bourcier, Julian Klug, Lee S Nguyen.
      Acute mesenteric ischemia (AMI) is a severe condition associated with poor prognosis, ultimately leading to death due to multiorgan failure. Several mechanisms may lead to AMI, and non-occlusive mesenteric ischemia (NOMI) represents a particular form of AMI. NOMI is prevalent in intensive care units in critically ill patients. In NOMI management, promptness and accuracy of diagnosis are paramount to achieve decisive treatment, but the last decades have been marked by failure to improve NOMI prognosis, due to lack of tools to detect this condition. While real-life diagnostic management relies on a combination of physical examination, several biomarkers, imaging, and endoscopy to detect the possibility of several grades of NOMI, research studies only focus on a few elements at a time. In the era of artificial intelligence (AI), which can aggregate thousands of variables in complex longitudinal models, the prospect of achieving accurate diagnosis through machine-learning-based algorithms may be sought. In the following work, we bring you a state-of-the-art literature review regarding NOMI, its presentation, its mechanics, and the pitfalls of routine work-up diagnostic exams including biomarkers, imaging, and endoscopy, we raise the perspectives of new biomarker exams, and finally we discuss what AI may add to the field, after summarizing what this technique encompasses.
    Keywords:  Artificial intelligence; Biomarkers; Critically ill; Machine learning; Mesenteric ischemia
    DOI:  https://doi.org/10.3748/wjg.v27.i26.4088
  11. World J Crit Care Med. 2021 Jul 09. 10(4): 102-111
    Glucocorticoid and mineralocorticoid receptor expression in critical illness: A narrative review.
    Alice G Vassiliou, Nikolaos Athanasiou, Dimitra A Vassiliadi, Edison Jahaj, Chrysi Keskinidou, Anastasia Kotanidou, Ioanna Dimopoulou.
      The glucocorticoid receptor (GCR) and the mineralocorticoid receptor (MR) are members of the steroid receptor superfamily of hormone-dependent transcription factors. The receptors are structurally and functionally related. They are localized in the cytosol and translocate into the nucleus after ligand binding. GCRs and MRs can be co-expressed within the same cell, and it is believed that the balance in GCR and MR expression is crucial for homeostasis and plays a key role in normal adaptation. In critical illness, the hypothalamic-pituitary-adrenal axis is activated, and as a consequence, serum cortisol concentrations are high. However, a number of patients exhibit relatively low cortisol levels for the degree of illness severity. Glucocorticoid (GC) actions are facilitated by GCR, whose dysfunction leads to GC tissue resistance. The MR is unique in this family in that it binds to both aldosterone and cortisol. Endogenous GCs play a critical role in controlling inflammatory responses in critical illness. Intracellular GC concentrations can differ greatly from blood levels due to the action of the two 11β-hydroxysteroid dehydrogenase isozymes, type 1 and type 2. 11β-hydroxysteroid dehydrogenases interconvert endogenous active cortisol and intrinsically inert cortisone. The degree of expression of the two isozymes has the potential to dramatically influence local GC availability within cells and tissues. In this review, we will explore the clinical studies that aimed to elucidate the role of MR and GCR expression in the inflammatory response seen in critical illness.
    Keywords:  11beta-hydroxysteroid dehydrogenase; Aldosterone; Cortisol; Glucocorticoid receptor, Critical illness; Mineralocorticoid receptor
    DOI:  https://doi.org/10.5492/wjccm.v10.i4.102
  12. Front Immunol. 2021 ;12 714340
    NLRP3 Inflammasome in Metabolic-Associated Kidney Diseases: An Update.
    Wei Xiong, Xian-Fang Meng, Chun Zhang.
      Metabolic syndrome (MS) is a group of complex metabolic disorders syndrome, which refers to the pathological state of metabolism disorder of protein, fat, carbohydrate and other substances in human body. The kidney is an important organ of metabolism, and various metabolic disorders can lead to the abnormalities in the structure and function of the kidney. The recognition of pathogenesis and treatment measures of renal damage in MS is a very important part for the renal function preserve. Inflammatory response caused by various metabolic factors is a protective mechanism of the body, but persistent inflammation will become a harmful factor and aggravate kidney damage. Inflammasomes are sensors of the innate immune system that play crucial roles in initiating inflammation in response to acute infections and chronic diseases. They are multiprotein complex composed of cytoplasmic sensors (mainly NLR family members), apoptosis-associated speck-like protein (ASC or PYCARD) and pro-caspase-1. After receiving exogenous and endogenous stimuli, the sensors begin to assemble inflammasome and then promote the release of inflammatory cytokines IL-1β and IL-18, resulting in a special way of cell death named pyroptosis. In the kidney, NLRP3 inflammasome can be activated by a variety of pathways, which eventually leads to inflammatory infiltration, renal intrinsic cell damage and renal function decline. This paper reviews the function and specific regulatory mechanism of inflammasome in kidney damage caused by various metabolic disorders, which will provide a new therapeutic perspective and targets for kidney diseases.
    Keywords:  NLRP3; inflammasome; innate immunity; kidney diseases; metabolic syndrome
    DOI:  https://doi.org/10.3389/fimmu.2021.714340
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