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Fan H, Sun M, Zhu JH. S-nitrosoglutathione inhibits pyroptosis of kidney tubular epithelial cells in sepsis via the SIRT3/SOD2/mtROS signaling pathway. Ren Fail 2025; 47:2472987. [PMID: 40050253 DOI: 10.1080/0886022x.2025.2472987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 02/08/2025] [Accepted: 02/16/2025] [Indexed: 03/12/2025] Open
Abstract
OBJECTIVES Pyroptosis is considered to play an important role in the occurrence, development and prognosis of septic acute kidney injury (SAKI). We aimed to explore the specific molecular mechanism of S-nitrosoglutathione (SNG) regulating pyroptosis of kidney tubular epithelial cells (KTECs). METHODS By constructing a mice model of sepsis, we pretreated them with SNG and used biochemical methods to detect the levels of serum inflammatory factors and mitochondrial reactive oxygen species (mtROS), assessed the severity of kidney injury and KTECs mitochondrial damage, and detected the expression of KTECs pyroptosis-related proteins and sirtuin 3 (SIRT3)/superoxide dismutase 2 (SOD2) pathway proteins. RESULTS The kidney injury caused by sepsis was significantly aggravated, and the levels of IL-1β, IL-6, IL-18, TNF-α, malondialdehyde (MDA) and mtROS were all increased, accompanied by the decrease of SIRT3 and SOD2 proteins, while NOD-like receptor with pyrin domain 3 (NLRP3), gasdermin D (GSDMD), Caspase-1 proteins expression and the number of KTECs apoptotic cells were all increased. However, after SNG pretreatment, the levels of IL-1β, IL-6, IL-18, TNF-α, MDA and mtROS were all significantly decreased, the expression of SIRT3 and SOD2 proteins were increased, NLRP3, GSDMD, Caspase-1 proteins expression and the number of KTECs apoptotic cells were decreased. CONCLUSIONS SNG protects SAKI by regulating the SIRT3/SOD2/mtROS signaling pathway to inhibit the pyroptosis of KTECs.
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Affiliation(s)
- Heng Fan
- Department of Intensive Care Unit, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang Province, P.R China
| | - Min Sun
- Department of Intensive Care Unit, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang Province, P.R China
| | - Jian-Hua Zhu
- Department of Intensive Care Unit, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang Province, P.R China
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Kounatidis D, Tzivaki I, Daskalopoulou S, Daskou A, Adamou A, Rigatou A, Sdogkos E, Karampela I, Dalamaga M, Vallianou NG. Sepsis-Associated Acute Kidney Injury: What's New Regarding Its Diagnostics and Therapeutics? Diagnostics (Basel) 2024; 14:2845. [PMID: 39767206 PMCID: PMC11674886 DOI: 10.3390/diagnostics14242845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 12/14/2024] [Accepted: 12/15/2024] [Indexed: 01/11/2025] Open
Abstract
Sepsis-associated acute kidney injury (SA-AKI) is defined as the development of AKI in the context of a potentially life-threatening organ dysfunction attributed to an abnormal immune response to infection. SA-AKI has been associated with increased mortality when compared to sepsis or AKI alone. Therefore, its early recognition is of the utmost importance in terms of its morbidity and mortality rates. The aim of this review is to shed light on the pathophysiological pathways implicated in SA-AKI as well as its diagnostics and therapeutics. In this review, we will elucidate upon serum and urinary biomarkers, such as creatinine, cystatin, neutrophil gelatinase-associated lipocalin (NGAL), proenkephalin A 119-159, interleukin-6, interleukin-8 and interleukin-18, soluble toll-like receptor 2 (sTLR2), chemokine ligand 2 (CCL2) and chemokine C-C-motif 14 (CCL14). In addition, the role of RNA omics as well as machine learning programs for the timely diagnosis of SA-AKI will be further discussed. Moreover, regarding SA-AKI treatment, we will elaborate upon potential therapeutic agents that are being studied, based on the pathophysiology of SA-AKI, in humans and in animal models.
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Affiliation(s)
- Dimitris Kounatidis
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Ilektra Tzivaki
- First Department of Internal Medicine, Sismanogleio General Hospital, 15126 Athens, Greece; (I.T.); (A.D.); (A.A.); (A.R.)
| | | | - Anna Daskou
- First Department of Internal Medicine, Sismanogleio General Hospital, 15126 Athens, Greece; (I.T.); (A.D.); (A.A.); (A.R.)
| | - Andreas Adamou
- First Department of Internal Medicine, Sismanogleio General Hospital, 15126 Athens, Greece; (I.T.); (A.D.); (A.A.); (A.R.)
| | - Anastasia Rigatou
- First Department of Internal Medicine, Sismanogleio General Hospital, 15126 Athens, Greece; (I.T.); (A.D.); (A.A.); (A.R.)
| | - Evangelos Sdogkos
- Department of Cardiology, Veria General Hospital, 59132 Veria, Greece;
| | - Irene Karampela
- Second Department of Critical Care, Attikon General University Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Natalia G. Vallianou
- First Department of Internal Medicine, Sismanogleio General Hospital, 15126 Athens, Greece; (I.T.); (A.D.); (A.A.); (A.R.)
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3
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Zhang Z, Yang M, Zhou T, Chen Y, Zhou X, Long K. Emerging trends and hotspots in intestinal microbiota research in sepsis: bibliometric analysis. Front Med (Lausanne) 2024; 11:1510463. [PMID: 39606629 PMCID: PMC11598531 DOI: 10.3389/fmed.2024.1510463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 11/01/2024] [Indexed: 11/29/2024] Open
Abstract
Background The association between the gut microbiota and sepsis has garnered attention in the field of intestinal research in sepsis. This study utilizes bibliometric methods to visualize and analyze the literature on gut microbiota research in sepsis from 2011 to 2024, providing a scientific foundation for research directions and key issues in this domain. Methods Original articles and reviews of gut microbiota research in sepsis, which published in English between 2011 and 2024, were obtained from the Web of Science Core Collection on June 21, 2024. Python, VOSviewer, and CiteSpace software were used for the visual analysis of the retrieved data. Results A total of 1,031 articles were analyzed, originating from 72 countries or regions, 1,614 research institutions, and 6,541 authors. The articles were published in 434 different journals, covering 89 different research fields. The number of publications and citations in this research area showed a significant growth trend from 2011 to 2024, with China, the United States, and the United Kingdom being the main research forces. Asada Leelahavanichkul from Thailand was identified as the most prolific author, making him the most authoritative expert in this field. "Nutrients" had the highest number of publications, while "Frontiers in Cellular and Infection Microbiology," "Frontiers in Immunology" and "the International Journal of Molecular Sciences" have shown increasing attention to this field in the past 2 years. Author keywords appearing more than 100 times included "gut microbiota (GM)," "sepsis" and "microbiota." Finally, this study identified "lipopolysaccharides (LPS)," "short-chain fatty acids (SCFAs)," "probiotics," "fecal microbiota transplantation (FMT)" and "gut-liver axis" as the research hotspots and potential frontier directions in this field. Conclusion This bibliometric study summarizes current important perspectives and offers comprehensive guidance between sepsis and intestinal microbiota, which may help researchers choose the most appropriate research directions.
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Affiliation(s)
- Zhengyi Zhang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Meijie Yang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tong Zhou
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yingjie Chen
- Department of Critical Care Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiujuan Zhou
- Department of Critical Care Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kunlan Long
- Department of Critical Care Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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4
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Huang L, Wu Y, Sai W, Wang Y, Feng G, Lu Y, Chen F, Huang X, Zhao H, Gu Z, Yang B. HBSP inhibits tubular cell pyroptosis and apoptosis, promotes macrophage M2 polarization, and protects LPS-induced acute kidney injury. J Cell Mol Med 2024; 28:e70202. [PMID: 39584501 PMCID: PMC11586777 DOI: 10.1111/jcmm.70202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 10/11/2024] [Accepted: 10/24/2024] [Indexed: 11/26/2024] Open
Abstract
Sepsis-associated acute kidney injury (AKI) has high morbidity and mortality, but without cause-specific treatment. Erythropoietin derived Helix B surface peptide (HBSP) alleviates AKI, whereas its underlying mechanisms remain to be further explored. Here, the effects of HBSP on pyroptosis, apoptosis, macrophage polarization and repair were investigated in lipopolysaccharide (LPS)-induced AKI mouse model and cultured kidney epithelial cells. Systemic inflammation, compromised renal function and histology were demonstrated in LPS-treated mice, with upregulated pyroptotic and apoptotic key proteins in the kidneys including GSDMD-N, cleaved IL-1β, IL-18 and caspase-3. These proteins were localized in tubular areas and colocalized with aquaporin-1 (AQP1), with increased F4/80+ M1 macrophages. However, HBSP mitigated pyroptosis, apoptosis and inflammation, and promoted macrophage M2 polarization. In addition, HMGB1 and erythropoietin receptor (EPOR) were increased by LPS and decreased by HBSP, both of which were positively correlated with pyroptotic and apoptotic proteins. Moreover, HBSP reduced TNF-α and IL-6 mRNA levels, as well as pyroptosis and apoptosis in LPS-stimulated TCMK-1 cells. In conclusion, HBSP inhibited tubular pyroptosis and apoptosis, EPOR expression, promoted macrophage M2 polarization, and protected against LPS-induced AKI. These findings provide new mechanistic insights into the renoprotection of HBSP, and facilitate its potential for clinical applications and therapeutic strategies in sepsis-associated AKI.
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Affiliation(s)
- Lili Huang
- Nantong‐Leicester Joint Institute of Kidney ScienceAffiliated Hospital of Nantong UniversityNantongChina
- Department of Critical Care MedicineAffiliated Hospital of Nantong UniversityNantongChina
| | - Yuanyuan Wu
- Nantong‐Leicester Joint Institute of Kidney ScienceAffiliated Hospital of Nantong UniversityNantongChina
- Department of Pathology, Medical SchoolNantong UniversityNantongChina
| | - Wenli Sai
- Nantong‐Leicester Joint Institute of Kidney ScienceAffiliated Hospital of Nantong UniversityNantongChina
- Clinical Medical Research CenterAffiliated Hospital of Nantong UniversityNantongChina
| | - Yanan Wang
- Nantong‐Leicester Joint Institute of Kidney ScienceAffiliated Hospital of Nantong UniversityNantongChina
- Department of NephrologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Guijuan Feng
- Department of StomatologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Yuqing Lu
- Nantong‐Leicester Joint Institute of Kidney ScienceAffiliated Hospital of Nantong UniversityNantongChina
- Department of NephrologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Fei Chen
- Nantong‐Leicester Joint Institute of Kidney ScienceAffiliated Hospital of Nantong UniversityNantongChina
- Department of NephrologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Xinzhong Huang
- Nantong‐Leicester Joint Institute of Kidney ScienceAffiliated Hospital of Nantong UniversityNantongChina
- Department of NephrologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Hongsheng Zhao
- Department of Critical Care MedicineAffiliated Hospital of Nantong UniversityNantongChina
| | - Zhifeng Gu
- Department of Rheumatology, Affiliated Hospital of Nantong University, Medical School of Nantong UniversityNantong UniversityNantongChina
| | - Bin Yang
- Nantong‐Leicester Joint Institute of Kidney ScienceAffiliated Hospital of Nantong UniversityNantongChina
- Department of NephrologyAffiliated Hospital of Nantong UniversityNantongChina
- Department of Cardiovascular Sciences, College of Life Sciences, University Hospitals of Leicester NHS TrustUniversity of LeicesterLeicesterUK
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5
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Zhao Q, Zhang R, Wang Y, Li T, Xue J, Chen Z. FOXQ1, deubiquitinated by USP10, alleviates sepsis-induced acute kidney injury by targeting the CREB5/NF-κB signaling axis. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167331. [PMID: 38960057 DOI: 10.1016/j.bbadis.2024.167331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 06/14/2024] [Accepted: 06/25/2024] [Indexed: 07/05/2024]
Abstract
Sepsis-induced acute kidney injury (S-AKI) is a severe and frequent complication that occurs during sepsis. This study aimed to understand the role of FOXQ1 in S-AKI and its potential upstream and downstream regulatory mechanisms. A cecal ligation and puncture induced S-AKI mouse model in vivo and an LPS-induced HK-2 cell model in vitro were used. FOXQ1 was significantly upregulated in CLP mice and downregulated in the LPS-induced HK-2 cells. Upregulation of FOXQ1 improved kidney injury and dysfunction in CLP mice. Overexpression of FOXQ1 remarkably suppressed the apoptosis and inflammatory response via down-regulating oxidative stress indicators and pro-inflammatory factors (IL-1β, IL-6, and TNF-α), both in vivo and in vitro. From online analysis, the CREB5/NF-κB axis was identified as the downstream target of FOXQ1. FOXQ1 transcriptionally activated CREB5, upregulating its expression. Overexpression of FOXQ1 suppressed the phosphorylation level and nucleus transport of p65. Rescue experiments showed that CREB5 mediates the protective role of FOXQ1 on S-AKI. Furthermore, FOXQ1 was identified as a substrate of USP10, a deubiquitinating enzyme. Ectopic expression of USP10 reduced the ubiquitination of FOXQ1, promoting its protein stability. USP10 upregulation alleviated LPS-induced cell apoptosis and inflammatory response, while suppression of FOXQ1 augmented these trends. Collectively, our results suggest that FOXQ1, deubiquitinated by USP10, plays a protective role in S-AKI induced inflammation and apoptosis by targeting CREB5/NF-κB axis.
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Affiliation(s)
- Qi Zhao
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ran Zhang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yu Wang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Tiegang Li
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Jinqi Xue
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Zhiguang Chen
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
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6
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Zhao L, Cheng H, Tong Z, Cai J. Nanoparticle-mediated cell pyroptosis: a new therapeutic strategy for inflammatory diseases and cancer. J Nanobiotechnology 2024; 22:504. [PMID: 39175020 PMCID: PMC11340130 DOI: 10.1186/s12951-024-02763-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 08/12/2024] [Indexed: 08/24/2024] Open
Abstract
Pyroptosis, a lytic form of cell death mediated by the gasdermin family, is characterized by cell swelling and membrane rupture. Inducing pyroptosis in cancer cells can enhance antitumor immune responses and is a promising strategy for cancer therapy. However, excessive pyroptosis may trigger the development of inflammatory diseases due to immoderate and continuous inflammatory reactions. Nanomaterials and nanobiotechnology, renowned for their unique advantages and diverse structures, have garnered increasing attention owing to their potential to induce pyroptosis in diseases such as cancer. A nano-delivery system for drug-induced pyroptosis in cancer cells can overcome the limitations of small molecules. Furthermore, nanomedicines can directly induce and manipulate pyroptosis. This review summarizes and discusses the latest advancements in nanoparticle-based treatments with pyroptosis among inflammatory diseases and cancer, focusing on their functions and mechanisms and providing valuable insights into selecting nanodrugs for pyroptosis. However, the clinical application of these strategies still faces challenges owing to a limited understanding of nanobiological interactions. Finally, future perspectives on the emerging field of pyroptotic nanomaterials are presented.
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Affiliation(s)
- Lin Zhao
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Human, 410011, China
| | - Haipeng Cheng
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Human, 410011, China
| | - Zhongyi Tong
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Human, 410011, China
| | - Jing Cai
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Human, 410011, China.
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7
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Bernard A, Eggstein C, Tang L, Keller M, Körner A, Mirakaj V, Rosenberger P. Plexin C1 influences immune response to intracellular LPS and survival in murine sepsis. J Biomed Sci 2024; 31:82. [PMID: 39169397 PMCID: PMC11337750 DOI: 10.1186/s12929-024-01074-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 08/08/2024] [Indexed: 08/23/2024] Open
Abstract
BACKGROUND Intracellular sensing of lipopolysaccharide (LPS) is essential for the immune response against gram-negative bacteria and results in activation of caspase-11 and pyroptotic cell death with fatal consequences in sepsis. We found the neuronal guidance receptor plexin C1 (PLXNC1) influences the intracellular response to LPS. METHODS We employed a murine model of sepsis via cecal ligation and binding (CLP), using PLXNC1-/- mice and littermate controls, and additionally transfected murine bone-marrow-derived macrophages (BMDMs) from both genotypes with LPS to achieve activation of the noncanonical inflammasome ex vivo. Additionally, we transfected the PLXNC1 ligand SL4c-d in vivo and ex vivo to examine its effect on intracellular LPS response. RESULTS We found the neuronal guidance receptor PLXNC1 dampens the intracellular response to LPS by interacting with adenylate cyclase 4 (ADCY4) and protein kinase A activity, which in turn diminishes caspase-11 expression. The absence of PLXNC1 results in excessive inflammation marked by increased cytokine release, increased secondary organ injury and reduced sepsis survival in a murine sepsis model induced by CLP. Notably, administration of SL4c-d-peptide ligand of PLXNC1-reduces the inflammatory response during CLP-induced sepsis and improves survival. CONCLUSIONS These results elucidate a previously unknown mechanism for PLXNC1 suppressing excessive noncanonical inflammasome activity and offer a new potential target for treatment of sepsis with its detrimental effects.
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Affiliation(s)
- Alice Bernard
- Department of Anaesthesiology and Intensive Care Medicine, Eberhard-Karls University Tübingen, Hoppe-Seyler-Straße 3, 72076, Tübingen, Germany
| | - Claudia Eggstein
- Department of Anaesthesiology and Intensive Care Medicine, Eberhard-Karls University Tübingen, Hoppe-Seyler-Straße 3, 72076, Tübingen, Germany
| | - Linyan Tang
- Department of Anaesthesiology and Intensive Care Medicine, Eberhard-Karls University Tübingen, Hoppe-Seyler-Straße 3, 72076, Tübingen, Germany
| | - Marius Keller
- Department of Anaesthesiology and Intensive Care Medicine, Eberhard-Karls University Tübingen, Hoppe-Seyler-Straße 3, 72076, Tübingen, Germany
| | - Andreas Körner
- Department of Anaesthesiology and Intensive Care Medicine, Eberhard-Karls University Tübingen, Hoppe-Seyler-Straße 3, 72076, Tübingen, Germany
| | - Valbona Mirakaj
- Department of Anaesthesiology and Intensive Care Medicine, Eberhard-Karls University Tübingen, Hoppe-Seyler-Straße 3, 72076, Tübingen, Germany
| | - Peter Rosenberger
- Department of Anaesthesiology and Intensive Care Medicine, Eberhard-Karls University Tübingen, Hoppe-Seyler-Straße 3, 72076, Tübingen, Germany.
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8
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Bayat M, Nahand JS. Let's make it personal: CRISPR tools in manipulating cell death pathways for cancer treatment. Cell Biol Toxicol 2024; 40:61. [PMID: 39075259 PMCID: PMC11286699 DOI: 10.1007/s10565-024-09907-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 07/18/2024] [Indexed: 07/31/2024]
Abstract
Advancements in the CRISPR technology, a game-changer in experimental research, have revolutionized various fields of life sciences and more profoundly, cancer research. Cell death pathways are among the most deregulated in cancer cells and are considered as critical aspects in cancer development. Through decades, our knowledge of the mechanisms orchestrating programmed cellular death has increased substantially, attributed to the revolution of cutting-edge technologies. The heroic appearance of CRISPR systems have expanded the available screening platform and genome engineering toolbox to detect mutations and create precise genome edits. In that context, the precise ability of this system for identification and targeting of mutations in cell death signaling pathways that result in cancer development and therapy resistance is an auspicious choice to transform and accelerate the individualized cancer therapy. The concept of personalized cancer therapy stands on the identification of molecular characterization of the individual tumor and its microenvironment in order to provide a precise treatment with the highest possible outcome and minimum toxicity. This study explored the potential of CRISPR technology in precision cancer treatment by identifying and targeting specific cell death pathways. It showed the promise of CRISPR in finding key components and mutations involved in programmed cell death, making it a potential tool for targeted cancer therapy. However, this study also highlighted the challenges and limitations that need to be addressed in future research to fully realize the potential of CRISPR in cancer treatment.
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Affiliation(s)
- Mobina Bayat
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, 15731, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, 15731, Iran.
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9
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Ma X, Lin Y, Zhang L, Miao S, Zhang H, Li H, Fu X, Han L, Li P. GSDMD in regulated cell death: A novel therapeutic target for sepsis. Int Immunopharmacol 2024; 135:112321. [PMID: 38795599 DOI: 10.1016/j.intimp.2024.112321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 04/30/2024] [Accepted: 05/19/2024] [Indexed: 05/28/2024]
Abstract
Sepsis is a life-threatening multi-organ dysfunction syndrome caused by an abnormal host response to infection. Regulated cell death is essential for maintaining tissue homeostasis and eliminating damaged, infected, or aging cells in multicellular organisms. Gasdermin D, as a member of the gasdermin family, plays a crucial role in the formation of cytoplasmic membrane pores. Research has found that GSDMD plays important roles in various forms of regulated cell death such as pyroptosis, NETosis, and necroptosis. Therefore, through mediating regulated cell death, GSDMD regulates different stages of disease pathophysiology. This article mainly summarizes the concept of GSDMD, its role in regulated cell death, its involvement in organ damage associated with sepsis-related injuries mediated by regulated cell death via GSDMD activation and introduces potential drugs targeting GSDMD that may provide more effective treatment options for sepsis patients through drug modification.
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Affiliation(s)
- Xiangli Ma
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China.
| | - Yujie Lin
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Ling Zhang
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Shaoyi Miao
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Haidan Zhang
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Hongyao Li
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Xu Fu
- Key Laboratory of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Li Han
- Key Laboratory of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Peiwu Li
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China.
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10
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Song R, He S, Wu Y, Tan S. Pyroptosis in sepsis induced organ dysfunction. Curr Res Transl Med 2024; 72:103419. [PMID: 38246070 DOI: 10.1016/j.retram.2023.103419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/27/2023] [Accepted: 10/05/2023] [Indexed: 01/23/2024]
Abstract
As an uncontrolled inflammatory response to infection, sepsis and sepsis induced organ dysfunction are great threats to the lives of septic patients. Unfortunately, the pathogenesis of sepsis is complex and multifactorial, which still needs to be elucidated. Pyroptosis is a newly discovered atypical form of inflammatory programmed cell death, which depends on the Caspase-1 dependent classical pathway or the non-classical Caspase-11 (mouse) or Caspase-4/5 (human) dependent pathway. Many studies have shown that pyroptosis is related to sepsis. The Gasdermin proteins are the key molecules in the membrane pores formation in pyroptosis. After cut by inflammatory caspase, the Gasdermin N-terminal fragments with perforation activity are released to cause pyroptosis. Pyroptosis is closely related to the occurrence and development of sepsis induced organ dysfunction. In this review, we summarized the molecular mechanism of pyroptosis, the key role of pyroptosis in sepsis and sepsis induced organ dysfunction, with the aim to bring new diagnostic biomarkers and potential therapeutic targets to improve sepsis clinical treatments.
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Affiliation(s)
- Ruoyu Song
- Department of Pathophysiology, School of Basic Medicine Science, Central South University, Changsha, China; Sepsis Translational Medicine Key Laboratory of Hunan Province, Central South University, Changsha, China; National Medicine Functional Experimental Teaching Center, Central South University, Changsha, China.
| | - Shijun He
- Department of Pathophysiology, School of Basic Medicine Science, Central South University, Changsha, China; Sepsis Translational Medicine Key Laboratory of Hunan Province, Central South University, Changsha, China; National Medicine Functional Experimental Teaching Center, Central South University, Changsha, China
| | - Yongbin Wu
- Department of Pathophysiology, School of Basic Medicine Science, Central South University, Changsha, China; Sepsis Translational Medicine Key Laboratory of Hunan Province, Central South University, Changsha, China; National Medicine Functional Experimental Teaching Center, Central South University, Changsha, China
| | - Sipin Tan
- Department of Pathophysiology, School of Basic Medicine Science, Central South University, Changsha, China; Sepsis Translational Medicine Key Laboratory of Hunan Province, Central South University, Changsha, China; National Medicine Functional Experimental Teaching Center, Central South University, Changsha, China.
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11
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Xu C, Wang Q, Du C, Chen L, Zhou Z, Zhang Z, Cai N, Li J, Huang C, Ma T. Histone deacetylase-mediated silencing of PSTPIP2 expression contributes to aristolochic acid nephropathy-induced PANoptosis. Br J Pharmacol 2024; 181:1452-1473. [PMID: 38073114 DOI: 10.1111/bph.16299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 11/21/2023] [Accepted: 11/29/2023] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND AND PURPOSE Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by using herbal medicines. Currently, no therapies are available to treat or prevent aristolochic acid nephropathy. Histone deacetylase (HDAC) plays a crucial role in the development and progression of renal disease. We tested whether HDAC inhibitors could prevent aristolochic acid nephropathy and determined the underlying mechanism. EXPERIMENTAL APPROACH HDACs expression in the aristolochic acid nephropathy model was examined. The activation of PANoptosis of mouse kidney and renal tubular epithelial cell were assessed after exposure to HDAC1 and HDAC2 blockade. Kidney-specific knock-in of proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) mice were used to investigate whether PSTPIP2 affected the production of PANoptosome. KEY RESULTS Aristolochic acid upregulated the expression of HDAC1 and HDAC2 in the kidneys. Notably, the HDAC1 and HDAC2 specific inhibitor, romidepsin (FK228, depsipeptide), suppressed aristolochic acid-induced kidney injury, epithelial cell pyroptosis, apoptosis and necroptosis (PANoptosis). Moreover, romidepsin upregulated PSTPIP2 in renal tubular epithelial cells, which was enhanced by aristolochic acid treatment. Conditional knock-in of PSTPIP2 in the kidney protected against aristolochic acid nephropathy. In contrast, the knockdown of PSTPIP2 expression in PSTPIP2-knock-in mice restored kidney damage and PANoptosis. PSTPIP2 function was determined in vitro using PSTPIP2 knockdown or overexpression in mouse renal tubular epithelial cells (mTECs). Additionally, PSTPIP2 was found to regulate caspase 8 in aristolochic acid nephropathy. CONCLUSION AND IMPLICATIONS HDAC-mediated silencing of PSTPIP2 may contribute to aristolochic acid nephropathy. Hence, HDAC1 and HDAC2 specific inhibitors or PSTPIP2 could be valuable therapeutic agents for preventing aristolochic acid nephropathy.
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Affiliation(s)
- Chuanting Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Center of Traditional Chinese Medicine Formula Granule, Anhui Medical University, Hefei, China
| | - Qi Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Changlin Du
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Lu Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Zhongnan Zhou
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Zhenming Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Na Cai
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Anhui Provincial Institute of Translational Medicine, Hefei, China
| | - Taotao Ma
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Center of Traditional Chinese Medicine Formula Granule, Anhui Medical University, Hefei, China
- Anhui Provincial Institute of Translational Medicine, Hefei, China
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12
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Jin Y, Song Q, He R, Diao H, Gaoyang H, Wang L, Fan L, Wang D. Nod-like receptor protein 3 inflammasome-mediated pyroptosis contributes to chronic NaAsO 2 exposure-induced fibrotic changes and dysfunction in the liver of SD rats. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 275:116282. [PMID: 38564859 DOI: 10.1016/j.ecoenv.2024.116282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 03/25/2024] [Accepted: 03/30/2024] [Indexed: 04/04/2024]
Abstract
The metalloid arsenic, known for its toxic properties, is widespread presence in the environment. Our previous research has confirmed that prolonged exposure to arsenic can lead to liver fibrosis injury in rats, while the precise pathogenic mechanism still requires further investigation. In the past few years, the Nod-like receptor protein 3 (NLRP3) inflammasome has been found to play a pivotal role in the occurrence and development of liver injury. In this study, we administered varying doses of sodium arsenite (NaAsO2) and 10 mg/kg.bw MCC950 (a particular tiny molecular inhibitor targeting NLRP3) to Sprague-Dawley (SD) rats for 36 weeks to explore the involvement of NLRP3 inflammasome in NaAsO2-induced liver injury. The findings suggested that prolonged exposure to NaAsO2 resulted in pyroptosis in liver tissue of SD rats, accompanied by the fibrotic injury, extracellular matrix (ECM) deposition and liver dysfunction. Moreover, long-term NaAsO2 exposure activated NLRP3 inflammasome, leading to the release of pro-inflammatory cytokines in liver tissue. After treatment with MCC950, the induction of NLRP3-mediated pyroptosis and release of pro-inflammatory cytokines were significantly attenuated, leading to a decrease in the severity of liver fibrosis and an improvement in liver function. To summarize, those results clearly indicate that hepatic fibrosis and liver dysfunction induced by NaAsO2 occur through the activation of NLRP3 inflammasome-mediated pyroptosis, shedding new light on the potential mechanisms underlying arsenic-induced liver damage.
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Affiliation(s)
- Ying Jin
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, School of Public Health, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou 550025, PR China
| | - Qian Song
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, School of Public Health, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou 550025, PR China
| | - Rui He
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, School of Public Health, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou 550025, PR China
| | - Heng Diao
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, School of Public Health, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou 550025, PR China
| | - Huijie Gaoyang
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, School of Public Health, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou 550025, PR China
| | - Lei Wang
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, School of Public Health, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou 550025, PR China
| | - Lili Fan
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, School of Public Health, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou 550025, PR China.
| | - Dapeng Wang
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, School of Public Health, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou 550025, PR China; Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, Guizhou Medical University, Guiyang, Guizhou 550025, PR China.
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13
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Xiong J, Zhao J. Pyroptosis: The Determinator of Cell Death and Fate in Acute Kidney Injury. KIDNEY DISEASES (BASEL, SWITZERLAND) 2024; 10:118-131. [PMID: 38751798 PMCID: PMC11095617 DOI: 10.1159/000535894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 12/15/2023] [Indexed: 05/18/2024]
Abstract
Background Acute kidney injury (AKI) is kidney damage that leads to a rapid decline in function. AKI primarily occurs when the tubular epithelium is damaged, causing swelling, loss of brush margin, and eventual apoptosis. Research has shown that tubular epithelial cell damage in AKI is linked to cell cycle arrest, autophagy, and regulation of cell death. Summary Pyroptosis, a type of programmed cell death triggered by inflammation, is believed to play a role in the pathophysiology of AKI. Cumulative evidence has shown that pyroptosis is the main cause of tubular cell death in AKI. Thus, targeted intervention of pyroptosis may be a promising therapeutic approach for AKI. This review delves deep into the cutting-edge research surrounding pyroptosis in the context of AKI, shedding light on its intricate mechanisms and potential implications for clinical practice. Additionally, we explore the exciting realm of potential preclinical treatment options for AKI, aiming to pave the way for future therapeutic advancements. Key Messages Pyroptosis, a highly regulated form of cell death, plays a crucial role in determining the fate of cells during the development of AKI. This intricate process involves the activation of inflammasomes, which are multi-protein complexes that initiate pyroptotic cell death. By understanding the mechanisms underlying pyroptosis, researchers aim to gain insights into the pathogenesis of AKI and potentially identify new therapeutic targets for this condition.
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Affiliation(s)
- Jiachuan Xiong
- Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Kidney Center of PLA, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, PR China
| | - Jinghong Zhao
- Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Kidney Center of PLA, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, PR China
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14
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Zhou Z, Li Q. The Role of Pyroptosis in the Pathogenesis of Kidney Diseases. KIDNEY DISEASES (BASEL, SWITZERLAND) 2023; 9:443-458. [PMID: 38089443 PMCID: PMC10712988 DOI: 10.1159/000531642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 06/12/2023] [Indexed: 01/21/2025]
Abstract
BACKGROUND Recently, in addition to apoptosis and necrosis, several other forms of cell death have been discovered, such as necroptosis, autophagy, pyroptosis, and ferroptosis. These cell death modalities play diverse roles in kidney diseases. Pyroptosis is a newly described type of proinflammatory programmed necrosis. Further exploring pyroptosis is helpful to slow the progression of kidney diseases and reduce their complications. SUMMARY Pyroptosis is mainly mediated by the cleavage of gasdermin D (GSDMD) along with downstream inflammasome activation. Activated caspase-1 induces the release of cytokines by cleaving GSDMD. Inflammation is a major pathogenic mechanism for kidney diseases. Increasing evidence corroborated that pyroptosis was closely related to the progression of renal diseases, including acute kidney injury, renal fibrosis, diabetic nephropathy, and kidney cancer. In this paper, we reviewed the role and the therapeutic treatment of pyroptosis in renal diseases. KEY MESSAGES The better understanding of the progress and new intervention approaches of pyroptosis in kidney diseases may pave the way for new therapeutic opportunities in clinical practice.
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Affiliation(s)
- Zhuanli Zhou
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qin Li
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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15
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Zhang H, Deng Z, Wang Y, Zheng X, Zhou L, Yan S, Wang Y, Dai Y, Kanwar Y, Deng F. CHIP protects against septic acute kidney injury by inhibiting NLRP3-mediated pyroptosis. iScience 2023; 26:107762. [PMID: 37692286 PMCID: PMC10492219 DOI: 10.1016/j.isci.2023.107762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 07/16/2023] [Accepted: 08/25/2023] [Indexed: 09/12/2023] Open
Abstract
Septic acute kidney injury (S-AKI), the most common type of acute kidney injury (AKI), is intimately related to pyroptosis and oxidative stress in its pathogenesis. Carboxy-terminus of Hsc70-interacting protein (CHIP), a U-box E3 ligase, modulates oxidative stress by degrading its targeted proteins. The role of CHIP in S-AKI and its relevance with pyroptosis have not been investigated. In this study, we showed that CHIP was downregulated in renal proximal tubular cells in lipopolysaccharide (LPS)-induced S-AKI. Besides, the extent of redox injuries in S-AKI was attenuated by CHIP overexpression or activation but accentuated by CHIP gene disruption. Mechanistically, our work demonstrated that CHIP interacted with and ubiquitinated NLRP3 to promote its proteasomal degradation, leading to the inhibition of NLRP3/ACS inflammasome-mediated pyroptosis. In summary, this study revealed that CHIP ubiquitinated NLRP3 to alleviate pyroptosis in septic renal injuries, suggesting that CHIP might be a potential therapeutic target for S-AKI.
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Affiliation(s)
- Hao Zhang
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Zebin Deng
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Yilong Wang
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaoping Zheng
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Lizhi Zhou
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Shu Yan
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yinhuai Wang
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Yingbo Dai
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Yashpal.S. Kanwar
- Departments of Pathology & Medicine, Northwestern University, Chicago, IL, USA
| | - Fei Deng
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
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16
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Balkrishna A, Sinha S, Kumar A, Arya V, Gautam AK, Valis M, Kuca K, Kumar D, Amarowicz R. Sepsis-mediated renal dysfunction: Pathophysiology, biomarkers and role of phytoconstituents in its management. Biomed Pharmacother 2023; 165:115183. [PMID: 37487442 DOI: 10.1016/j.biopha.2023.115183] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 07/08/2023] [Accepted: 07/18/2023] [Indexed: 07/26/2023] Open
Abstract
Sepsis has evolved as an enormous health issue amongst critically ill patients. It is a major risk factor that results in multiple organ failure and shock. Acute kidney injury (AKI) is one of the most frequent complications underlying sepsis, which portends a heavy burden of mortality and morbidity. Thus, the present review is aimed to provide an insight into the recent progression in the molecular mechanisms targeting dysregulated immune response and cellular dysfunction involved in the development of sepsis-associated AKI, accentuating the phytoconstituents as eligible candidates for attenuating the onset and progression of sepsis-associated AKI. The pathogenesis of sepsis-mediated AKI entails a complicated mechanism and is likely to involve a distinct constellation of hemodynamic, inflammatory, and immune mechanisms. Novel biomarkers like neutrophil gelatinase-associated lipocalin, soluble triggering receptor expressed on myeloid cells 1, procalcitonin, alpha-1-microglobulin, and presepsin can help in a more sensitive diagnosis of sepsis-associated AKI. Many bioactive compounds like curcumin, resveratrol, baicalin, quercetin, and polydatin are reported to play an important role in the prevention and management of sepsis-associated AKI by decreasing serum creatinine, blood urea nitrogen, cystatin C, lipid peroxidation, oxidative stress, IL-1β, TNF-α, NF-κB, and increasing the activity of antioxidant enzymes and level of PPARγ. The plant bioactive compounds could be developed into a drug-developing candidate in managing sepsis-mediated acute kidney injury after detailed follow-up studies. Lastly, the gut-kidney axis may be a more promising therapeutic target against the onset of septic AKI, but a deeper understanding of the molecular pathways is still required.
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Affiliation(s)
- Acharya Balkrishna
- Patanjali Herbal Research Department, Patanjali Research Institute, Haridwar, India
| | - Sugandh Sinha
- Patanjali Herbal Research Department, Patanjali Research Institute, Haridwar, India
| | - Ashwani Kumar
- Patanjali Herbal Research Department, Patanjali Research Institute, Haridwar, India.
| | - Vedpriya Arya
- Patanjali Herbal Research Department, Patanjali Research Institute, Haridwar, India
| | - Ajay Kumar Gautam
- Patanjali Herbal Research Department, Patanjali Research Institute, Haridwar, India
| | - Martin Valis
- Department of Neurology, Charles University in Prague, Faculty of Medicine in Hradec Králové and University Hospital, Hradec Králové, Czech Republic
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic; Biomedical Research Center, University Hospital in Hradec Kralove, Sokolska 581, Hradec Kralove, Czech Republic.
| | - Dinesh Kumar
- School of Bioengineering and Food Technology, Shoolini University of Biotechnology and Management Sciences, Solan, India
| | - Ryszard Amarowicz
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland
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17
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Mueen RM, Al-Juaifari M, Abosaooda M, Qassam H, Hadi NR. Lung protective effect of Ticagrelor in endotoxemia. J Med Life 2023; 16:941-947. [PMID: 37675176 PMCID: PMC10478651 DOI: 10.25122/jml-2022-0308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 03/03/2023] [Indexed: 09/08/2023] Open
Abstract
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. This study aimed to investigate the potential protective effect of the lungs in sepsis by modulating inflammatory and oxidative stress markers. Twenty-four adult male Swiss-albino mice, aged 8-12 weeks and weighing 20-30 g, were divided into four equal groups (n=6): sham (laparotomy only), CLP (laparotomy plus cecal ligation and puncture), vehicle (DMSO administered one hour before CLP), and Ticagrelor (50 mg/kg IP administered one hour before CLP). Tissue levels of pro-inflammatory and oxidative stress markers in the lung were assessed using ELISA. F2 isoprostane levels were significantly higher in the sepsis group (p<0.05) compared to the sham group, while Ticagrelor significantly decreased the inflammatory and oxidative stress markers compared to the sepsis group. All mice in the sepsis group had considerable (p=0.05) lung tissue damage, but Ticagrelor considerably decreased lung tissue injury (p=0.05). Furthermore, Ticagrelor was found to reduce tissue cytokine levels of the lung (IL-1, TNF a, IL-6, F2 isoprostane, GPR 17, MIF) in male mice during CLP-induced polymicrobial sepsis by modulation of pro-inflammatory and oxidative stress cascade signaling pathways.
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Affiliation(s)
- Ruaa Murtada Mueen
- Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Kufa, Kufa, Iraq
| | - Maytham Al-Juaifari
- KMG Klinikum Güstrow, Clinic for Trauma Surgery, Spinal Surgery and Orthopedics, Güstrow, Germany
| | | | - Heider Qassam
- Department of Pharmacology, Faculty of Medicine, University of Kufa, Iraq
| | - Najah Rayish Hadi
- Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Kufa, Kufa, Iraq
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18
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Chen X, Guo J, Mahmoud S, Vanga G, Liu T, Xu W, Xiong Y, Xiong W, Abdel-Razek O, Wang G. Regulatory roles of SP-A and exosomes in pneumonia-induced acute lung and kidney injuries. Front Immunol 2023; 14:1188023. [PMID: 37256132 PMCID: PMC10225506 DOI: 10.3389/fimmu.2023.1188023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 05/02/2023] [Indexed: 06/01/2023] Open
Abstract
Introduction Pneumonia-induced sepsis can cause multiple organ dysfunction including acute lung and kidney injury (ALI and AKI). Surfactant protein A (SP-A), a critical innate immune molecule, is expressed in the lung and kidney. Extracellular vesicles like exosomes are involved in the processes of pathophysiology. Here we tested one hypothesis that SP-A regulates pneumonia-induced AKI through the modulation of exosomes and cell death. Methods Wild-type (WT), SP-A knockout (KO), and humanized SP-A transgenic (hTG, lung-specific SP-A expression) mice were used in this study. Results After intratracheal infection with Pseudomonas aeruginosa, KO mice showed increased mortality, higher injury scores, more severe inflammation in the lung and kidney, and increased serum TNF-α, IL-1β, and IL-6 levels compared to WT and hTG mice. Infected hTG mice exhibited similar lung injury but more severe kidney injury than infected WT mice. Increased renal tubular apoptosis and pyroptosis in the kidney of KO mice were found when compared with WT and hTG mice. We found that serum exosomes from septic mice cause ALI and AKI through mediating apoptosis and proptosis when mice were injected intravenously. Furthermore, primary proximal tubular epithelial cells isolated from KO mice showed more sensitivity than those from WT mice after exposure to septic serum exosomes. Discussion Collectively, SP-A attenuates pneumonia-induced ALI and AKI by regulating inflammation, apoptosis and pyroptosis; serum exosomes are important mediators in the pathogenesis of AKI.
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Affiliation(s)
- Xinghua Chen
- Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, United States
- Department of Nephrology, Wuhan University, Renmin Hospital, Wuhan, Hubei, China
| | - Junping Guo
- Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, United States
| | - Salma Mahmoud
- Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, United States
| | - Gautam Vanga
- Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, United States
| | - Tianyi Liu
- Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, United States
| | - Wanwen Xu
- Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, United States
| | - Yunhe Xiong
- Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, United States
| | - Weichuan Xiong
- Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, United States
| | - Osama Abdel-Razek
- Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, United States
| | - Guirong Wang
- Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, United States
- Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, United States
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Sanz AB, Sanchez-Niño MD, Ramos AM, Ortiz A. Regulated cell death pathways in kidney disease. Nat Rev Nephrol 2023; 19:281-299. [PMID: 36959481 PMCID: PMC10035496 DOI: 10.1038/s41581-023-00694-0] [Citation(s) in RCA: 133] [Impact Index Per Article: 66.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2023] [Indexed: 03/25/2023]
Abstract
Disorders of cell number that result from an imbalance between the death of parenchymal cells and the proliferation or recruitment of maladaptive cells contributes to the pathogenesis of kidney disease. Acute kidney injury can result from an acute loss of kidney epithelial cells. In chronic kidney disease, loss of kidney epithelial cells leads to glomerulosclerosis and tubular atrophy, whereas interstitial inflammation and fibrosis result from an excess of leukocytes and myofibroblasts. Other conditions, such as acquired cystic disease and kidney cancer, are characterized by excess numbers of cyst wall and malignant cells, respectively. Cell death modalities act to clear unwanted cells, but disproportionate responses can contribute to the detrimental loss of kidney cells. Indeed, pathways of regulated cell death - including apoptosis and necrosis - have emerged as central events in the pathogenesis of various kidney diseases that may be amenable to therapeutic intervention. Modes of regulated necrosis, such as ferroptosis, necroptosis and pyroptosis may cause kidney injury directly or through the recruitment of immune cells and stimulation of inflammatory responses. Importantly, multiple layers of interconnections exist between different modalities of regulated cell death, including shared triggers, molecular components and protective mechanisms.
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Affiliation(s)
- Ana B Sanz
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain
- RICORS2040, Madrid, Spain
| | - Maria Dolores Sanchez-Niño
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain
- RICORS2040, Madrid, Spain
- Departamento de Medicina, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | - Adrian M Ramos
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain
- RICORS2040, Madrid, Spain
| | - Alberto Ortiz
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain.
- RICORS2040, Madrid, Spain.
- Departamento de Farmacología, Universidad Autonoma de Madrid, Madrid, Spain.
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Li HB, Mo YS, Zhang XZ, Zhou Q, Liang XD, Song JN, Hou LN, Wu JN, Guo Y, Feng DD, Sun Y, Yu JB. Heme oxygenase‑1 inhibits renal tubular epithelial cell pyroptosis by regulating mitochondrial function through PINK1. Exp Ther Med 2023; 25:213. [PMID: 37123216 PMCID: PMC10133796 DOI: 10.3892/etm.2023.11912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 02/24/2023] [Indexed: 05/02/2023] Open
Abstract
Endotoxin-induced acute kidney injury (AKI) is commonly observed in clinical practice. Renal tubular epithelial cell (RTEC) pyroptosis is one of the main factors leading to the development of endotoxin-induced AKI. Mitochondrial dysfunction can lead to pyroptosis. However, the biological pathways involved in the potential lipopolysaccharide (LPS)-induced pyroptosis of RTECs, notably those associated with mitochondrial dysfunction, are poorly understood. Previous studies have demonstrated that heme oxygenase (HO)-1 confers cell protection via the induction of PTEN-induced putative kinase 1 (PINK1) expression through PTEN to regulate mitochondrial fusion/fission during endotoxin-induced AKI in vivo. Therefore, the present study investigated the role of HO-1/PINK1 in maintaining mitochondrial function and inhibiting the pyroptosis of RTECs exposed to LPS. Primary cultures of RTECs were obtained from wild-type (WT) and PINK1-knockout (PINK1KO) rats. An in vitro model of endotoxin-associated RTEC injury was established following treatment of the cells with LPS. The WT RTECs were divided into the control, LPS, Znpp + LPS and Hemin + LPS groups, and the PINK1KO RTECs were divided into the control, LPS and Hemin + LPS groups. RTECs were exposed to LPS for 6 h to assess cell viability, inflammation, pyroptosis and mitochondrial function. In the LPS-treated RTECs, the mRNA and protein expression levels of HO-1 and PINK1 were upregulated. Cell viability, adenosine triphosphate (ATP) levels and the mitochondrial oxygen consumption rate were decreased, whereas the inflammatory response, pyroptosis and mitochondrial reactive oxygen species (ROS) levels were increased. The cell inflammatory response and the induction of pyroptosis were inhibited, whereas the levels of mitochondrial ROS were decreased. In addition, the cell viability and ATP levels were increased in the WT RTECs following the upregulation of HO-1 expression. These effects were reversed by the downregulation of HO-1 expression. However, no statistically significant differences were noted between the LPS and the Hemin + LPS groups in the PINK1KO RTECs. Collectively, the findings of the present study indicate that HO-1 inhibits inflammation and regulates mitochondrial function by inhibiting the pyroptosis of LPS-exposed RTECs via PINK1.
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Affiliation(s)
- Hai-Bo Li
- Department of Anesthesiology, Chifeng Municipal Hospital, Chifeng, Inner Mongolia 024000, P.R. China
| | - Yan-Shuai Mo
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300102, P.R. China
| | - Xi-Zhe Zhang
- Department of Anesthesiology, Chifeng Municipal Hospital, Chifeng, Inner Mongolia 024000, P.R. China
| | - Qi Zhou
- Department of Anesthesiology, Chifeng Municipal Hospital, Chifeng, Inner Mongolia 024000, P.R. China
| | - Xiao-Dong Liang
- Department of Anesthesiology, Chifeng Municipal Hospital, Chifeng, Inner Mongolia 024000, P.R. China
| | - Jian-Nan Song
- Department of Anesthesiology, Chifeng Municipal Hospital, Chifeng, Inner Mongolia 024000, P.R. China
| | - Li-Na Hou
- Department of Anesthesiology, Chifeng Municipal Hospital, Chifeng, Inner Mongolia 024000, P.R. China
| | - Jian-Nan Wu
- Department of Anesthesiology, Chifeng Municipal Hospital, Chifeng, Inner Mongolia 024000, P.R. China
| | - Ying Guo
- Department of Anesthesiology, Chifeng Municipal Hospital, Chifeng, Inner Mongolia 024000, P.R. China
| | - Dan-Dan Feng
- Department of Anesthesiology, Chifeng Municipal Hospital, Chifeng, Inner Mongolia 024000, P.R. China
| | - Yi Sun
- Department of Anesthesiology, Chifeng Municipal Hospital, Chifeng, Inner Mongolia 024000, P.R. China
| | - Jian-Bo Yu
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300102, P.R. China
- Correspondence to: Professor Jian-Bo Yu, Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, 102 Sanwei Road, Nankai, Tianjin 300102, P.R. China
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21
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Ding L, Yin J, Xu X, Xie D, Xiang D, Tong P, Liu S, Yang X. Bufalin alleviates acute kidney injury by regulating NLRP3 inflammasome-mediated pyroptosis. Apoptosis 2023; 28:539-548. [PMID: 36652129 DOI: 10.1007/s10495-023-01815-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/05/2023] [Indexed: 01/19/2023]
Abstract
BACKGROUND Recently, there has been an increasing clinical incidence of acute kidney injury (AKI), which rapidly declines renal function and leads to massive tubular cell necrosis. Pyroptosis is an inflammatory process of cell death that is more rapid than apoptosis, which is accompanied by a massive release of inflammasome activation. In the study, we aim to explore whether Bufalin regulates the AKI through the pyroptosis pathway. METHODS We have established gentamicin (GM)-induced AKI animal and cell models to simulate the pathological conditions of kidney injury. The expression of renal injury and pyroptosis-related indicators were detected by western blot. PAS staining and IHC staining were used to analyze renal function. CCK-8 assay was performed to detect cell viability after AKI with different treatments. TUNEL staining, flow cytometry and immunofluorescence assays were performed to measure pyroptosis. RESULTS After intraperitoneal injection of GM in rats, renal function was significantly decreased, along with a significant increase of damaged and necrotic cells as suggested by renal tubular epithelial tissue sections. In addition, there was an increase in the pyroptosis-related markers expression and pyroptosis-induced cell death. Consistently, studies in vitro found that GM significantly induced pyroptosis and its associated protein expression in NRK52e cells. Whereas, the administration of Bufalin reversed these effects of GM in vivo and in vitro. Further, we found that Nigericin (NLRP3 agonist) could reversed the effects of bufalin on GM-induced pyroptosis. CONCLUSION Bufalin attenuates pyroptosis generated AKI by inhibiting NLRP3 inflammasome.
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Affiliation(s)
- Ling Ding
- Department of Pediatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jie Yin
- Infectious Department, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xueping Xu
- Department of Pediatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dan Xie
- Department of Pediatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dongxiao Xiang
- Department of Pediatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Pingfan Tong
- Department of Pediatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shuyu Liu
- Department of General Practice, The Fourth Affiliated Hospital of Nanjing Medical University, 298 Nanpu road, Jiangbei New District, Nanjing, Jiangsu, China
| | - Xilan Yang
- Department of General Practice, The Fourth Affiliated Hospital of Nanjing Medical University, 298 Nanpu road, Jiangbei New District, Nanjing, Jiangsu, China.
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22
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Shao Y, Li C, Jiang Y, Li H, Tang X, Gao Z, Zhang D. Inhibition of Caspase-11-Mediated Pyroptosis Alleviates Acute Kidney Injury Associated with Severe Acute Pancreatitis in Rats. J INVEST SURG 2023; 36:1-7. [DOI: 10.1080/08941939.2022.2142868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Yang Shao
- Qingdao Medical College, Qingdao University, Qingdao, Shandong Province, China
- Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
| | - Chang Li
- Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
| | - Yingjian Jiang
- Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
| | - Hongbo Li
- Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
| | - Xuefei Tang
- Qingdao Medical College, Qingdao University, Qingdao, Shandong Province, China
- Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
| | - Zhaoyu Gao
- Qingdao Medical College, Qingdao University, Qingdao, Shandong Province, China
- Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
| | - Dianliang Zhang
- Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
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23
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Quaglia M, Fanelli V, Merlotti G, Costamagna A, Deregibus MC, Marengo M, Balzani E, Brazzi L, Camussi G, Cantaluppi V. Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury. Biomedicines 2022; 10:biomedicines10102448. [PMID: 36289710 PMCID: PMC9598620 DOI: 10.3390/biomedicines10102448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/25/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Extracellular vesicles form a complex intercellular communication network, shuttling a variety of proteins, lipids, and nucleic acids, including regulatory RNAs, such as microRNAs. Transfer of these molecules to target cells allows for the modulation of sets of genes and mediates multiple paracrine and endocrine actions. EVs exert broad pro-inflammatory, pro-oxidant, and pro-apoptotic effects in sepsis, mediating microvascular dysfunction and multiple organ damage. This deleterious role is well documented in sepsis-associated acute kidney injury and acute respiratory distress syndrome. On the other hand, protective effects of stem cell-derived extracellular vesicles have been reported in experimental models of sepsis. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, regenerative, and immunomodulatory properties of parental cells and have shown therapeutic effects in experimental models of sepsis with kidney and lung involvement. Extracellular vesicles are also likely to play a role in deranged kidney-lung crosstalk, a hallmark of sepsis, and may be key to a better understanding of shared mechanisms underlying multiple organ dysfunction. In this review, we analyze the state-of-the-art knowledge on the dual role of EVs in sepsis-associated kidney/lung injury and repair. PubMed library was searched from inception to July 2022, using a combination of medical subject headings (MeSH) and keywords related to EVs, sepsis, acute kidney injury (AKI), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Key findings are summarized into two sections on detrimental and beneficial mechanisms of actions of EVs in kidney and lung injury, respectively. The role of EVs in kidney-lung crosstalk is then outlined. Efforts to expand knowledge on EVs may pave the way to employ them as prognostic biomarkers or therapeutic targets to prevent or reduce organ damage in sepsis.
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Affiliation(s)
- Marco Quaglia
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
| | - Vito Fanelli
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | - Guido Merlotti
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
| | - Andrea Costamagna
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | | | - Marita Marengo
- Nephrology and Dialysis Unit, ASL CN1, 12038 Savigliano, Italy
| | - Eleonora Balzani
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | - Luca Brazzi
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
- Correspondence: (G.C.); (V.C.)
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
- Correspondence: (G.C.); (V.C.)
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24
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Cao Z, Huang D, Tang C, Lu Y, Huang S, Peng C, Hu X. Pyroptosis in diabetes and diabetic nephropathy. Clin Chim Acta 2022; 531:188-196. [DOI: 10.1016/j.cca.2022.04.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 12/14/2022]
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25
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Wang G, Wei W, Jiang Z, Jiang J, Han J, Zhang H, Hu J, Zhang P, Li X, Chen T, He J, Li Z, Lai J, Liang H, Ning C, Ye L. Talaromyces marneffei activates the AIM2-caspase-1/-4-GSDMD axis to induce pyroptosis in hepatocytes. Virulence 2022; 13:963-979. [PMID: 35639503 PMCID: PMC9176249 DOI: 10.1080/21505594.2022.2080904] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Talaromyces marneffei tends to induce systemic infection in immunocompromised individuals, which is one of the causes of the high mortality. The underlying molecular mechanisms of T.marneffei-induced abnormal liver function are still poorly understood. In this study, we found that T.marneffei-infected patients could develop abnormal liver function, evidenced by reduced albumin and increased levels of aspartate aminotransferase (AST) and AST/alanine aminotransferase (ALT). T. marneffei-infected mice exhibited similar characteristics. In vitro investigations showed that T.marneffei induced the death of AML-12 cells. Furthermore, we determined that T.marneffei infection induced pyroptosis in hepatocytes of C57BL/6J mice and AML-12 cells, demonstrated by the increase of AIM2, caspase-1/-4, Gasdermin D(GSDMD) and pyroptosis-related cytokines in T.marneffei-infected mice/cells. Importantly, cell death was markedly suppressed in the presence of VX765 (an inhibitor of caspase-1/-4). Furthermore, in the presence of VX765, T.marneffei-induced pyroptosis was blocked. Nevertheless, necroptosis and apoptosis were also detected in infected animal model at 14 days post-infection. In conclusion, T.marneffei induces pyroptosis in hepatocytes through activation of the AIM2-caspase-1/-4-GSDMD axis, which may be an important cause of liver damage, and other death pathways including necroptosis and apoptosis may also be involved in the later stage of infection.
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Affiliation(s)
- Gang Wang
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Wudi Wei
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Zhongsheng Jiang
- Department of Infectious Diseases, Liuzhou People's Hospital, Liuzhou, Guangxi, China
| | - Junjun Jiang
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Guangxi Collaborative Innovation Center for Biomedicine, Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Jing Han
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Guangxi Collaborative Innovation Center for Biomedicine, Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Hong Zhang
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Guangxi Collaborative Innovation Center for Biomedicine, Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Jiaguang Hu
- Department of Infectious Diseases, Liuzhou People's Hospital, Liuzhou, Guangxi, China
| | - Peng Zhang
- Department of Infectious Diseases, Liuzhou People's Hospital, Liuzhou, Guangxi, China
| | - Xu Li
- Department of Infectious Diseases, Liuzhou People's Hospital, Liuzhou, Guangxi, China
| | - Tao Chen
- Department of Infectious Diseases, Liuzhou People's Hospital, Liuzhou, Guangxi, China
| | - Jinhao He
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Guangxi Collaborative Innovation Center for Biomedicine, Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Zhen Li
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Guangxi Collaborative Innovation Center for Biomedicine, Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Jingzhen Lai
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Guangxi Collaborative Innovation Center for Biomedicine, Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Hao Liang
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Guangxi Collaborative Innovation Center for Biomedicine, Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Chuanyi Ning
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Nursing College, Guangxi Medical University, Nanning, Guangxi, China
| | - Li Ye
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
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26
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Wu Z, Deng J, Zhou H, Tan W, Lin L, Yang J. Programmed Cell Death in Sepsis Associated Acute Kidney Injury. Front Med (Lausanne) 2022; 9:883028. [PMID: 35655858 PMCID: PMC9152147 DOI: 10.3389/fmed.2022.883028] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 03/21/2022] [Indexed: 01/15/2023] Open
Abstract
Sepsis-associated acute kidney injury (SA-AKI) is common in patients with severe sepsis, and has a high incidence rate and high mortality rate in ICU patients. Most patients progress to AKI before drug treatment is initiated. Early studies suggest that the main mechanism of SA-AKI is that sepsis leads to vasodilation, hypotension and shock, resulting in insufficient renal blood perfusion, finally leading to renal tubular cell ischemia and necrosis. Research results in recent years have shown that programmed cell death such as apoptosis, necroptosis, pyroptosis and autophagy play important roles. In the early stage of sepsis-related AKI, autophagy bodies form and inhibit various types of programmed cell death. With the progress of disease, programmed cell death begins. Apoptosis promoter represents caspase-8-induced apoptosis and apoptosis effector represents caspase-3-induced apoptosis, however, caspase-11 and caspase-1 regulate gasdermin D-mediated pyroptosis. Caspase-8 and receptor interacting kinase 1 bodies mediate necroptosis. This review focuses on the pathophysiological mechanisms of various programmed cell death in sepsis-related AKI.
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Affiliation(s)
- Zhifen Wu
- Department of Nephrology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Junhui Deng
- Department of Nephrology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hongwen Zhou
- Department of Nephrology, Chongqing Liangping District People's Hospital, Chongqing, China
| | - Wei Tan
- Department of Nephrology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lirong Lin
- Department of Nephrology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jurong Yang
- Department of Nephrology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
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27
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Xu J, Wang Q, Song YF, Xu XH, Zhu H, Chen PD, Ren YP. Long noncoding RNA X-inactive specific transcript regulates NLR family pyrin domain containing 3/caspase-1-mediated pyroptosis in diabetic nephropathy. World J Diabetes 2022; 13:358-375. [PMID: 35582664 PMCID: PMC9052004 DOI: 10.4239/wjd.v13.i4.358] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 01/24/2022] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND NLRP3-mediated pyroptosis is recognized as an essential modulator of renal disease pathology. Long noncoding RNAs (lncRNAs) are active participators of diabetic nephropathy (DN). X inactive specific transcript (XIST) expression has been reported to be elevated in the serum of DN patients.
AIM To evaluate the mechanism of lncRNA XIST in renal tubular epithelial cell (RTEC) pyroptosis in DN.
METHODS A DN rat model was established through streptozotocin injection, and XIST was knocked down by tail vein injection of the lentivirus LV sh-XIST. Renal metabolic and biochemical indices were detected, and pathological changes in the renal tissue were assessed. The expression of indicators related to inflammation and pyroptosis was also detected. High glucose (HG) was used to treat HK2 cells, and cell viability and lactate dehydrogenase (LDH) activity were detected after silencing XIST. The subcellular localization and downstream mechanism of XIST were investigated. Finally, a rescue experiment was carried out to verify that XIST regulates NLR family pyrin domain containing 3 (NLRP3)/caspase-1-mediated RTEC pyroptosis through the microRNA-15-5p (miR-15b-5p)/Toll-like receptor 4 (TLR4) axis.
RESULTS XIST was highly expressed in the DN models. XIST silencing improved renal metabolism and biochemical indices and mitigated renal injury. The expression of inflammation and pyroptosis indicators was significantly increased in DN rats and HG-treated HK2 cells; cell viability was decreased and LDH activity was increased after HG treatment. Silencing XIST inhibited RTEC pyroptosis by inhibiting NLRP3/caspase-1. Mechanistically, XIST sponged miR-15b-5p to regulate TLR4. Silencing XIST inhibited TLR4 by promoting miR-15b-5p. miR-15b-5p inhibition or TLR4 overexpression averted the inhibitory effect of silencing XIST on HG-induced RTEC pyroptosis.
CONCLUSION Silencing XIST inhibits TLR4 by upregulating miR-15b-5p and ultimately inhibits renal injury in DN by inhibiting NLRP3/caspase-1-mediated RTEC pyroptosis.
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Affiliation(s)
- Jia Xu
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen 518000, Guangdong Province, China
| | - Qin Wang
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yi-Fan Song
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen 518000, Guangdong Province, China
| | - Xiao-Hui Xu
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen 518000, Guangdong Province, China
| | - He Zhu
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen 518000, Guangdong Province, China
| | - Pei-Dan Chen
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen 518000, Guangdong Province, China
| | - Ye-Ping Ren
- Department of Nephrology, Shenzhen University General Hospital, Shenzhen 518000, Guangdong Province, China
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28
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Chen Y, Jing H, Tang S, Liu P, Cheng Y, Fan Y, Chen H, Zhou J. Non-Coding RNAs in Sepsis-Associated Acute Kidney Injury. Front Physiol 2022; 13:830924. [PMID: 35464083 PMCID: PMC9024145 DOI: 10.3389/fphys.2022.830924] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 03/08/2022] [Indexed: 11/21/2022] Open
Abstract
Sepsis is a systemic inflammatory response caused by a severe infection that leads to multiple organ damage, including acute kidney injury (AKI). In intensive care units (ICU), the morbidity and mortality associated with sepsis-associated AKI (SA-AKI) are gradually increasing due to lack of effective and early detection, as well as proper treatment. Non-coding RNAs (ncRNAs) exert a regulatory function in gene transcription, RNA processing, post-transcriptional translation, and epigenetic regulation of gene expression. Evidence indicated that miRNAs are involved in inflammation and programmed cell death during the development of sepsis-associated AKI (SA-AKI). Moreover, lncRNAs and circRNAs appear to be an essential regulatory mechanism in SA-AKI. In this review, we summarized the molecular mechanism of ncRNAs in SA-AKI and discussed their potential in clinical diagnosis and treatment.
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Affiliation(s)
- Yanna Chen
- Department of Anesthesiology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Huan Jing
- Department of Anesthesiology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Simin Tang
- Department of Anesthesiology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Pei Liu
- Department of Anesthesiology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Ye Cheng
- Department of Anesthesiology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Youling Fan
- Department of Anesthesiology, The First People’s Hospital of Kashgar, Xinjiang, China
- Department of Anesthesiology, The Second People’s Hospital of Panyu, Guangzhou, China
| | - Hongtao Chen
- Department of Anesthesiology, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jun Zhou
- Department of Anesthesiology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
- *Correspondence: Jun Zhou,
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Duan X, Song Y, Li F, Liao Y, Liu W. Metadherin silencing results in the inhibition of pyroptosis in lipopolysaccharide/adenosine triphosphate - stimulated renal tubular epithelial cells. Tissue Cell 2022; 75:101722. [PMID: 35026615 DOI: 10.1016/j.tice.2021.101722] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 12/02/2021] [Accepted: 12/23/2021] [Indexed: 10/19/2022]
Abstract
Pyroptosis is induced following inflammation via activation of the NLRP3 inflammasome. Lipopolysaccharide (LPS)-induced acute inflammation causes pyroptosis in renal tubular epithelial cells, which aggravates kidney damage and is involved in physiopathological processes in multiple renal diseases. Metadherin (Mtdh) induces inflammation by NLRP3 inflammasome activation. Specifically, it induces inflammatory injury in the kidney by activating the nuclear factor kappa B (NF-κB) signaling pathway, which is involved in NLRP3 inflammasome activation. However, the role of Mtdh in pyroptosis in renal tubular epithelial cells is unclear. Therefore, we investigated whether Mtdh participates in pyroptosis in LPS/adenosine triphosphate (ATP)-treated NRK-52E cells by activating the NLRP3 inflammasome and NF-κB signaling pathway. We induced pyroptosis in NRK-52E cells with LPS/ATP, after which Mtdh was silenced via transfection with small interfering RNA. LPS/ATP upregulated Mtdh expression and induced pyroptosis and NLRP3 inflammasome activation in NRK-52E cells. However, downregulation of Mtdh expression resulted in the alleviation of pyroptosis in LPS/ATP-treated NRK-52E cells. Additionally, activation of the NLRP3 inflammasome and NF-κB signaling pathway was inhibited. This demonstrates that downregulation of Mtdh expression results in the inhibition of pyroptosis in LPS/ATP-treated NRK-52E cells through the suppression of NLRP3 inflammasome activation, which occurs via inhibition of the NF-κB signaling pathway.
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Affiliation(s)
- Xiuping Duan
- Department of Nephrology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530022, China
| | - Yashan Song
- Department of Nephrology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530022, China
| | - Fuji Li
- Department of Nephrology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530022, China
| | - Yunhua Liao
- Department of Nephrology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530022, China.
| | - Wenting Liu
- Department of Nephrology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530022, China.
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30
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Gao M, Li H, Liu Q, Ma N, Zi P, Shi H, Du Y. KLF6 Promotes Pyroptosis of Renal Tubular Epithelial Cells in Septic Acute Kidney Injury. Shock 2022; 57:417-426. [PMID: 34710881 DOI: 10.1097/shk.0000000000001881] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
ABSTRACT Septic acute kidney injury (SAKI) represents a clinical challenge with high morbidity and mortality. The current study aimed to analyze the effects and molecular mechanism of Krüppel-like factor 6 (KLF6) on SAKI. First, SAKI mouse models were established by cecum ligation and puncture, while in vivo cell models were established using lipopolysaccharide (LPS). RT-qPCR assay was subsequently performed to detect the levels of KLF6 mRNA. SAKI mice and LPS-treated TCMK-1 cells were further treated with KLF6 siRNA. Afterward, HE staining, PAS staining, Western blot assay, and ELISA were adopted to ascertain the effects of KLF6 in pyroptosis. The binding relationships between KLF6 and miR-223-3p promoter /miR-223-3p and NLRP3 were analyzed with the help of CHIP and dual-luciferase reporter assays. RT-qPCR was adopted to determine the expression patterns of miR-223-3p and NLRP3. Lastly, a rescue experiment was designed to confirm the role of miR-223-3p. It was found that KLF6 was highly expressed in SAKI, whereas knockdown of KLF6 alleviated oxidative stress (OS) and pyroptosis in SAKI mice and LPS-treated TCMK-1 cells. Mechanistic results confirmed that KLF6 inhibited miR-223-3p via binding to the miR-223-3p promoter and promoted NLRP3. On the other hand, downregulation of miR-223-3p activated the NLRP3/Caspase-1/IL-1β pathway and aggravated OS and pyroptosis. Overall, our findings indicated that KLF6 inhibited miR-223-3p via binding to the miR-223-3p promoter and promoted NLRP3, and activated the NLRP3/Caspase-1/IL-1β pathway, thereby aggravating pyroptosis and SAKI.
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Affiliation(s)
- Min Gao
- Department of Critical Care Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Sun J, Ge X, Wang Y, Niu L, Tang L, Pan S. USF2 knockdown downregulates THBS1 to inhibit the TGF-β signaling pathway and reduce pyroptosis in sepsis-induced acute kidney injury. Pharmacol Res 2022; 176:105962. [PMID: 34756923 DOI: 10.1016/j.phrs.2021.105962] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 10/20/2021] [Accepted: 10/25/2021] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Acute kidney injury (AKI) is a serious complication of sepsis. This study was performed to explore the mechanism that THBS1 mediated pyroptosis by regulating the TGF-β signaling pathway in sepsis-induced AKI. METHODS Gene expression microarray related to sepsis-induced AKI was obtained from the GEO database, and the mechanism in sepsis-induced AKI was predicted by bioinformatics analysis. qRT-PCR and ELISA were performed to detect expressions of THBS1, USF2, TNF-α, IL-1β, and IL-18 in sepsis-induced AKI patients and healthy volunteers. The mouse model of sepsis-induced AKI was established, with serum creatinine, urea nitrogen, 24-h urine output measured, and renal tissue lesions observed by HE staining. The cell model of sepsis-induced AKI was cultured in vitro, with expressions of TNF-α, IL-1β, and IL-18, pyroptosis, Caspase-1 and GSDMD-N, and activation of TGF-β/Smad3 pathway detected. The upstream transcription factor USF2 was knocked down in cells to explore its effect on sepsis-induced AKI. RESULTS THBS1 and USF2 were highly expressed in patients with sepsis-induced AKI. Silencing THBS1 protected mice against sepsis-induced AKI, and significantly decreased the expressions of NLRP3, Caspase-1, GSDMD-N, IL-1β, and IL-18, increased cell viability, and decreased LDH activity, thus partially reversing the changes in cell morphology. Mechanistically, USF2 promoted oxidative stress responses by transcriptionally activating THBS1 to activate the TGF-β/Smad3/NLRP3/Caspase-1 signaling pathway and stimulate pyroptosis, and finally exacerbated sepsis-induced AKI. CONCLUSION USF2 knockdown downregulates THBS1 to inhibit the TGF-β/Smad3 signaling pathway and reduce pyroptosis and further ameliorate sepsis-induced AKI.
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Affiliation(s)
- Jian Sun
- Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Yangpu District, Shanghai 518110, China
| | - Xiaoli Ge
- Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Yangpu District, Shanghai 518110, China
| | - Yang Wang
- Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Yangpu District, Shanghai 518110, China
| | - Lei Niu
- Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Yangpu District, Shanghai 518110, China
| | - Lujia Tang
- Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Yangpu District, Shanghai 518110, China
| | - Shuming Pan
- Department of Emergency, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Yangpu District, Shanghai 518110, China.
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Aranda-Rivera AK, Srivastava A, Cruz-Gregorio A, Pedraza-Chaverri J, Mulay SR, Scholze A. Involvement of Inflammasome Components in Kidney Disease. Antioxidants (Basel) 2022; 11:246. [PMID: 35204131 PMCID: PMC8868482 DOI: 10.3390/antiox11020246] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/21/2022] [Accepted: 01/22/2022] [Indexed: 02/01/2023] Open
Abstract
Inflammasomes are multiprotein complexes with an important role in the innate immune response. Canonical activation of inflammasomes results in caspase-1 activation and maturation of cytokines interleukin-1β and -18. These cytokines can elicit their effects through receptor activation, both locally within a certain tissue and systemically. Animal models of kidney diseases have shown inflammasome involvement in inflammation, pyroptosis and fibrosis. In particular, the inflammasome component nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) and related canonical mechanisms have been investigated. However, it has become increasingly clear that other inflammasome components are also of importance in kidney disease. Moreover, it is becoming obvious that the range of molecular interaction partners of inflammasome components in kidney diseases is wide. This review provides insights into these current areas of research, with special emphasis on the interaction of inflammasome components and redox signalling, endoplasmic reticulum stress, and mitochondrial function. We present our findings separately for acute kidney injury and chronic kidney disease. As we strictly divided the results into preclinical and clinical data, this review enables comparison of results from those complementary research specialities. However, it also reveals that knowledge gaps exist, especially in clinical acute kidney injury inflammasome research. Furthermore, patient comorbidities and treatments seem important drivers of inflammasome component alterations in human kidney disease.
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Affiliation(s)
- Ana Karina Aranda-Rivera
- Laboratory F-315, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico; (A.K.A.-R.); (A.C.-G.); (J.P.-C.)
| | - Anjali Srivastava
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; (A.S.); (S.R.M.)
| | - Alfredo Cruz-Gregorio
- Laboratory F-315, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico; (A.K.A.-R.); (A.C.-G.); (J.P.-C.)
| | - José Pedraza-Chaverri
- Laboratory F-315, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico; (A.K.A.-R.); (A.C.-G.); (J.P.-C.)
| | - Shrikant R. Mulay
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; (A.S.); (S.R.M.)
| | - Alexandra Scholze
- Department of Nephrology, Odense University Hospital, Odense, Denmark, and Institute of Clinical Research, University of Southern Denmark, 5000 Odense C, Denmark
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Li C, Wang W, Xie SS, Ma WX, Fan QW, Chen Y, He Y, Wang JN, Yang Q, Li HD, Jin J, Liu MM, Meng XM, Wen JG. The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI. Front Med (Lausanne) 2021; 8:796724. [PMID: 34926535 PMCID: PMC8674574 DOI: 10.3389/fmed.2021.796724] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022] Open
Abstract
Sepsis is a systemic inflammatory response syndrome caused by infection, following with acute injury to multiple organs. Sepsis-induced acute kidney injury (AKI) is currently recognized as one of the most severe complications related to sepsis. The pathophysiology of sepsis-AKI involves multiple cell types, including macrophages, vascular endothelial cells (ECs) and renal tubular epithelial cells (TECs), etc. More significantly, programmed cell death including apoptosis, necroptosis and pyroptosis could be triggered by sepsis in these types of cells, which enhances AKI progress. Moreover, the cross-talk and connections between these cells and cell death are critical for better understanding the pathophysiological basis of sepsis-AKI. Mitochondria dysfunction and oxidative stress are traditionally considered as the leading triggers of programmed cell death. Recent findings also highlight that autophagy, mitochondria quality control and epigenetic modification, which interact with programmed cell death, participate in the damage process in sepsis-AKI. The insightful understanding of the programmed cell death in sepsis-AKI could facilitate the development of effective treatment, as well as preventive methods.
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Affiliation(s)
- Chao Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines (Ministry of Education), Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Wei Wang
- Anhui Province Key Laboratory of Genitourinary Diseases, Department of Urology and Institute of Urology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China
| | - Shuai-Shuai Xie
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines (Ministry of Education), Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Wen-Xian Ma
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines (Ministry of Education), Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Qian-Wen Fan
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines (Ministry of Education), Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Ying Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines (Ministry of Education), Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yuan He
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines (Ministry of Education), Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jia-Nan Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines (Ministry of Education), Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Qin Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines (Ministry of Education), Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Hai-di Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines (Ministry of Education), Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Juan Jin
- Key Laboratory of Anti-inflammatory and Immunopharmacology (Ministry of Education), Department of Pharmacology, Anhui Medical University, Hefei, China
| | - Ming-Ming Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines (Ministry of Education), Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines (Ministry of Education), Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jia-Gen Wen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines (Ministry of Education), Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
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Li N, Wang Y, Wang X, Sun N, Gong YH. Pathway network of pyroptosis and its potential inhibitors in acute kidney injury. Pharmacol Res 2021; 175:106033. [PMID: 34915124 DOI: 10.1016/j.phrs.2021.106033] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 12/18/2022]
Abstract
Acute kidney injury (AKI) is a worldwide problem, and there is no effective drug to eliminate AKI. The death of renal cells is an important pathological basis of intrinsic AKI. At present, targeted therapy for TEC death is a research hotspot in AKI therapy. There are many ways of cell death involved in the occurrence and development of AKI, such as apoptosis, necrosis, ferroptosis, and pyroptosis. This article mainly focuses on the role of pyroptosis in AKI. The assembly and activation of NLRP3 inflammasome is a key event in the occurrence of pyroptosis, which is affected by many factors, such as the activation of the NF-κB signaling pathway, mitochondrial instability and excessive endoplasmic reticulum (ER) stress. The activation of NLRP3 inflammasome can trigger its downstream inflammatory cytokines, which will lead to pyroptosis and eventually induce AKI. In this paper, we reviewed the possible mechanism of pyroptosis in AKI and the potential effective inhibitors of various key targets in this process. It may provide potential therapeutic targets for novel intrinsic AKI therapies based on pyroptosis, so as to develop better therapeutic strategies.
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Affiliation(s)
- Ning Li
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300350, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China; Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou 325000, China
| | - Yuru Wang
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China; Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou 325000, China
| | - Xinyue Wang
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China; Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou 325000, China
| | - Na Sun
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China; Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou 325000, China
| | - Yan-Hua Gong
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China; Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou 325000, China.
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Dai S, Ye B, Zhong L, Chen Y, Hong G, Zhao G, Su L, Lu Z. GSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation. Front Cell Dev Biol 2021; 9:779432. [PMID: 34820388 PMCID: PMC8606561 DOI: 10.3389/fcell.2021.779432] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 10/22/2021] [Indexed: 01/06/2023] Open
Abstract
Myocardial dysfunction is a serious consequence of sepsis and contributes to high mortality. Currently, the molecular mechanism of myocardial dysfunction induced by sepsis remains unclear. In the present study, we investigated the role of gasdermin D (GSDMD) in cardiac dysfunction in septic mice and the underlying mechanism. C57BL/6 wild-type (WT) mice and age-matched Gsdmd-knockout (Gsdmd -/-) mice were intraperitoneally injected with lipopolysaccharide (LPS) (10 mg/kg) to mimic sepsis. The results showed that GSDMD-NT, the functional fragment of GSDMD, was upregulated in the heart tissue of septic WT mice induced by LPS, which was accompanied by decreased cardiac function and myocardial injury, as shown by decreased ejection fraction (EF) and fractional shortening (FS) and increased cardiac troponin I (cTnI), creatine kinase isoenzymes MB (CK-MB), and lactate dehydrogenase (LDH). Gsdmd -/- mice exhibited protection against LPS-induced myocardial dysfunction and had a higher survival rate. Gsdmd deficiency attenuated LPS-induced myocardial injury and cell death. Gsdmd deficiency prevented LPS-induced the increase of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in serum, as well as IL-1β and TNF-α mRNA levels in myocardium. In addition, LPS-mediated inflammatory cell infiltration into the myocardium was ameliorated and activation of NF-κB signaling pathway and the NOD-like receptor protein 3 (NLPR3) inflammasome were suppressed in Gsdmd -/- mice. Further research showed that in the myocardium of LPS-induced septic mice, GSDMD-NT enrichment in mitochondria led to mitochondrial dysfunction and reactive oxygen species (ROS) overproduction, which further regulated the activation of the NLRP3 inflammasome. In summary, our data suggest that GSDMD plays a vital role in the pathophysiology of LPS-induced myocardial dysfunction and may be a crucial target for the prevention and treatment of sepsis-induced myocardial dysfunction.
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Affiliation(s)
- Shanshan Dai
- The Key Laboratory of Emergency and Disaster Medicine of Wenzhou, Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Bozhi Ye
- The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lingfeng Zhong
- The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yanghao Chen
- The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guangliang Hong
- The Key Laboratory of Emergency and Disaster Medicine of Wenzhou, Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guangju Zhao
- The Key Laboratory of Emergency and Disaster Medicine of Wenzhou, Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lan Su
- The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhongqiu Lu
- The Key Laboratory of Emergency and Disaster Medicine of Wenzhou, Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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An Epigenetic Insight into NLRP3 Inflammasome Activation in Inflammation-Related Processes. Biomedicines 2021; 9:biomedicines9111614. [PMID: 34829842 PMCID: PMC8615487 DOI: 10.3390/biomedicines9111614] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/25/2021] [Accepted: 10/29/2021] [Indexed: 12/13/2022] Open
Abstract
Aberrant NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome activation in innate immune cells, triggered by diverse cellular danger signals, leads to the production of inflammatory cytokines (IL-1β and IL-18) and cell death by pyroptosis. These processes are involved in the pathogenesis of a wide range of diseases such as autoimmune, neurodegenerative, renal, metabolic, vascular diseases and cancer, and during physiological processes such as aging. Epigenetic dynamics mediated by changes in DNA methylation patterns, chromatin assembly and non-coding RNA expression are key regulators of the expression of inflammasome components and its further activation. Here, we review the role of the epigenome in the expression, assembly, and activation of the NLRP3 inflammasome, providing a critical overview of its involvement in the disease and discussing how targeting these mechanisms by epigenetic treatments could be a useful strategy for controlling NLRP3-related inflammatory diseases.
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Mechanisms of Kidney Cell Pyroptosis in Chronic Kidney Disease and the Effects of Traditional Chinese Medicine. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:1173324. [PMID: 34671403 PMCID: PMC8523237 DOI: 10.1155/2021/1173324] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 09/01/2021] [Accepted: 09/17/2021] [Indexed: 12/19/2022]
Abstract
Chronic kidney disease (CKD) is a major public health issue that is highly prevalent worldwide. Pyroptosis is an important pathological mechanism underlying kidney cell damage in CKD and is associated with the classic caspase-1-mediated pathway and nonclassic caspase-4/5/11-mediated pathway. The NLRP3-caspase-1-GSDMD signaling pathway is the key mechanism of kidney cell pyroptosis in CKD, and noncoding RNAs such as lncRNAs and miRNAs are important regulators of kidney cell pyroptosis in CKD. In addition, the NLRP1/AIM2-caspase-1-GSDMD and caspase-3-GSDME signaling pathways have also been shown to mediate kidney cell pyroptosis. Traditional Chinese medicine (TCM) and extracts can interfere with the occurrence and development of kidney cell pyroptosis in CKD by inhibiting the NLRP3 signaling pathway and oxidative stress, activating Nrf-2 signaling, protecting mitochondrial integrity, regulating AMPK signaling, and regulating TXNIP/NLRP3 axis, which have become increasingly prominent. It is critical to explore the effects of TCM on kidney cell pyroptosis in CKD and its mechanisms to identify targets and develop new and effective drugs.
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Zhang H, Yang T. FBXW7alpha Promotes the Recovery of Traumatic Spinal Cord. Curr Mol Med 2021; 20:494-504. [PMID: 31870261 DOI: 10.2174/1566524020666191223164916] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 11/20/2019] [Accepted: 12/12/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND White matter damage and neuronal cell death are incurred by spinal cord injury (SCI). FBXW7α, an important mediator of cell division and growth was investigated to explore its role in repairing the traumatic spinal cord in rats. Underlying mechanisms such as oxidative stress and inflammasomes signaling were also studied. METHODS Spinal cord injury in rats was established by longitudinal surgical incision from the lower to mid-thoracic vertebrae on the backside, followed by 20-g weight placed on the exposed Th12 surface for 30 min. AAV-delivered FBXW7α and -sh-FBXW7α were intrathecally injected into the rat spinal cord. Indices of oxidation, neurotrophic factors, and pyroptosis were measured by Western blot, Elisa, and RT-PCR. RESULTS We found the overexpression of FBXW7α in spinal cord rescue neuronal death triggered by the injury. Specifically, the nutritional condition, oxidative stress, and pyroptosis were improved. A synchronization of BNDF and GDNF expression patterns in various groups indicated the secretion of neurotrophic factors affect the outcome of SCI. The SOD1, CAT, and GSH-px were suppressed after trauma but all restored in response to FBXW7α overexpression. Inflammasomes-activated pyroptosis was incurred after the injury, and relevant biomarkers such as GSDMD, caspase-1, caspase- 11, IL-1β, and IL-18 were down-regulated after the introduction of FBXW7α into the injured cord. Additionally, up-regulating FBXW7α also repaired the mitochondria dysfunction. CONCLUSION Our data indicate FBXW7α probably serves as an important molecular target for the therapy of spinal cord injury.
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Affiliation(s)
- Hong Zhang
- Department of Trauma Center, The First People's Hospital of Lianyungang, Lianyungang City, Jiangsu Province, 222061, China
| | - Tao Yang
- Department of Orthopedics, 4th (Xing Yuan) Hospital of Yulin, Yulin City, Shaanxi Province, 719000, China
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Zheng X, Chen W, Gong F, Chen Y, Chen E. The Role and Mechanism of Pyroptosis and Potential Therapeutic Targets in Sepsis: A Review. Front Immunol 2021; 12:711939. [PMID: 34305952 PMCID: PMC8293747 DOI: 10.3389/fimmu.2021.711939] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 06/22/2021] [Indexed: 01/15/2023] Open
Abstract
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Recently was been found that pyroptosis is a unique form of proinflammatory programmed death, that is different from apoptosis. A growing number of studies have investigated pyroptosis and its relationship with sepsis, including the mechanisms, role, and relevant targets of pyroptosis in sepsis. While moderate pyroptosis in sepsis can control pathogen infection, excessive pyroptosis can lead to a dysregulated host immune response and even organ dysfunction. This review provides an overview of the mechanisms and potential therapeutic targets underlying pyroptosis in sepsis identified in recent decades, looking forward to the future direction of treatment for sepsis.
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Affiliation(s)
| | | | | | - Ying Chen
- Department of Emergency, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Erzhen Chen
- Department of Emergency, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Abstract
Significance: Kidney diseases remain a worldwide public health problem resulting in millions of deaths each year; they are characterized by progressive destruction of renal function by sustained inflammation. Pyroptosis is a lytic type of programmed cell death involved in inflammation, as well as a key fibrotic mechanism that is critical in the development of kidney pathology. Pyroptosis is induced by the cleavage of Gasdermins by various caspases and is executed by the insertion of the N-terminal fragment of cleaved Gasdermins into the plasma membrane, creating oligomeric pores and allowing the release of diverse proinflammatory products into the extracellular space. Inflammasomes are multiprotein complexes leading to the activation of caspase-1, which will cleave Gasdermin D, releasing several proinflammatory cytokines; this results in the initiation and amplification of the inflammatory response. Recent Advances: The efficacy of Gasdermin D cleavage is reduced by a change in the redox balance. Recently, several studies have shown that the attenuation of reactive oxygen species (ROS) production induced by antioxidant pathways results in a reduction of renal pyroptosis. In this review, we discuss the role of pyroptosis in the pathogenesis of chronic kidney disease (CKD) and acute kidney disease; summarize the clinical outcomes and different molecular mechanisms leading to Gasdermin activation; and examine studies about the capacity of antioxidants, particularly Nrf2 activators, to ameliorate Gasdermin activity. Future Directions: We illustrate the potential influence of the deregulation of redox balance on inflammasome activity and pyroptosis as a novel therapeutic approach for the treatment of kidney diseases. Antioxid. Redox Signal. 35, 40-60.
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Affiliation(s)
- Santiago Cuevas
- Molecular Inflammation Group, Biomedical Research Institute of Murcia, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Pablo Pelegrín
- Molecular Inflammation Group, Biomedical Research Institute of Murcia, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
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Dai S, Ye B, Chen L, Hong G, Zhao G, Lu Z. Emodin alleviates LPS-induced myocardial injury through inhibition of NLRP3 inflammasome activation. Phytother Res 2021; 35:5203-5213. [PMID: 34131970 DOI: 10.1002/ptr.7191] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 04/19/2021] [Accepted: 04/26/2021] [Indexed: 12/26/2022]
Abstract
Myocardial injury and cardiovascular dysfunction are serious consequences of sepsis and contribute to high mortality. Currently, the pathogenesis of myocardial injury in sepsis is still unclear, and therapeutic approaches are limited. In this study, we investigated the protective effect of emodin on septic myocardial injury and the underlying mechanism. Lipopolysaccharide (LPS)-induced C57BL/6 mice and cardiomyocytes were used as models of sepsis in vivo and in vitro, respectively. The results showed that emodin alleviated cardiac dysfunction, myocardial injury and improved survival rate in LPS-induced septic mice. Emodin attenuated the levels of inflammatory cytokines and cardiac inflammation induced by LPS. Emodin reduced NOD-like receptor protein 3 (NLRP3) and Gasdermin D (GSDMD) expression in the heart tissue of LPS-induced septic mice. In vitro, emodin alleviated LPS-induced cell injury and inflammation in cardiomyocytes by inhibiting NLRP3 inflammasome activation. In addition, an NLRP3 inhibitor was used to further confirm the function of the NLRP3 inflammasome in LPS-induced myocardial injury. Taken together, our findings suggest that emodin improves LPS-induced myocardial injury and cardiac dysfunction by alleviating the inflammatory response and cardiomyocyte pyroptosis by inhibiting NLRP3 inflammasome activation, which provides a feasible strategy for preventing and treating myocardial injury in sepsis.
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Affiliation(s)
- Shanshan Dai
- Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Bozhi Ye
- Department of Cardiology, The Key Laboratory of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Longwang Chen
- Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Guangliang Hong
- Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Guangju Zhao
- Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Zhongqiu Lu
- Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
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Li X, Zou Y, Fu YY, Xing J, Wang KY, Wan PZ, Wang M, Zhai XY. Ibudilast Attenuates Folic Acid-Induced Acute Kidney Injury by Blocking Pyroptosis Through TLR4-Mediated NF-κB and MAPK Signaling Pathways. Front Pharmacol 2021; 12:650283. [PMID: 34025417 PMCID: PMC8139578 DOI: 10.3389/fphar.2021.650283] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/19/2021] [Indexed: 02/06/2023] Open
Abstract
Folic acid (FA)-induced renal tubule damage, which is characterized by extensive inflammation, is a common model of acute kidney injury (AKI). Pyroptosis, a pro-inflammatory form of cell death due to the activation of inflammatory caspases, is involved in AKI progression. Ibudilast, a TLR4 antagonist, has been used in the clinic to exert an anti-inflammatory effect on asthma. However, researchers have not explored whether ibudilast exerts a protective effect on AKI by inhibiting inflammation. In the present study, ibudilast reversed FA-induced AKI in mice, as indicated by the reduced serum creatinine and urea nitrogen levels, and improved renal pathology, as well as the downregulation of kidney injury marker-1. In addition, ibudilast significantly increased the production of the anti-inflammatory factor IL-10 while suppressing the secretion of the pro-inflammatory cytokine TNF-α and macrophage infiltration. Moreover, in the injured kidney, ibudilast reduced the levels of both inflammasome markers (NLRP3) and pyroptosis-related proteins (caspase-1, IL1-β, IL-18, and GSDMD cleavage), and decreased the number of TUNEL-positive cells. Further mechanistic studies showed that ibudilast administration inhibited the FA-induced upregulation of TLR4, blocked NF-κB nuclear translocation, and reduced the phosphorylation of NF-κB and IκBα, p38, ERK, and JNK. Thus, this study substantiates the protective effect of ibudilast on FA-induced AKI in mice and suggests that protection might be achieved by reducing pyroptosis and inflammation, likely through the inhibition of TLR4-mediated NF-κB and MAPK signaling pathways.
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Affiliation(s)
- Xue Li
- Department of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, China.,Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yu Zou
- Department of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, China
| | - Yuan-Yuan Fu
- Department of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, China
| | - Jia Xing
- Department of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, China
| | - Kai-Yue Wang
- Department of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, China
| | - Peng-Zhi Wan
- Department of Nephrology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Mo Wang
- Department of Surgery, Yale School of Medicine, New Haven, CT, United States
| | - Xiao-Yue Zhai
- Department of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, China.,Institute of Nephropathology, China Medical University, Shenyang, China
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Deng J, Tan W, Luo Q, Lin L, Zheng L, Yang J. Long Non-coding RNA MEG3 Promotes Renal Tubular Epithelial Cell Pyroptosis by Regulating the miR-18a-3p/GSDMD Pathway in Lipopolysaccharide-Induced Acute Kidney Injury. Front Physiol 2021; 12:663216. [PMID: 34012408 PMCID: PMC8128073 DOI: 10.3389/fphys.2021.663216] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/31/2021] [Indexed: 12/14/2022] Open
Abstract
Background and Objective: Acute kidney injury (AKI) is a complication of sepsis. Pyroptosis of gasdermin D (GSDMD)-mediated tubular epithelial cells (TECs) play important roles in pathogenesis of sepsis-associated AKI. Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3), an imprinted gene involved in tumorigenesis, is implicated in pyroptosis occurring in multiple organs. Herein, we investigated the role and mechanisms of MEG3 in regulation of TEC pyroptosis in lipopolysaccharide (LPS)-induced AKI. Materials and Methods: Male C57BL/6 mice and primary human TECs were treated with LPS for 24 h to establish the animal and cell models, respectively, of sepsis-induced AKI. Renal function was assessed by evaluation of serum creatinine and urea levels. Renal tubule injury score was assessed by Periodic acid-Schiff staining. Renal pyroptosis was assessed by evaluating expression of caspase-1, GSDMD, and inflammatory factors IL-1β and IL-18. Cellular pyroptosis was assessed by analyzing the release rate of LDH, expression of IL-1β, IL-18, caspase-1, and GSDMD, and using EtBr and EthD2 staining. MEG3 expression in renal tissues and cells was detected using RT-qPCR. The molecular mechanisms of MEG3 in LPS-induced AKI were assessed through bioinformatics analysis, RNA-binding protein immunoprecipitation, dual luciferase reporter gene assays, and a rescue experiment. Results: Pyroptosis was detected in both LPS-induced animal and cell models, and the expression of MEG3 in these models was significantly up-regulated. MEG3-knockdown TECs treated with LPS showed a decreased number of pyroptotic cells, down-regulated secretion of LDH, IL-1β, and IL-18, and decreased expression of GSDMD, compared with those of controls; however, there was no difference in the expression of caspase-1 between MEG3 knockdown cells and controls. Bioinformatics analysis screened out miR-18a-3P, and further experiments demonstrated that MEG3 controls GSDMD expression by acting as a ceRNA for miR-18a-3P to promote TECs pyroptosis. Conclusion: Our study demonstrates that lncRNA MEG3 promoted renal tubular epithelial pyroptosis by regulating the miR-18a-3p/GSDMD pathway in LPS-induced AKI.
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Affiliation(s)
- Junhui Deng
- The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wei Tan
- The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qinglin Luo
- The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lirong Lin
- The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Luquan Zheng
- The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jurong Yang
- The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
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44
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Deng F, Zheng X, Sharma I, Dai Y, Wang Y, Kanwar YS. Regulated cell death in cisplatin-induced AKI: relevance of myo-inositol metabolism. Am J Physiol Renal Physiol 2021; 320:F578-F595. [PMID: 33615890 PMCID: PMC8083971 DOI: 10.1152/ajprenal.00016.2021] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/08/2021] [Accepted: 02/09/2021] [Indexed: 12/14/2022] Open
Abstract
Regulated cell death (RCD), distinct from accidental cell death, refers to a process of well-controlled programmed cell death with well-defined pathological mechanisms. In the past few decades, various terms for RCDs were coined, and some of them have been implicated in the pathogenesis of various types of acute kidney injury (AKI). Cisplatin is widely used as a chemotherapeutic drug for a broad spectrum of cancers, but its usage was hampered because of being highly nephrotoxic. Cisplatin-induced AKI is commonly seen clinically, and it also serves as a well-established prototypic model for laboratory investigations relevant to acute nephropathy affecting especially the tubular compartment. Literature reports over a period of three decades have indicated that there are multiple types of RCDs, including apoptosis, necroptosis, pyroptosis, ferroptosis, and mitochondrial permeability transition-mediated necrosis, and some of them are pertinent to the pathogenesis of cisplatin-induced AKI. Interestingly, myo-inositol metabolism, a vital biological process that is largely restricted to the kidney, seems to be relevant to the pathogenesis of certain forms of RCDs. A comprehensive understanding of RCDs in cisplatin-induced AKI and their relevance to myo-inositol homeostasis may yield novel therapeutic targets for the amelioration of cisplatin-related nephropathy.
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Affiliation(s)
- Fei Deng
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, China
- Department of Pathology, Northwestern University, Chicago, Illinois
- Department of Medicine, Northwestern University, Chicago, Illinois
| | - Xiaoping Zheng
- Department of Pathology, Northwestern University, Chicago, Illinois
- Department of Medicine, Northwestern University, Chicago, Illinois
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Isha Sharma
- Department of Pathology, Northwestern University, Chicago, Illinois
- Department of Medicine, Northwestern University, Chicago, Illinois
| | - Yingbo Dai
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, China
- Department of Urology, The Fifth Affiliated Hospital of Sun Yet-Sen University, Zhuhai, China
| | - Yinhuai Wang
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yashpal S Kanwar
- Department of Pathology, Northwestern University, Chicago, Illinois
- Department of Medicine, Northwestern University, Chicago, Illinois
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Acetylbritannilactone attenuates contrast-induced acute kidney injury through its anti-pyroptosis effects. Biosci Rep 2021; 40:221974. [PMID: 31998952 PMCID: PMC7029155 DOI: 10.1042/bsr20193253] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 01/21/2020] [Accepted: 01/24/2020] [Indexed: 02/07/2023] Open
Abstract
Contrast-induced acute kidney injury (CI-AKI) is a severe complication caused by intravascular applied radial contrast media (CM). Pyroptosis is a lytic type of cell death inherently associated with inflammation response and the secretion of pro-inflammatory cytokines following caspase-1 activation. The aim of the present study was to investigate the protective effects of acetylbritannilactone (ABL) on iopromide (IOP)-induced acute renal failure and reveal the underlying mechanism. In vivo and in vitro, IOP treatment caused renal damage and elevated the caspase-1 (+) propidium iodide (PI) (+) cell count, interleukin (IL)-1β and IL-18 levels, lactate dehydrogenase (LDH) release, and the relative expression of nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and gasdermin D (GSDMD), suggesting that IOP induces AKI via the activation of pyroptosis. Furthermore, the pretreatment of ABL partly mitigated the CI-AKI, development of pyroptosis, and subsequent kidney inflammation. These data revealed that ABL partially prevents renal dysfunction and reduces pyroptosis in CI-AKI, which may provide a therapeutic target for the treatment of CM-induced AKI.
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46
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Xia W, Li Y, Wu M, Jin Q, Wang Q, Li S, Huang S, Zhang A, Zhang Y, Jia Z. Gasdermin E deficiency attenuates acute kidney injury by inhibiting pyroptosis and inflammation. Cell Death Dis 2021; 12:139. [PMID: 33542198 PMCID: PMC7862699 DOI: 10.1038/s41419-021-03431-2] [Citation(s) in RCA: 105] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 01/11/2021] [Accepted: 01/13/2021] [Indexed: 12/11/2022]
Abstract
Pyroptosis, one kind of inflammatory regulated cell death, is involved in various inflammatory diseases, including acute kidney injury (AKI). Besides Gasdermin D (GSDMD), GSDME is a newly identified mediator of pyroptosis via the cleavage of caspase-3 generating pyroptotic GSDME-N. Here, we investigated the role of GSDME in renal cellular pyroptosis and AKI pathogenesis employing GSDME-deficient mice and human tubular epithelial cells (TECs) with the interventions of pharmacological and genetic approaches. After cisplatin treatment, GSDME-mediated pyroptosis was induced as shown by the characteristic pyroptotic morphology in TECs, upregulated GSDME-N expression and enhanced release of IL-1β and LDH, and decreased cell viability. Strikingly, silencing GSDME in mice attenuated acute kidney injury and inflammation. The pyroptotic role of GSDME was also verified in human TECs in vitro. Further investigation showed that inhibition of caspase-3 blocked GSDME-N cleavage and attenuated cisplatin-induced pyroptosis and kidney dysfunction. Moreover, deletion of GSDME also protected against kidney injury induced by ischemia-reperfusion. Taken together, the findings from current study demonstrated that caspase-3/GSDME-triggered pyroptosis and inflammation contributes to AKI, providing new insights into the understanding and treatment of this disease.
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Affiliation(s)
- Weiwei Xia
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, 210008, Nanjing, China.,Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, 210008, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, 210029, Nanjing, China
| | - Yuanyuan Li
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, 210008, Nanjing, China.,Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, 210008, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, 210029, Nanjing, China
| | - Mengying Wu
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, 210008, Nanjing, China.,Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, 210008, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, 210029, Nanjing, China
| | - Qianqian Jin
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, 210008, Nanjing, China.,Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, 210008, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, 210029, Nanjing, China
| | - Qian Wang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, 210008, Nanjing, China.,Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, 210008, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, 210029, Nanjing, China
| | - Shuzhen Li
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, 210008, Nanjing, China.,Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, 210008, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, 210029, Nanjing, China
| | - Songming Huang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, 210008, Nanjing, China.,Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, 210008, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, 210029, Nanjing, China
| | - Aihua Zhang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, 210008, Nanjing, China.,Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, 210008, Nanjing, China.,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, 210029, Nanjing, China
| | - Yue Zhang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, 210008, Nanjing, China. .,Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, 210008, Nanjing, China. .,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, 210029, Nanjing, China.
| | - Zhanjun Jia
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, 210008, Nanjing, China. .,Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, 210008, Nanjing, China. .,Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, 210029, Nanjing, China.
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47
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Li L, Lu YQ. The Regulatory Role of High-Mobility Group Protein 1 in Sepsis-Related Immunity. Front Immunol 2021; 11:601815. [PMID: 33552058 PMCID: PMC7862754 DOI: 10.3389/fimmu.2020.601815] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 12/07/2020] [Indexed: 12/16/2022] Open
Abstract
High-mobility group box 1 (HMGB1), a prototypical damage-associated molecular pattern (DAMP) molecule, participates in multiple processes of various inflammatory diseases through binding to its corresponding receptors. In the early phase, sepsis is mainly characterized as a multi-bacterial-induced complex, excessive inflammatory response accompanied by the release of pro-inflammatory mediators, which subsequently develops into immune paralysis. A growing number of in vivo and in vitro investigations reveal that HMGB1 plays a pivotal role in the processes of inflammatory response and immunosuppression of sepsis. Therefore, HMGB1 exerts an indispensable role in the immune disorder and life-threatening inflammatory syndrome of sepsis. HMGB1 mainly mediate the release of inflammatory factors via acting on immune cells, pyroptosis pathways and phosphorylating nuclear factor-κB. Moreover HMGB1 is also associated with the process of sepsis-related immunosuppression. Neutrophil dysfunction mediated by HMGB1 is also an aspect of the immunosuppressive mechanism of sepsis. Myeloid-derived suppressor cells (MDSCs), which are also one of the important cells that play an immunosuppressive effect in sepsis, may connect with HMGB1. Thence, further understanding of HMGB1-associated pathogenesis of sepsis may assist in development of promising treatment strategies. This review mainly discusses current perspectives on the roles of HMGB1 in sepsis-related inflammation and immunosuppressive process and its related internal regulatory mechanisms.
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Affiliation(s)
- Li Li
- Department of Emergency Medicine, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Department of Geriatrics, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases, Hangzhou, China
| | - Yuan-Qiang Lu
- Department of Emergency Medicine, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Department of Geriatrics, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases, Hangzhou, China
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48
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Moore CL, Savenka AV, Basnakian AG. TUNEL Assay: A Powerful Tool for Kidney Injury Evaluation. Int J Mol Sci 2021; 22:ijms22010412. [PMID: 33401733 PMCID: PMC7795088 DOI: 10.3390/ijms22010412] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/23/2020] [Accepted: 12/28/2020] [Indexed: 02/06/2023] Open
Abstract
Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay is a long-established assay used to detect cell death-associated DNA fragmentation (3'-OH DNA termini) by endonucleases. Because these enzymes are particularly active in the kidney, TUNEL is widely used to identify and quantify DNA fragmentation and cell death in cultured kidney cells and animal and human kidneys resulting from toxic or hypoxic injury. The early characterization of TUNEL as an apoptotic assay has led to numerous misinterpretations of the mechanisms of kidney cell injury. Nevertheless, TUNEL is becoming increasingly popular for kidney injury assessment because it can be used universally in cultured and tissue cells and for all mechanisms of cell death. Furthermore, it is sensitive, accurate, quantitative, easily linked to particular cells or tissue compartments, and can be combined with immunohistochemistry to allow reliable identification of cell types or likely mechanisms of cell death. Traditionally, TUNEL analysis has been limited to the presence or absence of a TUNEL signal. However, additional information on the mechanism of cell death can be obtained from the analysis of TUNEL patterns.
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Affiliation(s)
- Christopher L. Moore
- Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street, #638, Little Rock, AR 72205, USA; (C.L.M.); (A.V.S.)
| | - Alena V. Savenka
- Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street, #638, Little Rock, AR 72205, USA; (C.L.M.); (A.V.S.)
| | - Alexei G. Basnakian
- Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street, #638, Little Rock, AR 72205, USA; (C.L.M.); (A.V.S.)
- John L. McClellan Memorial VA Hospital, Central Arkansas Veterans Healthcare System, 4300 West 7th Street, Little Rock, AR 72205, USA
- Correspondence: ; Tel.: +1-501-352-2870
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Downs KP, Nguyen H, Dorfleutner A, Stehlik C. An overview of the non-canonical inflammasome. Mol Aspects Med 2020; 76:100924. [PMID: 33187725 PMCID: PMC7808250 DOI: 10.1016/j.mam.2020.100924] [Citation(s) in RCA: 181] [Impact Index Per Article: 36.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 10/30/2020] [Accepted: 11/03/2020] [Indexed: 12/21/2022]
Abstract
Inflammasomes are large cytosolic multiprotein complexes assembled in response to infection and cellular stress, and are crucial for the activation of inflammatory caspases and the subsequent processing and release of pro-inflammatory mediators. While caspase-1 is activated within the canonical inflammasome, the related caspase-4 (also known as caspase-11 in mice) and caspase-5 are activated within the non-canonical inflammasome upon sensing of cytosolic lipopolysaccharide (LPS) from Gram-negative bacteria. However, the consequences of canonical and non-canonical inflammasome activation are similar. Caspase-1 promotes the processing and release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and the release of danger signals, as well as a lytic form of cell death called pyroptosis, whereas caspase-4, caspase-5 and caspase-11 directly promote pyroptosis through cleavage of the pore-forming protein gasdermin D (GSDMD), and trigger a secondary activation of the canonical NLRP3 inflammasome for cytokine release. Since the presence of the non-canonical inflammasome activator LPS leads to endotoxemia and sepsis, non-canonical inflammasome activation and regulation has important clinical ramifications. Here we discuss the mechanism of non-canonical inflammasome activation, mechanisms regulating its activity and its contribution to health and disease.
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Affiliation(s)
- Kevin P Downs
- Department of Pathology and Laboratory Medicine, Cedars Sinai, Los Angeles, CA, 90048, USA.
| | - Huyen Nguyen
- Department of Pathology and Laboratory Medicine, Cedars Sinai, Los Angeles, CA, 90048, USA.
| | - Andrea Dorfleutner
- Department of Pathology and Laboratory Medicine, Cedars Sinai, Los Angeles, CA, 90048, USA; Department of Biomedical Sciences, Cedars Sinai, Los Angeles, CA, 90048, USA.
| | - Christian Stehlik
- Department of Pathology and Laboratory Medicine, Cedars Sinai, Los Angeles, CA, 90048, USA; Department of Biomedical Sciences, Cedars Sinai, Los Angeles, CA, 90048, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai, Los Angeles, CA, 90048, USA.
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50
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HO-1/PINK1 Regulated Mitochondrial Fusion/Fission to Inhibit Pyroptosis and Attenuate Septic Acute Kidney Injury. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2148706. [PMID: 33145342 PMCID: PMC7599399 DOI: 10.1155/2020/2148706] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 09/01/2020] [Accepted: 09/20/2020] [Indexed: 12/27/2022]
Abstract
Background Endotoxin-associated acute kidney injury (AKI), a disease characterized by marked oxidative stress and inflammation disease, is a major cause of mortality in critically ill patients. Mitochondrial fission and pyroptosis often occur in AKI. However, the underlying biological pathways involved in endotoxin AKI remain poorly understood, especially those related to mitochondrial dynamics equilibrium disregulation and pyroptosis. Previous studies suggest that heme oxygenase- (HO-) 1 confers cytoprotection against AKI during endotoxic shock, and PTEN-induced putative kinase 1 (PINK1) takes part in mitochondrial dysfunction. Thus, in this study, we examine the roles of HO-1/PINK1 in maintaining the dynamic process of mitochondrial fusion/fission to inhibit pyroptosis and mitigate acute kidney injury in rats exposed to endotoxin. Methods An endotoxin-associated AKI model induced by lipopolysaccharide (LPS) was used in our study. Wild-type (WT) rats and PINK1 knockout (PINK1KO) rats, respectively, were divided into four groups: the control, LPS, Znpp+LPS, and Hemin+LPS groups. Rats were sacrificed 6 h after intraperitoneal injecting LPS to assess renal function, oxidative stress, and inflammation by plasma. Mitochondrial dynamics, morphology, and pyroptosis were evaluated by histological examinations. Results In the rats with LPS-induced endotoxemia, the expression of HO-1 and PINK1 were upregulated at both mRNA and protein levels. These rats also exhibited inflammatory response, oxidative stress, mitochondrial fission, pyroptosis, and decreased renal function. After upregulating HO-1 in normal rats, pyroptosis was inhibited; mitochondrial fission and inflammatory response to oxidative stress were decreased; and the renal function was improved. The effects were reversed by adding Znpp (a type of HO-1 inhibitor). Finally, after PINK1 knockout, there is no statistical difference in the LPS-treated group and Hemin or Znpp pretreated group. Conclusions HO-1 inhibits inflammation response and oxidative stress and regulates mitochondria fusion/fission to inhibit pyroptosis, which can alleviate endotoxin-induced AKI by PINK1.
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