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Li ZL, Li XY, Zhou Y, Wang B, Lv LL, Liu BC. Renal tubular epithelial cells response to injury in acute kidney injury. EBioMedicine 2024; 107:105294. [PMID: 39178744 PMCID: PMC11388183 DOI: 10.1016/j.ebiom.2024.105294] [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] [Revised: 07/19/2024] [Accepted: 08/06/2024] [Indexed: 08/26/2024] Open
Abstract
Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid and significant decrease in renal function that can arise from various etiologies, and is associated with high morbidity and mortality. The renal tubular epithelial cells (TECs) represent the central cell type affected by AKI, and their notable regenerative capacity is critical for the recovery of renal function in afflicted patients. The adaptive repair process initiated by surviving TECs following mild AKI facilitates full renal recovery. Conversely, when injury is severe or persistent, it allows the TECs to undergo pathological responses, abnormal adaptive repair and phenotypic transformation, which will lead to the development of renal fibrosis. Given the implications of TECs fate after injury in renal outcomes, a deeper understanding of these mechanisms is necessary to identify promising therapeutic targets and biomarkers of the repair process in the human kidney.
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Affiliation(s)
- Zuo-Lin Li
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Xin-Yan Li
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Yan Zhou
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Bin Wang
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Lin-Li Lv
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
| | - Bi-Cheng Liu
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
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Steenvoorden TS, Rood JAJ, Bemelman FJ, Armstrong Jr. R, Leuvenink HGD, van der Heijden JW, Vogt L. Alkaline phosphatase treatment of acute kidney injury-an update. Nephrol Dial Transplant 2024; 39:1239-1247. [PMID: 38400561 PMCID: PMC11334066 DOI: 10.1093/ndt/gfae028] [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: 11/02/2023] [Indexed: 02/25/2024] Open
Abstract
Through improved insights into the increasing incidence and detrimental effects of acute kidney injury (AKI), its clinical relevance has become more and more apparent. Although treatment strategies for AKI have also somewhat improved, an adequate remedy still does not exist. Finding one is complicated by a multifactorial pathophysiology and by heterogeneity in the patient population. Alkaline phosphatase (ALP) has been suggested as a therapy for sepsis-associated AKI because of its protective effects against lipopolysaccharide (LPS)-induced inflammation and kidney injury in animals. However, its effectiveness as an AKI treatment has not been demonstrated definitively. Because the anti-inflammatory properties of ALP are likely not reliant on a direct effect on LPS itself, we postulate that other pathways are much more important in explaining the renoprotective properties ascribed to ALP. The re-evaluation of which properties of the ALP enzyme are responsible for the benefit seen in the lab is an important step in determining where the true potential of ALP as a treatment strategy for AKI in the clinic lies. In this review we will discuss how ALP can prevent activation of harmful pro-inflammatory receptors, redirect cell-cell signalling and protect barrier tissues, which together form the basis for current knowledge of the role of ALP in the kidney. With this knowledge in mind and by analysing currently available clinical evidence, we propose directions for new research that can determine whether ALP as a treatment strategy for AKI has a future in the clinical field.
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Affiliation(s)
- Thei S Steenvoorden
- Department of Internal Medicine, Section Nephrology, Amsterdam UMC, location AMC, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, The Netherlands
| | - Janneke A J Rood
- Department of Internal Medicine, Section Nephrology, Amsterdam UMC, location VU University Medical Center, Amsterdam, Vrije Universiteit, Amsterdam, The Netherlands
| | - Frederike J Bemelman
- Department of Internal Medicine, Section Nephrology, Amsterdam UMC, location AMC, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, The Netherlands
| | - Roberto Armstrong Jr.
- Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
| | - Henri G D Leuvenink
- Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Liffert Vogt
- Department of Internal Medicine, Section Nephrology, Amsterdam UMC, location AMC, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, The Netherlands
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3
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Blanco NG, Machado NM, Castro LL, Antunes MA, Takiya CM, Trugilho MRO, Silva LR, Paes Leme AF, Domingues RR, Pauletti BA, Miranda BT, Silva JD, Dos Santos CC, Silva PL, Rocco PRM, Cruz FF. Extracellular Vesicles from Different Sources of Mesenchymal Stromal Cells Have Distinct Effects on Lung and Distal Organs in Experimental Sepsis. Int J Mol Sci 2023; 24:ijms24098234. [PMID: 37175936 PMCID: PMC10179270 DOI: 10.3390/ijms24098234] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/24/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
The effects of the administration of mesenchymal stromal cells (MSC) may vary according to the source. We hypothesized that MSC-derived extracellular vesicles (EVs) obtained from bone marrow (BM), adipose (AD), or lung (L) tissues may also lead to different effects in sepsis. We profiled the proteome from EVs as a first step toward understanding their mechanisms of action. Polymicrobial sepsis was induced in C57BL/6 mice by cecal ligation and puncture (SEPSIS) and SHAM (control) animals only underwent laparotomy. Twenty-four hours after surgery, animals in the SEPSIS group were randomized to receive saline or 3 × 106 MSC-derived EVs from BM, AD, or L. The diffuse alveolar damage was decreased with EVs from all three sources. In kidneys, BM-, AD-, and L-EVs reduced edema and expression of interleukin-18. Kidney injury molecule-1 expression decreased only in BM- and L-EVs groups. In the liver, only BM-EVs reduced congestion and cell infiltration. The size and number of EVs from different sources were not different, but the proteome of the EVs differed. BM-EVs were enriched for anti-inflammatory proteins compared with AD-EVs and L-EVs. In conclusion, BM-EVs were associated with less organ damage compared with the other sources of EVs, which may be related to differences detected in their proteome.
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Affiliation(s)
- Natália G Blanco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
| | - Natália M Machado
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
| | - Ligia L Castro
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
| | - Mariana A Antunes
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
| | - Christina M Takiya
- Laboratory of Immunopathology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Monique R O Trugilho
- Toxinology Laboratory, Center for Technological Development Health, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040-900, RJ, Brazil
| | - Luana R Silva
- Toxinology Laboratory, Center for Technological Development Health, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040-900, RJ, Brazil
| | - Adriana F Paes Leme
- Mass Spectrometry Laboratory, Brazilian Bioscience National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials, Campinas 13083-970, SP, Brazil
| | - Romênia R Domingues
- Mass Spectrometry Laboratory, Brazilian Bioscience National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials, Campinas 13083-970, SP, Brazil
| | - Bianca A Pauletti
- Mass Spectrometry Laboratory, Brazilian Bioscience National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials, Campinas 13083-970, SP, Brazil
| | - Beatriz T Miranda
- Laboratory of Cellular and Molecular Cardiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Johnatas D Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
| | - Claudia C Dos Santos
- The Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, 209 Victoria Street, Toronto, ON M5B 1T8, Canada
- Institute of Medical Sciences, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada
- Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada
| | - Pedro L Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
| | - Patricia R M Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
| | - Fernanda F Cruz
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, RJ, Brazil
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Arnaud M, Loiselle M, Vaganay C, Pons S, Letavernier E, Demonchy J, Fodil S, Nouacer M, Placier S, Frère P, Arrii E, Lion J, Mooney N, Itzykson R, Djediat C, Puissant A, Zafrani L. Tumor Lysis Syndrome and AKI: Beyond Crystal Mechanisms. J Am Soc Nephrol 2022; 33:1154-1171. [PMID: 35523579 PMCID: PMC9161807 DOI: 10.1681/asn.2021070997] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 03/12/2022] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The pathophysiology of AKI during tumor lysis syndrome (TLS) is not well understood due to the paucity of data. We aimed to decipher crystal-dependent and crystal-independent mechanisms of TLS-induced AKI. METHODS Crystalluria, plasma cytokine levels, and extracellular histones levels were measured in two cohorts of patients with TLS. We developed a model of TLS in syngeneic mice with acute myeloid leukemia, and analyzed ultrastructural changes in kidneys and endothelial permeability using intravital confocal microscopy. In parallel, we studied the endothelial toxicity of extracellular histones in vitro. RESULTS: The study provides the first evidence that previously described crystal-dependent mechanisms are insufficient to explain TLS-induced AKI. Extracellular histones that are released in huge amounts during TLS caused profound endothelial alterations in the mouse model. The mechanisms of histone-mediated damage implicates endothelial cell activation mediated by Toll-like receptor 4. Heparin inhibits extracellular histones and mitigates endothelial dysfunction during TLS. CONCLUSION This study sheds new light on the pathophysiology of TLS-induced AKI and suggests that extracellular histones may constitute a novel target for therapeutic intervention in TLS when endothelial dysfunction occurs.
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Affiliation(s)
- Marine Arnaud
- Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale (INSERM) U 976, University of Paris Cité, Paris, France
| | - Maud Loiselle
- Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale (INSERM) U 976, University of Paris Cité, Paris, France
| | - Camille Vaganay
- INSERM UMR 944, Saint Louis Hospital, University of Paris Cité, Paris, France
| | - Stéphanie Pons
- Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale (INSERM) U 976, University of Paris Cité, Paris, France
| | - Emmanuel Letavernier
- INSERM UMR S 1155, Sorbonne University, Paris, France,Multidisciplinary Functional Explorations Department, Assistance Publique des Hôpitaux de Paris, Tenon Hospital, Paris, France
| | - Jordane Demonchy
- Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale (INSERM) U 976, University of Paris Cité, Paris, France
| | - Sofiane Fodil
- Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale (INSERM) U 976, University of Paris Cité, Paris, France
| | - Manal Nouacer
- Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale (INSERM) U 976, University of Paris Cité, Paris, France
| | | | - Perrine Frère
- INSERM UMR S 1155, Sorbonne University, Paris, France
| | - Eden Arrii
- Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale (INSERM) U 976, University of Paris Cité, Paris, France
| | - Julien Lion
- Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale (INSERM) U 976, University of Paris Cité, Paris, France
| | - Nuala Mooney
- Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale (INSERM) U 976, University of Paris Cité, Paris, France
| | - Raphael Itzykson
- INSERM UMR 944, Saint Louis Hospital, University of Paris Cité, Paris, France,Department of Hematology, Assistance Publique des Hôpitaux de Paris, Saint Louis Hospital, Paris, France
| | - Chakib Djediat
- Electron Microscopy Department, UMR 7245, Museum National D’Histoire Naturelle, Paris, France
| | - Alexandre Puissant
- INSERM UMR 944, Saint Louis Hospital, University of Paris Cité, Paris, France
| | - Lara Zafrani
- Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale (INSERM) U 976, University of Paris Cité, Paris, France .,Medical Intensive Care Unit, Assistance Publique des Hôpitaux de Paris, Saint Louis Hospital, Paris, France
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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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Zhou Y, Qing M, Xu M. Circ-BNIP3L knockdown alleviates LPS-induced renal tubular epithelial cell injury during sepsis-associated acute kidney injury by miR-370-3p/MYD88 axis. J Bioenerg Biomembr 2021; 53:665-677. [PMID: 34731384 DOI: 10.1007/s10863-021-09925-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 10/14/2021] [Indexed: 12/13/2022]
Abstract
Sepsis-associated acute kidney injury (SA-AKI) is a frequent complication of the critically ill patient with high morbidity and mortality. Thus, the goal of this study was to investigate the role of circular RNA BCL2 Interacting Protein 3 Like (circ-BNIP3L) in the pathophysiological mechanism of SA-AKI. The SA-AKI cell model was established by using lipopolysaccharide (LPS)-induced HK-2 cells in vitro. Cell survival was analyzed using cell counting kit-8 (CCK-8) assay, EdU (5-ethynyl-2'-deoxyuridine) assay, flow cytometry and Western blot, respectively. Levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were detected using ELISA analysis. The superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were examined using commercial kits. Levels of genes and proteins were detected by qRT-PCR and Western blot. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were used to identify the target relationship between miR-370-3p and circ-BNIP3L or MYD88 (myeloid differentiation primary response 88). Circ-BNIP3L was highly expressed in SA-AKI patients and LPS-induced HK-2 cells. Silencing of circ-BNIP3L attenuated LPS-induced growth inhibition, inflammation, and oxidative stress in HK-2 cells. Mechanistically, circ-BNIP3L competitively bound to miR-370-3p to up-regulate the expression of its target MYD88. Moreover, miR-370-3p inhibition reversed the beneficial effects of circ-BNIP3L knockdown on LPS-stimulated HK-2 cells. Meanwhile, miR-370-3p overexpression abolished LPS-induced injury in HK-2 cells, which was counteracted by MYD88 up-regulation. Circ-BNIP3L knockdown alleviated LPS-induced renal tubular epithelial cell injury by miR-370-3p/MYD88 axis, opening up a completely new avenue for the treatment of sepsis-associated AKI.
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Affiliation(s)
- Yanyan Zhou
- Department of Critical Care Medicine, The Second Xiangya Hospital, Central South University, No.139 Renmin Road, 410000, Changsha City, Hunan Province, China
| | - Meiying Qing
- Department of Urinary Surgery, The Second Xiangya Hospital, Central South University, Changsha City, Hunan Province, China
| | - Min Xu
- Department of Critical Care Medicine, The Second Xiangya Hospital, Central South University, No.139 Renmin Road, 410000, Changsha City, Hunan Province, China.
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7
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Andargie TE, Tsuji N, Seifuddin F, Jang MK, Yuen PS, Kong H, Tunc I, Singh K, Charya A, Wilkins K, Nathan S, Cox A, Pirooznia M, Star RA, Agbor-Enoh S. Cell-free DNA maps COVID-19 tissue injury and risk of death and can cause tissue injury. JCI Insight 2021; 6:147610. [PMID: 33651717 PMCID: PMC8119224 DOI: 10.1172/jci.insight.147610] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 03/02/2021] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION The clinical course of coronavirus 2019 (COVID-19) is heterogeneous, ranging from mild to severe multiorgan failure and death. In this study, we analyzed cell-free DNA (cfDNA) as a biomarker of injury to define the sources of tissue injury that contribute to such different trajectories. METHODS We conducted a multicenter prospective cohort study to enroll patients with COVID-19 and collect plasma samples. Plasma cfDNA was subject to bisulfite sequencing. A library of tissue-specific DNA methylation signatures was used to analyze sequence reads to quantitate cfDNA from different tissue types. We then determined the correlation of tissue-specific cfDNA measures to COVID-19 outcomes. Similar analyses were performed for healthy controls and a comparator group of patients with respiratory syncytial virus and influenza. RESULTS We found markedly elevated levels and divergent tissue sources of cfDNA in COVID-19 patients compared with patients who had influenza and/or respiratory syncytial virus and with healthy controls. The major sources of cfDNA in COVID-19 were hematopoietic cells, vascular endothelium, hepatocytes, adipocytes, kidney, heart, and lung. cfDNA levels positively correlated with COVID-19 disease severity, C-reactive protein, and D-dimer. cfDNA profile at admission identified patients who subsequently required intensive care or died during hospitalization. Furthermore, the increased cfDNA in COVID-19 patients generated excessive mitochondrial ROS (mtROS) in renal tubular cells in a concentration-dependent manner. This mtROS production was inhibited by a TLR9-specific antagonist. CONCLUSION cfDNA maps tissue injury that predicts COVID-19 outcomes and may mechanistically propagate COVID-19–induced tissue injury. FUNDING Intramural Targeted Anti–COVID-19 grant, NIH.
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Affiliation(s)
- Temesgen E Andargie
- Genomic Research Alliance for Transplantation (GRAfT) and Laboratory of Applied Precision Omics, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, Maryland, USA.,Department of Biology, Howard University, Washington DC, USA
| | - Naoko Tsuji
- Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA
| | | | - Moon Kyoo Jang
- Genomic Research Alliance for Transplantation (GRAfT) and Laboratory of Applied Precision Omics, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, Maryland, USA
| | - Peter St Yuen
- Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA
| | - Hyesik Kong
- Genomic Research Alliance for Transplantation (GRAfT) and Laboratory of Applied Precision Omics, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, Maryland, USA
| | - Ilker Tunc
- Bioinformatics and Computation Core, NHLBI, Maryland, USA
| | - Komudi Singh
- Bioinformatics and Computation Core, NHLBI, Maryland, USA
| | - Ananth Charya
- Genomic Research Alliance for Transplantation (GRAfT) and Laboratory of Applied Precision Omics, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, Maryland, USA
| | | | - Steven Nathan
- Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Fairfax, Virginia, USA
| | - Andrea Cox
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Robert A Star
- Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA
| | - Sean Agbor-Enoh
- Genomic Research Alliance for Transplantation (GRAfT) and Laboratory of Applied Precision Omics, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, Maryland, USA.,Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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8
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Tsuji N, Agbor-Enoh S. Cell-free DNA beyond a biomarker for rejection: Biological trigger of tissue injury and potential therapeutics. J Heart Lung Transplant 2021; 40:405-413. [PMID: 33926787 DOI: 10.1016/j.healun.2021.03.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/01/2021] [Accepted: 03/03/2021] [Indexed: 12/13/2022] Open
Abstract
Cell-free DNA, measured as donor-derived cell-free DNA is developed as a non-specific biomarker for allograft injury and transplant rejection. However, cell-free DNA characteristics are more specific, its fragment length, nucleotide content, and composition, as well as the tissue source of origin, are intrinsically linked to the underlying disease pathogenesis, showing distinct features in acute cellular rejection and antibody-mediated rejection for example. Further, cell-free DNA and cell-free mitochondrial DNA can directly trigger tissue injury as damage-associated molecular patterns through three major intracellular receptors, toll-like receptor 9 , cyclic guanosine monophosphate-adenosine monophosphate synthase, and inflammasomes (i.e., absent in melanoma 2: AIM2). Therefore, in addition to its role as a non-specific marker for allograft injury, cell-free DNA analysis may be used to phenotype transplant rejection, and to non-invasively point the underlying molecular mechanisms with allograft injury. Novel treatment approaches targeting these cell-free DNA pathways may be useful to treat transplant rejection and prevent end-organ dysfunction. In this review, we discuss the link between cell-free DNA characteristics and disease, the role of cell-free DNA as a damage-associated molecular pattern, and novel therapeutics targeting these cell-free DNA molecular pathways and their potential utility to treat transplant rejection.
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Affiliation(s)
- Naoko Tsuji
- Renal Diagnostics and Therapeutics Unit, National Institutes of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland
| | - Sean Agbor-Enoh
- Lasker Clinical Research Tenure Track Investigator and Laboratory Chief, Laboratory of Applied Precision Omics, National Heart, Lung, and Blood Institute, Bethesda, Maryland; Lung Transplantation Program, Johns Hopkins School of Medicine, Baltimore, M.
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9
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Margraf A, Ley K, Zarbock A. Neutrophil Recruitment: From Model Systems to Tissue-Specific Patterns. Trends Immunol 2019; 40:613-634. [PMID: 31175062 PMCID: PMC6745447 DOI: 10.1016/j.it.2019.04.010] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 04/22/2019] [Accepted: 04/25/2019] [Indexed: 12/11/2022]
Abstract
Neutrophil recruitment is not only vital for host defense, but also relevant in pathological inflammatory reactions, such as sepsis. Model systems have been established to examine different steps of the leukocyte recruitment cascade in vivo and in vitro under inflammatory conditions. Recently, tissue-specific recruitment patterns have come into focus, requiring modification of formerly generalized assumptions. Here, we summarize existing models of neutrophil recruitment and highlight recent discoveries in organ-specific recruitment patterns. New techniques show that previously stated assumptions of integrin activation and tissue invasion may need revision. Similarly, neutrophil recruitment to specific organs can rely on different organ properties, adhesion molecules, and chemokines. To advance our understanding of neutrophil recruitment, organ-specific intravital microscopy methods are needed.
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Affiliation(s)
- Andreas Margraf
- Department of Anesthesiology, Intensive Care Therapy and Pain Medicine, University Hospital Muenster, Muenster, Germany
| | - Klaus Ley
- Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, CA, USA; Department of Bioengineering, University of California San Diego, La Jolla, CA, USA
| | - Alexander Zarbock
- Department of Anesthesiology, Intensive Care Therapy and Pain Medicine, University Hospital Muenster, Muenster, Germany.
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Sukkummee W, Jittisak P, Wonganan P, Wittayalertpanya S, Chariyavilaskul P, Leelahavanichkul A. The prominent impairment of liver/intestinal cytochrome P450 and intestinal drug transporters in sepsis-induced acute kidney injury over acute and chronic renal ischemia, a mouse model comparison. Ren Fail 2019; 41:314-325. [PMID: 30991873 PMCID: PMC6484470 DOI: 10.1080/0886022x.2019.1602054] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Drug dosing adjustment in sepsis-induced acute kidney injury (sepsis-AKI) is currently adjusted based on renal function. Sepsis is a multiorgan injury, and thus, drug metabolism in sepsis-AKI might be interfered by non-renal factors such as changes in functions of drug-metabolizing enzymes in the liver and functions of intestinal drug transporters. We compared the defect on mouse CYP3A11 (human CYP3A4 representative) in liver and intestine along with several intestinal drug transporters (MDR1a, MRP2, and OATP3) in three mouse models; chronic ischemic reperfusion injury (Chr I/R; 4-week), acute ischemic reperfusion injury (Acute I/R; 24-h), and cecal ligation and puncture (CLP; 24-h) as representative of sepsis-AKI. Decreased expression of CYP3A11 and drug transporters was demonstrated in all models. Among these models, sepsis-AKI had the least severe renal injury (increased BUN and Scr) with the most severe liver injury (increased ALT and changes in liver histopathology), the most severe intestinal leakage (increased serum (1→3)-β-D-glucan) and the highest increase in serum IL-6. A reduced expression and activity of liver and intestinal CYP3A11 along with intestinal efflux-drug transporter expressions (MDR1a and MRP2), but not drug uptake transporter (OATP3), was predominant in sepsis-AKI compared with acute I/R. Additionally, a reduction of CYP3A4 expression with IL-6 was demonstrated on HepG2 cells implying a direct injury of IL-6 on human liver cells. Differences in drug metabolism were reported between sepsis-AKI and ischemic-AKI confirming that drug dosing adjustment in sepsis-AKI depends not just only on renal function but also on several non-renal factors. Further studies are warranted.
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Affiliation(s)
- Warumphon Sukkummee
- a Clinical Pharmacokinetics and Pharmacogenomics Research Unit , Chulalongkorn University , Bangkok , Thailand
| | - Patcharin Jittisak
- a Clinical Pharmacokinetics and Pharmacogenomics Research Unit , Chulalongkorn University , Bangkok , Thailand
| | - Piyanuch Wonganan
- b Department of Pharmacology, Faculty of Medicine , Chulalongkorn University , Bangkok , Thailand
| | - Supeecha Wittayalertpanya
- a Clinical Pharmacokinetics and Pharmacogenomics Research Unit , Chulalongkorn University , Bangkok , Thailand.,b Department of Pharmacology, Faculty of Medicine , Chulalongkorn University , Bangkok , Thailand
| | - Pajaree Chariyavilaskul
- a Clinical Pharmacokinetics and Pharmacogenomics Research Unit , Chulalongkorn University , Bangkok , Thailand.,b Department of Pharmacology, Faculty of Medicine , Chulalongkorn University , Bangkok , Thailand.,c Center of Excellence in Immunology and Immune-mediated Diseases , Chulalongkorn University , Bangkok , Thailand
| | - Asada Leelahavanichkul
- c Center of Excellence in Immunology and Immune-mediated Diseases , Chulalongkorn University , Bangkok , Thailand.,d Department of Microbiology, Faculty of Medicine , Chulalongkorn University , Bangkok , Thailand
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11
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Krivan S, Kapelouzou A, Vagios S, Tsilimigras DI, Katsimpoulas M, Moris D, Aravanis CV, Demesticha TD, Schizas D, Mavroidis M, Pavlakis K, Machairas A, Misiakos E, Liakakos T. Increased expression of Toll-like receptors 2, 3, 4 and 7 mRNA in the kidney and intestine of a septic mouse model. Sci Rep 2019; 9:4010. [PMID: 30850654 PMCID: PMC6408498 DOI: 10.1038/s41598-019-40537-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 02/15/2019] [Indexed: 12/15/2022] Open
Abstract
Toll-like receptors (TLRs) are the key regulators of innate and adaptive immunity and are highly expressed during sepsis. Thus, studying the expression of TLRs in an animal septic model might indicate their possible association with acute kidney injury in sepsis. Seventy-two male C57BL/6J mice were used for this study. Randomly, these animals were divided into 6 groups (N = 12/group): 3 control and 3 septic groups depending on the euthanasia time (24 h, 48 h, 72 h). Septic groups underwent cecal ligation and puncture (CLP) to induce peritonitis, while control groups had a sham operation. Hematological tests were performed in serum for immune biomarkers; immunohistochemistry, morphometry and qRT-PCR analysis were used on both kidney and intestine tissues to evaluate the expression of TLR 2, 3, 4 and 7 in a septic process. At the end of each experimental period, we found that TLRs 2, 3, 4 and 7 were expressed in both tissues but there were differences between those at various time points. Also, we found that mRNA levels were significantly higher in qRT-PCR evaluation in septic groups than control groups in both kidney and intestinal tissues (p < 0.05); showing a steady increase in the septic groups as the time to euthanasia was prolonged (p < 0.05). Overall, our study provides a suggestion that TLRs 2, 3, 4 and 7 are highly expressed in the kidneys of septic mice and especially that these TLRs are sensitive and specific markers for sepsis. Finally, our study supports the diagnostic importance of TLRs in AKI and provides an insight on the contribution of septic mice models in the study of multi organ dysfunction syndrome in general.
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Affiliation(s)
- Sylvia Krivan
- Department of Upper Gastrointestinal and Bariatric Surgery, Luton and Dunstable University Hospital, LU4 0DZ, Luton, United Kingdom
| | - Alkistis Kapelouzou
- Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece
| | - Stylianos Vagios
- School of Medicine, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | | | - Michalis Katsimpoulas
- Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece
| | - Demetrios Moris
- First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece.
| | - Chrysostomos V Aravanis
- Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece
| | - Theano D Demesticha
- Department of Anatomy, Faculty of Medicine, National and Kapodistrian, University of Athens, 11527, Athens, Greece
| | - Dimitrios Schizas
- First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Manolis Mavroidis
- Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece
| | - Kitty Pavlakis
- Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Anastasios Machairas
- Third Department of Surgery, Attikon General Hospital, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Evangelos Misiakos
- Third Department of Surgery, Attikon General Hospital, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Theodore Liakakos
- First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece
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12
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Liu BC, Tang TT, Lv LL. How Tubular Epithelial Cell Injury Contributes to Renal Fibrosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1165:233-252. [PMID: 31399968 DOI: 10.1007/978-981-13-8871-2_11] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The renal tubules are the major component of the kidney and are vulnerable to a variety of injuries including ischemia, proteinuria, toxins, and metabolic disorders. It has long been believed that tubules are the victim of injury. In this review, we shift this concept to renal tubules as a driving force in the progression of kidney disease. In response to injury, tubular epithelial cells (TECs) can synthesize and secrete varieties of bioactive molecules that drive interstitial inflammation and fibrosis. Innate immune-sensing receptors on the TECs also aggravate immune responses. Necroinflammation, an auto-amplification loop between tubular cell death and interstitial inflammation, leads to the exacerbation of renal injury. Furthermore, TECs also play an active role in progressive renal injury via mechanisms associated with the conversion into collagen-producing fibroblast phenotype, cell cycle arrest at both G1/S and G2/M checkpoints, and metabolic disorder. Thus, a better understanding the mechanisms by which tubular injury drives AKI and CKD is necessary for the development of therapeutics to halt the progression of CKD.
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Affiliation(s)
- Bi-Cheng Liu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.
| | - Tao-Tao Tang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Lin-Li Lv
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
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13
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Liu BC, Tang TT, Lv LL, Lan HY. Renal tubule injury: a driving force toward chronic kidney disease. Kidney Int 2018; 93:568-579. [DOI: 10.1016/j.kint.2017.09.033] [Citation(s) in RCA: 260] [Impact Index Per Article: 37.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 08/17/2017] [Accepted: 09/06/2017] [Indexed: 12/13/2022]
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14
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Wang Y, Yin X, Yang F. Comprehensive Analysis of Gene Expression Profiles of Sepsis-Induced Multiorgan Failure Identified Its Valuable Biomarkers. DNA Cell Biol 2017; 37:90-98. [PMID: 29251990 DOI: 10.1089/dna.2017.3944] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Sepsis is an inflammatory-related disease, and severe sepsis would induce multiorgan dysfunction, which is the most common cause of death of patients in noncoronary intensive care units. Progression of novel therapeutic strategies has proven to be of little impact on the mortality of severe sepsis, and unfortunately, its mechanisms still remain poorly understood. In this study, we analyzed gene expression profiles of severe sepsis with failure of lung, kidney, and liver for the identification of potential biomarkers. We first downloaded the gene expression profiles from the Gene Expression Omnibus and performed preprocessing of raw microarray data sets and identification of differential expression genes (DEGs) through the R programming software; then, significantly enriched functions of DEGs in lung, kidney, and liver failure sepsis samples were obtained from the Database for Annotation, Visualization, and Integrated Discovery; finally, protein-protein interaction network was constructed for DEGs based on the STRING database, and network modules were also obtained through the MCODE cluster method. As a result, lung failure sepsis has the highest number of DEGs of 859, whereas the number of DEGs in kidney and liver failure sepsis samples is 178 and 175, respectively. In addition, 17 overlaps were obtained among the three lists of DEGs. Biological processes related to immune and inflammatory response were found to be significantly enriched in DEGs. Network and module analysis identified four gene clusters in which all or most of genes were upregulated. The expression changes of Icam1 and Socs3 were further validated through quantitative PCR analysis. This study should shed light on the development of sepsis and provide potential therapeutic targets for sepsis-induced multiorgan failure.
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Affiliation(s)
- Yumei Wang
- Department of Critical Care Medicine, Weihai Central Hospital , Weihai, China
| | - Xiaoling Yin
- Department of Critical Care Medicine, Weihai Central Hospital , Weihai, China
| | - Fang Yang
- Department of Critical Care Medicine, Weihai Central Hospital , Weihai, China
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15
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Van Beusecum JP, Zhang S, Cook AK, Inscho EW. Acute toll-like receptor 4 activation impairs rat renal microvascular autoregulatory behaviour. Acta Physiol (Oxf) 2017; 221:204-220. [PMID: 28544543 DOI: 10.1111/apha.12899] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 12/16/2016] [Accepted: 05/18/2017] [Indexed: 12/24/2022]
Abstract
AIM Little is known about how toll-like receptor 4 (TLR4) influences the renal microvasculature. We hypothesized that acute TLR4 stimulation with lipopolysaccharide (LPS) impairs afferent arteriole autoregulatory behaviour, partially through reactive oxygen species (ROS). METHODS We assessed afferent arteriole autoregulatory behaviour after LPS treatment (1 mg kg-1 ; i.p.) using the in vitro blood-perfused juxtamedullary nephron preparation. Autoregulatory behaviour was assessed by measuring diameter responses to stepwise changes in renal perfusion pressure. TLR4 expression was assessed by immunofluorescence, immunohistochemistry and Western blot analysis in the renal cortex and vasculature. RESULTS Baseline arteriole diameter at 100 mmHg averaged 15.2 ± 1.2 μm and 12.2 ± 1.0 μm for control and LPS groups (P < 0.05) respectively. When perfusion pressure was increased in 15 mmHg increments from 65 to 170 mmHg, arteriole diameter in control kidneys decreased significantly to 69 ± 6% of baseline diameter. In the LPS-treated group, arteriole diameter remained essentially unchanged (103 ± 9% of baseline), indicating impaired autoregulatory behaviour. Pre-treatment with anti-TLR4 antibody or the TLR4 antagonist, LPS-RS, preserved autoregulatory behaviour during LPS treatment. P2 receptor reactivity was normal in control and LPS-treated rats. Pre-treatment with Losartan (angiotensin type 1 receptor blocker; (AT1 ) 2 mg kg-1 ; i.p.) increased baseline afferent arteriole diameter but did not preserve autoregulatory behaviour in LPS-treated rats. Acute exposure to Tempol (10-3 mol L-1 ), a superoxide dismutase mimetic, restored pressure-mediated vasoconstriction in kidneys from LPS-treated rats. CONCLUSION These data demonstrate that TLR4 activation impairs afferent arteriole autoregulatory behaviour, partially through ROS, but independently of P2 and AT1 receptor activation.
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Affiliation(s)
- J. P. Van Beusecum
- Division of Nephrology; Department of Medicine; University of Alabama at Birmingham; Birmingham AL USA
- Department of Physiology; Augusta University; Augusta GA USA
| | - S. Zhang
- Division of Nephrology; Department of Medicine; University of Alabama at Birmingham; Birmingham AL USA
- Department of Physiology; Augusta University; Augusta GA USA
| | - A. K. Cook
- Division of Nephrology; Department of Medicine; University of Alabama at Birmingham; Birmingham AL USA
- Department of Physiology; Augusta University; Augusta GA USA
| | - E. W. Inscho
- Division of Nephrology; Department of Medicine; University of Alabama at Birmingham; Birmingham AL USA
- Department of Physiology; Augusta University; Augusta GA USA
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16
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Delayed Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Inhibition by Trametinib Attenuates Systemic Inflammatory Responses and Multiple Organ Injury in Murine Sepsis. Crit Care Med 2017; 44:e711-20. [PMID: 27031380 DOI: 10.1097/ccm.0000000000001672] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVE The mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway is an essential component of innate immunity necessary for mediating proinflammatory responses in the setting of sepsis. We previously demonstrated that the mitogen-activated protein kinase 1/2 inhibitor trametinib prevents endotoxin-induced renal injury in mice. We therefore assessed efficacy of trametinib in a more clinically relevant experimental model of sepsis. DESIGN Controlled in vivo laboratory study. SETTING University animal research laboratory. SUBJECTS Male C57BL/6 mice. INTERVENTIONS Mice were subjected to cecal ligation and puncture to induce sepsis or underwent sham operation as controls. Six hours after cecal ligation and puncture, mice were randomized to four experimental groups as follows: 1) sham control; 2) sham control + trametinib (1 mg/kg, IP); 3) cecal ligation and puncture; and 4) cecal ligation and puncture + trametinib. All animals received buprenorphine (0.05 mg/kg, SC) and imipenem/cilastatin (14 mg/kg, SC) in 1.5 mL of warm saline (40 mL/kg) at the 6-hour time point. Mice were euthanized at 18 hours after induction of cecal ligation and puncture. MEASUREMENTS AND MAIN RESULTS Trametinib inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase signaling 6 hours after cecal ligation and puncture attenuated increases in circulating proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6, and granulocyte macrophage colony-stimulating factor) and hypothermia at 18 hours. Trametinib also attenuated multiple organ injury as determined by serum creatinine, alanine aminotransferase, lactate dehydrogenase, and creatine kinase. At the organ level, trametinib completely restored peritubular capillary perfusion in the kidney. Restoration of microvascular perfusion was associated with reduced messenger RNA expression of well-characterized markers of proximal tubule injury. mitogen-activated protein kinase/extracellular signal-regulated kinase blockade attenuated cecal ligation and puncture-mediated up-regulation of cytokines (tumor necrosis factor-α, interleukin-1β) and restored interleukin-6 to control levels in the renal cortex, indicating the protective effects on the proximal tubule occur primarily through modulation of the proinflammatory response in sepsis. CONCLUSIONS These data reveal that the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor trametinib attenuates systemic inflammation and multiple organ damage in a clinically relevant model of sepsis. Because trametinib has been safely used in humans, we propose that this drug might represent a translatable approach to limit organ injury in septic patients.
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17
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Anderberg SB, Luther T, Frithiof R. Physiological aspects of Toll-like receptor 4 activation in sepsis-induced acute kidney injury. Acta Physiol (Oxf) 2017; 219:573-588. [PMID: 27602552 PMCID: PMC5324638 DOI: 10.1111/apha.12798] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 04/08/2016] [Accepted: 09/05/2016] [Indexed: 12/21/2022]
Abstract
Sepsis‐induced acute kidney injury (SI‐AKI) is common and associated with high mortality. Survivors are at increased risk of chronic kidney disease. The precise mechanism underlying SI‐AKI is unknown, and no curative treatment exists. Toll‐like receptor 4 (TLR4) activates the innate immune system in response to exogenous microbial products. The result is an inflammatory reaction aimed at clearing a potential infection. However, the consequence may also be organ dysfunction as the immune response can cause collateral damage to host tissue. The purpose of this review is to describe the basis for how ligand binding to TLR4 has the potential to cause renal dysfunction and the mechanisms by which this may take place in gram‐negative sepsis. In addition, we highlight areas for future research that can further our knowledge of the pathogenesis of SI‐AKI in relation to TLR4 activation. TLR4 is expressed in the kidney. Activation of TLR4 causes cytokine and chemokine release as well as renal leucocyte infiltration. It also results in endothelial and tubular dysfunction in addition to altered renal metabolism and circulation. From a physiological standpoint, inhibiting TLR4 in large animal experimental SI‐AKI significantly improves renal function. Thus, current evidence indicates that TLR4 has the ability to mediate SI‐AKI by a number of mechanisms. The strong experimental evidence supporting a role of TLR4 in the pathogenesis of SI‐AKI in combination with the availability of pharmacological tools to target TLR4 warrants future human studies.
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Affiliation(s)
- S. B. Anderberg
- Department of Surgical Sciences; Section of Anesthesia & Intensive Care; Uppsala University; Uppsala Sweden
| | - T. Luther
- Department of Surgical Sciences; Section of Anesthesia & Intensive Care; Uppsala University; Uppsala Sweden
| | - R. Frithiof
- Department of Surgical Sciences; Section of Anesthesia & Intensive Care; Uppsala University; Uppsala Sweden
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18
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Histone deacetylase–mediated silencing of AMWAP expression contributes to cisplatin nephrotoxicity. Kidney Int 2017; 89:317-26. [PMID: 26509586 PMCID: PMC4848209 DOI: 10.1038/ki.2015.326] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 08/06/2015] [Accepted: 09/03/2015] [Indexed: 12/11/2022]
Abstract
Cisplatin-induced acute kidney injury is a serious problem in cancer patients during treatment of solid tumors. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. Since histone deacetylase (HDAC) inhibition augments cisplatin anti-tumor activity, we tested whether HDAC inhibitors can prevent cisplatin-induced nephrotoxicity and determined the underlying mechanism. Cisplatin upregulated the expression of several HDACs in the kidney. Inhibition of HDAC with clinically used trichostatin A suppressed cisplatin-induced kidney injury, inflammation, and epithelial cell apoptosis. Moreover, trichostatin A upregulated the novel anti-inflammatory protein, activated microglia/macrophage WAP domain protein (AMWAP), in epithelial cells which was enhanced with cisplatin treatment. Interestingly, HDAC1 and -2 specific inhibitors are sufficient to potently upregulate AMWAP in epithelial cells. Administration of recombinant AMWAP or its epithelial cell-specific overexpression reduced cisplatin-induced kidney dysfunction. Moreover, AMWAP treatment suppressed epithelial cell apoptosis, and siRNA-based knockdown of AMWAP expression abolished trichostatin A-mediated suppression of epithelial cell apoptosis in vitro. Thus, HDAC-mediated silencing of AMWAP may contribute to cisplatin nephrotoxicity. Hence, HDAC1 and -2 specific inhibitors or AMWAP could be useful therapeutic agents for the prevention of cisplatin nephrotoxicity.
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19
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Biron BM, Chung CS, O'Brien XM, Chen Y, Reichner JS, Ayala A. Cl-Amidine Prevents Histone 3 Citrullination and Neutrophil Extracellular Trap Formation, and Improves Survival in a Murine Sepsis Model. J Innate Immun 2016; 9:22-32. [PMID: 27622642 DOI: 10.1159/000448808] [Citation(s) in RCA: 119] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 08/02/2016] [Indexed: 01/24/2023] Open
Abstract
Sepsis refers to the presence of a serious infection that correlates with systemic and uncontrolled immune activation. Posttranslational histone modification plays an important role in chromatin decondensation, which is regulated by citrullination. Citrullinated histone H3 (H3cit) has been identified as a component of neutrophil extracellular traps (NETs), which are released into the extracellular space as part of the neutrophil response to infection. The conversion of arginine to citrulline residues on histones is catalyzed by peptidylarginine deiminase 4 (PAD4). This study's goals were to characterize the presence of PAD4-catalyzed H3cit and NET formation during the onset of sepsis and elucidate the effects on the immune response when this mechanism of action is blocked. Adult C57BL/6 male mice were treated with Cl-amidine, an inhibitor of PAD4, 1 h prior to sepsis induced by cecal ligation and puncture (CLP). Twenty-four hours after CLP, cytokine levels, H3cit protein expression, neutrophil counts, and NET production were evaluated in the peritoneal cavity. Survival studies were also performed. Here we demonstrate that Cl-amidine treatment prior to CLP improves overall survival in sepsis and the abrogation of PAD4 has minimal effects on the proinflammatory immune response to sepsis, while it has no effect on overall neutrophil migration to the peritoneum.
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Affiliation(s)
- Bethany M Biron
- Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Brown University, Providence, R.I., USA
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20
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Tsuji N, Tsuji T, Ohashi N, Kato A, Fujigaki Y, Yasuda H. Role of Mitochondrial DNA in Septic AKI via Toll-Like Receptor 9. J Am Soc Nephrol 2016; 27:2009-2020. [PMID: 26574043 PMCID: PMC4926971 DOI: 10.1681/asn.2015040376] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 09/27/2015] [Indexed: 12/13/2022] Open
Abstract
Toll-like receptor 9 (TLR9) contributes to the development of polymicrobial septic AKI. However, the mechanisms that activate the TLR9 pathway and cause kidney injury during sepsis remain unknown. To determine the role of mitochondrial DNA (mtDNA) in TLR9-associated septic AKI, we established a cecal ligation and puncture (CLP) model of sepsis in wild-type (WT) and Tlr9-knockout (Tlr9KO) mice. We evaluated systemic circulation and peritoneal cavity dynamics and immune response and tubular mitochondrial dysfunction to determine upstream and downstream effects on the TLR9 pathway, respectively. CLP increased mtDNA levels in the plasma and peritoneal cavity of WT and Tlr9KO mice in the early phase, but the increase in the peritoneal cavity was significantly higher in Tlr9KO mice than in WT mice. Concomitantly, leukocyte migration to the peritoneal cavity increased, and plasma cytokine production and splenic apoptosis decreased in Tlr9KO mice compared with WT mice. Furthermore, CLP-generated renal mitochondrial oxidative stress and mitochondrial vacuolization in the proximal tubules in the early phase were reversed in Tlr9KO mice. To elucidate the effects of mtDNA on immune response and kidney injury, we intravenously injected mice with mitochondrial debris (MTD), including substantial amounts of mtDNA. MTD caused an immune response similar to that induced by CLP, including upregulated levels of plasma IL-12, splenic apoptosis, and mitochondrial injury, but this effect was attenuated by Tlr9KO. Moreover, MTD-induced renal mitochondrial injury was abolished by DNase pretreatment. These findings suggest that mtDNA activates TLR9 and contributes to cytokine production, splenic apoptosis, and kidney injury during polymicrobial sepsis.
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Affiliation(s)
| | | | | | - Akihiko Kato
- Blood Purification Unit, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan; and
| | - Yoshihide Fujigaki
- Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
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21
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Sims CR, Nguyen TC, Mayeux PR. Could Biomarkers Direct Therapy for the Septic Patient? J Pharmacol Exp Ther 2016; 357:228-39. [PMID: 26857961 PMCID: PMC4851319 DOI: 10.1124/jpet.115.230797] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 02/05/2016] [Indexed: 01/25/2023] Open
Abstract
Sepsis is a serious medical condition caused by a severe systemic inflammatory response to a bacterial, fungal, or viral infection that most commonly affects neonates and the elderly. Advances in understanding the pathophysiology of sepsis have resulted in guidelines for care that have helped reduce the risk of dying from sepsis for both children and older adults. Still, over the past three decades, a large number of clinical trials have been undertaken to evaluate pharmacological agents for sepsis. Unfortunately, all of these trials have failed, with the use of some agents even shown to be harmful. One key issue in these trials was the heterogeneity of the patient population that participated. What has emerged is the need to target therapeutic interventions to the specific patient's underlying pathophysiological processes, rather than looking for a universal therapy that would be effective in a "typical" septic patient, who does not exist. This review supports the concept that identification of the right biomarkers that can direct therapy and provide timely feedback on its effectiveness will enable critical care physicians to decrease mortality of patients with sepsis and improve the quality of life of survivors.
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Affiliation(s)
- Clark R Sims
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (C.R.S., P.R.M.); and Department of Pediatrics, Section of Critical Care Medicine, Baylor College of Medicine/Texas Children's Hospital, Houston, Texas (T.C.N.)
| | - Trung C Nguyen
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (C.R.S., P.R.M.); and Department of Pediatrics, Section of Critical Care Medicine, Baylor College of Medicine/Texas Children's Hospital, Houston, Texas (T.C.N.)
| | - Philip R Mayeux
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (C.R.S., P.R.M.); and Department of Pediatrics, Section of Critical Care Medicine, Baylor College of Medicine/Texas Children's Hospital, Houston, Texas (T.C.N.)
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22
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Moser J, Heeringa P, Jongman RM, Zwiers PJ, Niemarkt AE, Yan R, de Graaf IA, Li R, Ravasz Regan E, Kümpers P, Aird WC, van Nieuw Amerongen GP, Zijlstra JG, Molema G, van Meurs M. Intracellular RIG-I Signaling Regulates TLR4-Independent Endothelial Inflammatory Responses to Endotoxin. THE JOURNAL OF IMMUNOLOGY 2016; 196:4681-91. [PMID: 27183587 DOI: 10.4049/jimmunol.1501819] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 04/01/2016] [Indexed: 12/25/2022]
Abstract
Sepsis is a systemic inflammatory response to infections associated with organ failure that is the most frequent cause of death in hospitalized patients. Exaggerated endothelial activation, altered blood flow, vascular leakage, and other disturbances synergistically contribute to sepsis-induced organ failure. The underlying signaling events associated with endothelial proinflammatory activation are not well understood, yet they likely consist of molecular pathways that act in an endothelium-specific manner. We found that LPS, a critical factor in the pathogenesis of sepsis, is internalized by endothelial cells, leading to intracellular signaling without the need for priming as found recently in immune cells. By identifying a novel role for retinoic acid-inducible gene-I (RIG-I) as a central regulator of endothelial activation functioning independent of TLR4, we provide evidence that the current paradigm of TLR4 solely being responsible for LPS-mediated endothelial responses is incomplete. RIG-I, as well as the adaptor protein mitochondrial antiviral signaling protein, regulates NF-κB-mediated induction of adhesion molecules and proinflammatory cytokine expression in response to LPS. Our findings provide essential new insights into the proinflammatory signaling pathways in endothelial cells and suggest that combined endothelial-specific inhibition of RIG-I and TLR4 will provide protection from aberrant endothelial responses associated with sepsis.
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Affiliation(s)
- Jill Moser
- Department of Critical Care, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands; Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands
| | - Peter Heeringa
- Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands
| | - Rianne M Jongman
- Department of Critical Care, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands; Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands; Department of Anesthesiology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands
| | - Peter J Zwiers
- Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands
| | - Anita E Niemarkt
- Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands
| | - Rui Yan
- Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands
| | - Inge A de Graaf
- Groningen Research Institute of Pharmacy, Division of Pharmacokinetics, Toxicology, and Targeting, University of Groningen, 9713 AV Groningen, the Netherlands
| | - Ranran Li
- Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands
| | - Erzsébet Ravasz Regan
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA 02215; Biochemistry and Molecular Biology Program, Department of Biology, The College of Wooster, Wooster, OH 44691
| | - Philipp Kümpers
- Division of General Internal Medicine, Nephrology, and Rheumatology, Department of Medicine D, University Hospital Muenster, 48149 Muenster, Germany; and
| | - William C Aird
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA 02215
| | - Geerten P van Nieuw Amerongen
- Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, 1081 HZ Amsterdam, the Netherlands
| | - Jan G Zijlstra
- Department of Critical Care, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands
| | - Grietje Molema
- Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands;
| | - Matijs van Meurs
- Department of Critical Care, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands; Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands
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Lakshmikanth CL, Jacob SP, Chaithra VH, de Castro-Faria-Neto HC, Marathe GK. Sepsis: in search of cure. Inflamm Res 2016; 65:587-602. [PMID: 26995266 DOI: 10.1007/s00011-016-0937-y] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Revised: 02/23/2016] [Accepted: 02/29/2016] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Sepsis is a complex inflammatory disorder believed to originate from an infection by any types of microbes and/or their products. It is the leading cause of death in intensive care units (ICUs) throughout the globe. The mortality rates depend both on the severity of infection and the host's response to infection. METHODS Literature survey on pathobiology of sepsis in general and failure of more than hundred clinical trials conducted so far in search of a possible cure for sepsis resulted in the preparation of this manuscript. FINDINGS Sepsis lacks a suitable animal model that mimics human sepsis. However, based on the results obtained in animal models of sepsis, clinical trials conducted so far have been disappointing. Although involvement of multiple mediators and pathways in sepsis has been recognized, only few components are being targeted and this could be the major reason behind the failure of clinical trials. CONCLUSION Inability to recognize a single critical mediator of sepsis may be the underlying cause for the poor therapeutic intervention of sepsis. Therefore, sepsis is still considered as a disease-in search of cure.
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Affiliation(s)
| | - Shancy Petsel Jacob
- Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysore, 570 006, India
| | | | | | - Gopal Kedihithlu Marathe
- Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysore, 570 006, India.
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24
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Yu JB, Shi J, Zhang Y, Gong LR, Dong SA, Cao XS, Wu LL, Wu LN. Electroacupuncture Ameliorates Acute Renal Injury in Lipopolysaccharide-Stimulated Rabbits via Induction of HO-1 through the PI3K/Akt/Nrf2 Pathways. PLoS One 2015; 10:e0141622. [PMID: 26524181 PMCID: PMC4629879 DOI: 10.1371/journal.pone.0141622] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Accepted: 10/07/2015] [Indexed: 11/18/2022] Open
Abstract
Electroacupuncture at select acupoints have been verified to protect against organ dysfunctions during endotoxic shock. And, heme oxygenase (HO)-1 as a phase II enzyme and antioxidant contributed to the protection of kidney in septic shock rats. The phosphatidylinositol 3-kinase (PI3K)-Akt pathway mediated the activation of NF-E2 related factor-2 (Nrf2), which was involved in HO-1 induction. To understand the efficacy of electroacupuncture stimulation in ameliorating acute kidney injury (AKI) through the PI3K/Akt/Nrf2 pathway and subsequent HO-1 upregulation, a dose of LPS 5mg/kg was administered intravenously to replicate the rabbit model of AKI induced by endotoxic shock. Electroacupuncture pretreatment was handled bilaterally at Zusanli and Neiguan acupoints for five consecutive days while sham electroacupuncture at non-acupoints as control. Results displayed that electroacupuncture stimulation significantly alleviated the morphologic renal damage, attenuated renal tubular apoptosis, suppressed the elevated biochemical indicators of AKI caused by LPS, enhanced the expressions of phospho-Akt, HO-1protein, Nrf2 total and nucleoprotein, and highlighted the proportions of Nrf2 nucleoprotein as a parallel. Furthermore, partial protective effects of elecroacupuncture were counteracted by preconditioning with wortmannin (the selective PI3K inhibitor), indicating a direct involvement of PI3K/Akt pathway. Inconsistently, wortmannin pretreatment made little difference to the expressions of HO-1, Nrf2 nucleoprotein and total protein, which indicated that PI3K/Akt may be not the only pathway responsible for electroacupuncture-afforded protection against LPS-induced AKI. These findings provide new insights into the potential future clinical applications of electroacupuncture for AKI induced by endotoxic shock instead of traditional remedies.
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Affiliation(s)
- Jian-bo Yu
- Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
- * E-mail:
| | - Jia Shi
- Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Yuan Zhang
- Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Li-rong Gong
- Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Shu-an Dong
- Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Xin-shun Cao
- Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Li-li Wu
- Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Li-na Wu
- Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
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25
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Liu JR, Han X, Soriano SG, Yuki K. Leukocyte function-associated antigen-1 deficiency impairs responses to polymicrobial sepsis. World J Clin Cases 2015; 3:793-806. [PMID: 26380827 PMCID: PMC4568529 DOI: 10.12998/wjcc.v3.i9.793] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Revised: 04/10/2015] [Accepted: 06/15/2015] [Indexed: 02/05/2023] Open
Abstract
AIM To determine the role of leukocyte function-associated antigen-1 (LFA-1) in polymicrobial sepsis model in mice. METHODS Cecal ligation and puncture model was used to study polymicrobial sepsis in wild type and LFA-1 knockout (KO) (= CD11a KO) mice. Their survivals were examined. Neutrophil recruitment to the abdominal cavity, bacterial tissue load and bacterial killing by neutrophils, tissue cytokine profiles, and serum cytokines were examined. Apoptosis of tissues was assessed using cleaved-caspase 3 and TUNNEL staining. The recruitment of neutrophils to various tissues was assessed using myeloperoxidase staining or measuring myeloperoxidase activity. RESULTS LFA-1 deficiency significantly decreased survival (P = 0.0024) with the reduction of neutrophil recruitment to the abdominal cavity and higher bacterial load in blood. It was also associated with increased apoptosis in spleen and more organ injuries probed by interleukin-6 mRNA level. However, the deficiency of LFA-1 did not prevent neutrophil recruitment to lung, liver, spleen or kidney, which suggested the existence of LFA-1 independent recruitment mechanism in these organs. CONCLUSION LFA-1 deficiency did not attenuate neutrophil recruitment to various organs to adequately mitigate secondary tissue injury in sepsis. It was associated with decreased neutrophil recruitment to the abdominal cavity, higher bacterial load, leading to increased mortality in an abdominal, polymicrobial sepsis.
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26
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Urner M, Schläpfer M, Herrmann IK, Hasler M, Schimmer RR, Booy C, Roth Z'graggen B, Rehrauer H, Aigner F, Minshall RD, Stark WJ, Beck-Schimmer B. Insight into the beneficial immunomodulatory mechanism of the sevoflurane metabolite hexafluoro-2-propanol in a rat model of endotoxaemia. Clin Exp Immunol 2015; 181:468-79. [PMID: 25925908 DOI: 10.1111/cei.12648] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2015] [Indexed: 12/13/2022] Open
Abstract
Volatile anaesthetics such as sevoflurane attenuate inflammatory processes, thereby impacting patient outcome significantly. Their inhalative administration is, however, strictly limited to controlled environments such as operating theatres, and thus an intravenously injectable immunomodulatory drug would offer distinct advantages. As protective effects of volatile anaesthetics have been associated with the presence of trifluorinated carbon groups in their basic structure, in this study we investigated the water-soluble sevoflurane metabolite hexafluoro-2-propanol (HFIP) as a potential immunomodulatory drug in a rat model of endotoxic shock. Male Wistar rats were subjected to intravenous lipopolysaccharide (LPS) and thereafter were treated with HFIP. Plasma and tissue inflammatory mediators, neutrophil invasion, tissue damage and haemodynamic stability were the dedicated end-points. In an endotoxin-induced endothelial cell injury model, underlying mechanisms were elucidated using gene expression and gene reporter analyses. HFIP reduced the systemic inflammatory response significantly and decreased endotoxin-induced tissue damage. Additionally, the LPS-provoked drop in blood pressure of animals was resolved by HFIP treatment. Pathway analysis revealed that the observed attenuation of the inflammatory process was associated with reduced nuclear factor kappa B (NF-κΒ) activation and suppression of its dependent transcripts. Taken together, intravenous administration of HFIP exerts promising immunomodulatory effects in endotoxaemic rats. The possibility of intravenous administration would overcome limitations of volatile anaesthetics, and thus HFIP might therefore represent an interesting future drug candidate for states of severe inflammation.
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Affiliation(s)
- M Urner
- Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.,Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - M Schläpfer
- Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.,Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - I K Herrmann
- Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland
| | - M Hasler
- Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland
| | - R R Schimmer
- Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - C Booy
- Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.,Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - B Roth Z'graggen
- Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.,Functional Genomics Center Zurich, University of Zurich, Zurich, Switzerland
| | - H Rehrauer
- Functional Genomics Center Zurich, University of Zurich, Zurich, Switzerland
| | - F Aigner
- Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - R D Minshall
- Department of Anesthesiology, University of Illinois Chicago, Chicago, IL, USA
| | - W J Stark
- Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, Zurich, Switzerland
| | - B Beck-Schimmer
- Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.,Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.,Department of Anesthesiology, University of Illinois Chicago, Chicago, IL, USA
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27
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El-Achkar TM, Dagher PC. Tubular cross talk in acute kidney injury: a story of sense and sensibility. Am J Physiol Renal Physiol 2015; 308:F1317-23. [PMID: 25877507 DOI: 10.1152/ajprenal.00030.2015] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 04/10/2015] [Indexed: 01/20/2023] Open
Abstract
The mammalian kidney is an organ composed of numerous functional units or nephrons. Beyond the filtering glomerulus of each nephron, various tubular segments with distinct populations of epithelial cells sequentially span the kidney from cortex to medulla. The highly organized folding of the tubules results in a spatial distribution that allows intimate contact between various tubular subsegments. This unique arrangement can promote a newly recognized type of horizontal epithelial-to-epithelial cross talk. In this review, we discuss the importance of this tubular cross talk in shaping the response of the kidney to acute injury in a sense and sensibility model. We propose that injury-resistant tubules such as S1 proximal segments and thick ascending limbs (TAL) can act as "sensors" and thus modulate the responsiveness or "sensibility" of the S2-S3 proximal segments to injury. We also discuss new findings that highlight the importance of tubular cross talk in regulating homeostasis and inflammation not only in the kidney, but also systemically.
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Affiliation(s)
- Tarek M El-Achkar
- Indiana University School of Medicine, Indianapolis, Indiana; and Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana
| | - Pierre C Dagher
- Indiana University School of Medicine, Indianapolis, Indiana; and
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28
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Circulating microRNA-223 serum levels do not predict sepsis or survival in patients with critical illness. DISEASE MARKERS 2015; 2015:384208. [PMID: 25810564 PMCID: PMC4355123 DOI: 10.1155/2015/384208] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 02/04/2015] [Indexed: 12/01/2022]
Abstract
Background and Aims. Dysregulation of miR-223 was recently linked to various diseases associated with systemic inflammatory responses such as type 2 diabetes, cancer, and bacterial infections. However, contradictory results are available on potential alterations of miR-223 serum levels during sepsis. We thus aimed to evaluate the diagnostic and prognostic value of miR-223 serum concentrations in patients with critical illness and sepsis. Methods. We used i.v. injection of lipopolysaccharide (LPS) as well as cecal pole ligation and puncture (CLP) for induction of polymicrobial sepsis in mice and measured alterations in serum levels of miR-223. These results from mice were translated into a large and well-characterized cohort of critically ill patients admitted to the medical intensive care unit (ICU). Finally, results from analysis in patients were correlated with clinical data and extensive sets of routine and experimental biomarkers. Results. Although LPS injection induced moderately elevated serum miR-223 levels in mice, no significant alterations in miR-223 serum levels were found in mice after CLP-induced sepsis. In accordance with these results from animal models, serum miR-223 levels did not differ between critically ill patients and healthy controls. However, ICU patients with more severe disease (APACHE-II score) showed moderately reduced circulating miR-223. Strikingly, no differences in miR-223 levels were found in critically ill patients with or without sepsis, and serum levels of miR-223 did not correlate with classical markers of inflammation or bacterial infection. Finally, low miR-223 serum levels were moderately associated with an unfavorable prognosis of patients during the ICU treatment but did not predict long-term mortality. Conclusion. Recent reports on alterations in miR-223 serum levels during sepsis revealed contradictory results, preventing a potential use of this miRNA in clinical routine. We clearly show that miR-223 serum levels do not reflect the presence of sepsis neither in mouse models nor in a large cohort of ICU patients and do not indicate clinical outcome of critically ill patients. Thus miR-223 serum levels should not be used as a biomarker in this setting.
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29
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Otto GP, Grünwald B, Geis C, Köthe S, Hurtado-Oliveros J, Chung HY, Ekaney M, Bockmeyer CL, Sossdorf M, Busch M, Claus RA. Impact of antibiotic treatment intensity on long-term sepsis-associated kidney injury in a polymicrobial peritoneal contamination and infection model. Nephron Clin Pract 2015; 129:137-42. [PMID: 25634142 DOI: 10.1159/000368701] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2014] [Accepted: 09/26/2014] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS Long-term kidney affections after sepsis are poorly understood. Animal models for investigating kidney damage in the late phase of disease progression are limited. The aim of this study was to investigate the impact of two antibiotic regimes on persistence of kidney injury after peritonitis. METHODS Kidney damage was investigated 65 days after polymicrobial peritoneal contamination and infection (PCI) sepsis induction in C57BL/6 mice. Short-term antibiotic therapy (STA, 4 days) was compared to long-term (LTA, 10 days) treatment using plasma creatinine, plasma and urine neutrophil gelatinase-associated lipocalin (NGAL), urine albumin/creatinine ratio and renal histology. RESULTS Sepsis resulted in mortality rates of 68.2% (STA) and 61.0% (LTA). Surviving STA animals showed the most pronounced kidney damage indicated by significantly elevated levels of creatinine and acute tubular damage (ATD), whereas NGAL was significantly increased in LTA survivors only. A creatinine level above 0.3 mg/dl was used to define kidney injury, found in 21.4% of STA animals and 7.8% of LTA animals. While animals with kidney injury demonstrated significantly higher ATD scores and persistent tubular damage, no significant differences were found for plasma or urine NGAL levels or urine albumin/creatinine ratios. CONCLUSION Prolonged antibiotic treatment reduced the rate of ongoing peritonitis-induced kidney injury in a C57BL/6 mouse model. Plasma or urine NGAL levels were not able to identify animals with or without persistent kidney injury. The kidney injury after the PCI mouse model represents prototypic clinical findings and should be used for further studies investigating disease mechanisms.
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Affiliation(s)
- Gordon P Otto
- Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
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30
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Gong W, Hu E, Dou H, Song Y, Yang L, Ji J, Li E, Tan R, Hou Y. A novel 1,2-benzenediamine derivative FC-99 suppresses TLR3 expression and ameliorates disease symptoms in a mouse model of sepsis. Br J Pharmacol 2014; 171:4866-78. [PMID: 24903157 DOI: 10.1111/bph.12797] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 05/13/2014] [Accepted: 05/28/2014] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND AND PURPOSE Sepsis is a clinical condition characterized by overwhelming systemic inflammation with high mortality rate and high prevalence, but effective treatment is still lacking. Toll-like receptor 3 (TLR3) is an endogenous sensor, thought to regulate the amplification of immune response during sepsis. Modulators of TLR3 have an advantage in the treatment of sepsis. Here, we aimed to explore the mechanism of a monosubstituted 1,2-benzenediamine derivative FC-99 {N(1) -[(4-methoxy)methyl]-4-methyl-1,2-benzenediamine}on modulating TLR3 expression and its therapeutic potential on mouse model of sepsis. EXPERIMENTAL APPROACH Cells were pretreated with FC-99 followed by poly(I:C) or IFN-α stimulation; TLR3 and other indicators were assayed. Female C57BL/6 mice were subjected to sham or caecal ligation puncture (CLP) surgery after i.p. injection of vehicle or FC-99; serum and tissues were collected for further experiments. KEY RESULTS FC-99 suppressed inflammatory response induced by poly(I:C) with no effect on cell viability or uptake of poly(I:C). FC-99 also inhibited TLR3 expression induced by not only poly(I:C) but also by exogenous IFN-α. This inhibition of FC-99 was related to the poly(I:C)-evoked IRF3/IFN-α/JAK/STAT1 signalling pathway. In CLP-induced model of sepsis, FC-99 administration decreased mice mortality and serum levels of inflammatory factors, attenuated multiple organ dysfunction and enhanced bacterial clearance. Accordingly, systemic and local expression of TLR3 was reduced by FC-99 in vivo. CONCLUSION AND IMPLICATIONS FC-99 reversed TLR3 expression and ameliorate CLP-induced sepsis in mice. Thus, FC-99 will be a potential therapeutic candidate for sepsis.
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Affiliation(s)
- Wei Gong
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China
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Doi K, Yahagi N, Nangaku M, Noiri E. [Acute kidney injury: progress in diagnosis and treatments. Topics: IV. Pathophysiology and treatments; 2. Acute kidney injury in intensive care unit]. ACTA ACUST UNITED AC 2014; 103:1081-7. [PMID: 25026777 DOI: 10.2169/naika.103.1081] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Morrell ED, Kellum JA, Pastor-Soler NM, Hallows KR. Septic acute kidney injury: molecular mechanisms and the importance of stratification and targeting therapy. Crit Care 2014; 18:501. [PMID: 25575158 PMCID: PMC4729166 DOI: 10.1186/s13054-014-0501-5] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The most common cause of acute kidney injury (AKI) in hospitalized patients is sepsis. However, the molecular pathways and mechanisms that mediate septic AKI are not well defined. Experiments performed over the past 20 years suggest that there are profound differences in the pathogenesis between septic and ischemic AKI. Septic AKI often occurs independently of hypoperfusion, and is mediated by a concomitant pro- and anti-inflammatory state that is activated in response to various pathogen-associated molecular patterns, such as endotoxin, as well as damage-associated molecular patterns. These molecular patterns are recognized by Toll-like receptors (TLRs) found in the kidney, and effectuate downstream inflammatory pathways. Additionally, apoptosis has been proposed to play a role in the pathogenesis of septic AKI. However, targeted therapies designed to mitigate the above aspects of the inflammatory state, TLR-related pathways, and apoptosis have failed to show significant clinical benefit. This failure is likely due to the protean nature of septic AKI, whereby different patients present at different points along the immunologic spectrum. While one patient may benefit from targeted therapy at one end of the spectrum, another patient at the other end may be harmed by the same therapy. We propose that a next important step in septic AKI research will be to identify where patients lie on the immunologic spectrum in order to appropriately target therapies at the inflammatory cascade, TLRs, and possibly apoptosis.
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Affiliation(s)
- Eric D Morrell
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
| | - John A Kellum
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
- The Center for Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
- CRISMA (Clinical Research Systems Modeling of Acute Illness) Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
| | - Núria M Pastor-Soler
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
- The Center for Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
| | - Kenneth R Hallows
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
- The Center for Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
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Khowailed A, Younan SM, Ashour H, Kamel AE, Sharawy N. Effects of ghrelin on sepsis-induced acute kidney injury: one step forward. Clin Exp Nephrol 2014; 19:419-26. [PMID: 25002019 DOI: 10.1007/s10157-014-1006-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 06/19/2014] [Indexed: 01/05/2023]
Abstract
BACKGROUND Among the several disorders induced by sepsis, acute kidney injury (AKI) represents the most important economic burden problem that is associated with high mortality and morbidity rates. The aim of this study was to investigate the anti-inflammatory effects of ghrelin in sepsis-induced AKI and the possible role of vagus nerve. METHODS Five groups were included: sham, cecal ligation and puncture (CLP), CLP-ghrelin, CLP-vagotomy and CLP-vagotomy-ghrelin group. RESULTS Ghrelin treatment immediately after induction of CLP, significantly improved renal Glomerular filtration rate (GFR), serum creatinine, BUN and renal necrosis score as compared to the unprotected CLP group. In addition, ghrelin significantly decreased renal TNF alpha (111.5 ± 10.35 vs. 291.8 ± 15.8 pg/mg ptn), VCAM1 (6.28 ± 1.7 vs. 12.9 ± 1.2 µ/g ptn) and MPO (0.95 ± 0.13 vs. 2.5 ± 0.4 µ/g ptn) without significant increase in renal IL-10. Those effects were abolished by vagotomy. CONCLUSION We concluded that ghrelin could represent new therapeutic window in early treatment of sepsis-induced AKI and this could be mainly due to its anti-inflammatory effects.
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Affiliation(s)
- Akef Khowailed
- Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Hend Ashour
- Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Abd Elkarim Kamel
- Department of Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Nivin Sharawy
- Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt. .,Departments of Anesthesia, Pain Management and Perioperative Medicine's, Faculty of Medicine, Dalhousie University, Halifax, Canada.
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Gao R, Chen J, Hu Y, Li Z, Wang S, Shetty S, Fu J. Sirt1 deletion leads to enhanced inflammation and aggravates endotoxin-induced acute kidney injury. PLoS One 2014; 9:e98909. [PMID: 24896770 PMCID: PMC4045768 DOI: 10.1371/journal.pone.0098909] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 05/08/2014] [Indexed: 01/20/2023] Open
Abstract
Bacterial endotoxin has been known to induce excessive inflammatory responses and acute kidney injury. In the present study, we used a mouse model of endotoxemia to investigate the role of Sirt1 in inflammatory kidney injury. We examined molecular and cellular responses in inducible Sirt1 knockout (Sirt1-/-) mice and wild type littermates (Sirt1+/+) in lipopolysaccharide (LPS)-induced kidney injury. Our studies demonstrated that Sirt1 deletion caused aggravated kidney injury, which was associated with increased inflammatory responses including elevated pro-inflammatory cytokine production, and increased ICAM-1 and VCAM-1 expression. Inflammatory signaling such as STAT3/ERK phosphorylation and NF-κB activation was markedly elevated in kidney tissues of Sirt1 knockout mice after LPS challenge. The results indicate that Sirt1 is protective against LPS-induced acute kidney injury by suppressing kidney inflammation and down-regulating inflammatory signaling.
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Affiliation(s)
- Rong Gao
- The Second Hospital of Jilin University, Changchun, Jilin, China
- Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America
| | - Jiao Chen
- Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America
| | - Yuxin Hu
- The Second Hospital of Jilin University, Changchun, Jilin, China
- Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America
| | - Zhenyu Li
- Division of Cardiovascular Medicine, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America
| | - Shuxia Wang
- Graduate Center for Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America
| | - Sreerama Shetty
- Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America
| | - Jian Fu
- Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America
- Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America
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Abstract
Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain receptors (NLRs) are families of pattern recognition receptors that, together with inflammasomes, sense and respond to highly conserved pathogen motifs and endogenous molecules released upon cell damage or stress. Evidence suggests that TLRs, NLRs and the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome have important roles in kidney diseases through regulation of inflammatory and tissue-repair responses to infection and injury. In this Review, we discuss the pathological mechanisms that are related to TLRs, NLRs and NLRP3 in various kidney diseases. In general, these receptors are protective in the host defence against urinary tract infection, but can sustain and self-perpetuate tissue damage in sterile inflammatory and immune-mediated kidney diseases. TLRs, NLRs and NLRP3, therefore, have become promising drug targets to enable specific modulation of kidney inflammation and suppression of immunopathology in kidney disease.
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Ramesh G, Ranganathan P. Mouse models and methods for studying human disease, acute kidney injury (AKI). Methods Mol Biol 2014; 1194:421-36. [PMID: 25064118 DOI: 10.1007/978-1-4939-1215-5_24] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Acute kidney injury (AKI) is serious complication in hospitalized patients with high level of mortality. There is not much progress made for the past 50 years in reducing the mortality rate despite advances in understanding disease pathology. Using variety of animal models of acute kidney injury, scientist studies the pathogenic mechanism of AKI and to test therapeutic drugs, which may reduce renal injury. Among them, renal pedicle clamping and cisplatin induced nephrotoxicity in mice are most prominently used, mainly due to the availability of gene knockouts to study specific gene functions, inexpensive and availability of the inbred strain with less genetic variability. However, ischemic mouse model is highly variable and require excellent surgical skills to reduce variation in the observation. In this chapter, we describe a detailed protocol of the mouse model of bilateral renal ischemia-reperfusion and cisplatin induced nephrotoxicity. We also discuss the protocol for the isolation and analysis of infiltrated inflammatory cell into the kidney by flow cytometry. Information provided in this chapter will help scientist who wants to start research on AKI and want to establish the mouse model for ischemic and toxic kidney injury.
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Affiliation(s)
- Ganesan Ramesh
- Department of Medicine and Vascular Biology Center, CB-3330, Georgia Health Sciences University, 1459 Laney-Walker Blvd, Augusta, GA, 30912, USA,
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Bomsztyk K, Flanagin S, Mar D, Mikula M, Johnson A, Zager R, Denisenko O. Synchronous recruitment of epigenetic modifiers to endotoxin synergistically activated Tnf-α gene in acute kidney injury. PLoS One 2013; 8:e70322. [PMID: 23936185 PMCID: PMC3728219 DOI: 10.1371/journal.pone.0070322] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Accepted: 06/18/2013] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND As a consequence of acute kidney injury (AKI), proximal tubular cells hyperrespond to endotoxin (lipopolysaccharide, LPS) by exaggerated renal Tnf-α Production. This LPS hyperresponsiveness is transcriptionally mediated. The epigenetic pathways that control these responses are unknown. METHODS/FINDINGS We applied multiplex chromatin immunoprecipitation platform (Matrix ChIP) to explore epigenetic pathways that underlie endotoxin hyperresponsiveness in the setting of preceding unilateral renal ischemia/reperfusion (I/R) in mouse AKI model. Endotoxin exposure after I/R resulted in enhanced transcription, manifested by hyperresponsive recruitment of RNA polymerase II (Pol II) at the Tnf-α gene. At this locus, LPS but not I/R increased levels of Pol II C-terminal domain (CTD) phosho-serine2 &5 and induced dephosphorylation of the transcription-repressive histone H4 phospho-serine-1. In contrast, I/R but not LPS increased the transcription-permissive histone phosphorylation (H3 phospho-serine-10, H3.3 phospho-serine-31) at the Tnf-α gene. In agreement with these observations, I/R but not LPS increased activity of cognate kinases (Erk1/2, Msk1/2 and Aurora A) at the Tnf-α locus. Cross-talk of histone phosphorylation and acetylation synergize to active gene expression. I/R and LPS increased histone acetylation. (H3K9/14Ac, H4K5/8/12/16Ac, H2KA5Ac, H2BK4/7Ac). Levels of some histone acetyltransferases at this gene (PCAF and MOF) were increased by I/R but not by LPS, while others were induced by either I/R or LPS and exhibited endotoxin hyperresponsive patterns (GCN5, CBP and p300). The adaptor protein 14-3-3 couples histone phosphorylation with acetylation, and tethers chromatin modifiers/transcription elongation factors to target genes. Both I/R and LPS increased levels of 14-3-3 and several chromatin/transcription modifiers (BRD4, BRG1, HP-1γ and IKKα) at the Tnf-α gene, all exhibiting endotoxin hyperresponsive recruitment patterns similar to Pol II. CONCLUSIONS Our results suggest that I/R and LPS differentially trigger phosphorylation (Pol II and histone) and acetylation (histone) epigenetic pathways that interact at the Tnf-α gene to generate endotoxin hyperresponse in AKI.
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Affiliation(s)
- Karol Bomsztyk
- Department of Medicine, University of Washington, Seattle, Washington, USA.
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Deng M, Scott MJ, Loughran P, Gibson G, Sodhi C, Watkins S, Hackam D, Billiar TR. Lipopolysaccharide clearance, bacterial clearance, and systemic inflammatory responses are regulated by cell type-specific functions of TLR4 during sepsis. THE JOURNAL OF IMMUNOLOGY 2013; 190:5152-60. [PMID: 23562812 DOI: 10.4049/jimmunol.1300496] [Citation(s) in RCA: 155] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The morbidity associated with bacterial sepsis is the result of host immune responses to pathogens, which are dependent on pathogen recognition by pattern recognition receptors, such as TLR4. TLR4 is expressed on a range of cell types, yet the mechanisms by which cell-specific functions of TLR4 lead to an integrated sepsis response are poorly understood. To address this, we generated mice in which TLR4 was specifically deleted from myeloid cells (LysMTLR4KO) or hepatocytes (HCTLR4KO) and then determined survival, bacterial counts, host inflammatory responses, and organ injury in a model of cecal ligation and puncture (CLP), with or without antibiotics. LysM-TLR4 was required for phagocytosis and efficient bacterial clearance in the absence of antibiotics. Survival, the magnitude of the systemic and local inflammatory responses, and liver damage were associated with bacterial levels. HCTLR4 was required for efficient LPS clearance from the circulation, and deletion of HCTLR4 was associated with enhanced macrophage phagocytosis, lower bacterial levels, and improved survival in CLP without antibiotics. Antibiotic administration during CLP revealed an important role for hepatocyte LPS clearance in limiting sepsis-induced inflammation and organ injury. Our work defines cell type-selective roles for TLR4 in coordinating complex immune responses to bacterial sepsis and suggests that future strategies for modulating microbial molecule recognition should account for varying roles of pattern recognition receptors in multiple cell populations.
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Affiliation(s)
- Meihong Deng
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
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Liu L, Li Y, Hu Z, Su J, Huo Y, Tan B, Wang X, Liu Y. Small interfering RNA targeting Toll-like receptor 9 protects mice against polymicrobial septic acute kidney injury. Nephron Clin Pract 2013; 122:51-61. [PMID: 23548820 DOI: 10.1159/000346953] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Accepted: 01/08/2013] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND/AIMS Although recent reports suggest that Toll-like receptor (TLR) 9 is associated with the pathogenesis of polymicrobial septic acute kidney injury (AKI), it is still unclear whether and how renal TLR9 is involved in the development of polymicrobial septic AKI. This study aimed to determine whether the expression of TLR9 in mouse renal cells is related to the development of polymicrobial septic AKI. METHODS The efficacy of small interfering RNA (siRNA) targeting TLR9 was tested in a cultured murine macrophage cell line (RAW264.7 cells). The most potent siRNA was transfected into mice using the hydrodynamic method prior to the induction of polymicrobial septic AKI being induced by cecal ligation and puncture (CLP). TLR9 knockdown was determined by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting in RAW264.7 cells and kidney tissues. The levels of serum creatinine and blood urea nitrogen (BUN) and the renal histopathology assessment were determined at 6-, 12-, and 24-hour time points after CLP, and renal cell apoptosis was studied at 24 h. The 4- and 7-day survival rates of mice were also observed. RESULTS We found that mice developed AKI in our model of polymicrobial sepsis, despite fluid and antibiotic resuscitation, which resembles human sepsis. siRNA to TLR9 successfully silenced the induction of renal TLR9 gene and protein expression following CLP. Effective silencing of renal TLR9 expression decreased renal cell apoptosis, mitigated the severity of AKI, and increased the survival of mice. CONCLUSIONS Our data demonstrates the induction of TLR9 expression in mouse kidney tissue following CLP. Renal cell apoptosis and AKI in our model of polymicrobial sepsis are dependent on TLR9. Thus, TLR9 may play a critical role in the pathophysiology of polymicrobial septic AKI.
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Affiliation(s)
- Lixia Liu
- Department of Intensive Care Unit, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, China
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Elias RM, Correa-Costa M, Barreto CR, Silva RC, Hayashida CY, Castoldi Â, Gonçalves GM, Braga TT, Barboza R, Rios FJ, Keller AC, Cenedeze MA, Hyane MI, D'Império-Lima MR, Figueiredo-Neto AM, Reis MA, Marinho CRF, Pacheco-Silva A, Câmara NOS. Oxidative stress and modification of renal vascular permeability are associated with acute kidney injury during P. berghei ANKA infection. PLoS One 2012; 7:e44004. [PMID: 22952850 PMCID: PMC3432099 DOI: 10.1371/journal.pone.0044004] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Accepted: 07/27/2012] [Indexed: 12/21/2022] Open
Abstract
Malaria associated-acute kidney injury (AKI) is associated with 45% of mortality in adult patients hospitalized with severe form of the disease. However, the causes that lead to a framework of malaria-associated AKI are still poorly characterized. Some clinical studies speculate that oxidative stress products, a characteristic of Plasmodium infection, as well as proinflammatory response induced by the parasite are involved in its pathophysiology. Therefore, we aimed to investigate the development of malaria-associated AKI during infection by P. berghei ANKA, with special attention to the role played by the inflammatory response and the involvement of oxidative stress. For that, we took advantage of an experimental model of severe malaria that showed significant changes in the renal pathophysiology to investigate the role of malaria infection in the renal microvascular permeability and tissue injury. Therefore, BALB/c mice were infected with P. berghei ANKA. To assess renal function, creatinine, blood urea nitrogen, and ratio of proteinuria and creatininuria were evaluated. The products of oxidative stress, as well as cytokine profile were quantified in plasma and renal tissue. The change of renal microvascular permeability, tissue hypoxia and cellular apoptosis were also evaluated. Parasite infection resulted in renal dysfunction. Furthermore, we observed increased expression of adhesion molecule, proinflammatory cytokines and products of oxidative stress, associated with a decrease mRNA expression of HO-1 in kidney tissue of infected mice. The measurement of lipoprotein oxidizability also showed a significant increase in plasma of infected animals. Together, our findings support the idea that products of oxidative stress, as well as the immune response against the parasite are crucial to changes in kidney architecture and microvascular endothelial permeability of BALB/c mice infected with P. berghei ANKA.
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Affiliation(s)
- Rosa Maria Elias
- Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Matheus Correa-Costa
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
| | | | - Reinaldo Correia Silva
- Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Caroline Y. Hayashida
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
| | - Ângela Castoldi
- Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Giselle Martins Gonçalves
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
| | - Tarcio Teodoro Braga
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
| | - Renato Barboza
- Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Francisco José Rios
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
| | | | - Marcos Antonio Cenedeze
- Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Meire Ioshie Hyane
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
| | - Maria Regina D'Império-Lima
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
| | | | - Marlene Antônia Reis
- Divisão de Patologia, Universidade Federal do Triângulo Mineiro, Uberaba, Brazil
| | | | - Alvaro Pacheco-Silva
- Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Instituto Israelita de Ensino e Pesquisa Albert Einstein, São Paulo, Brazil
| | - Niels Olsen Saraiva Câmara
- Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
- * E-mail:
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Castoldi A, Braga TT, Correa-Costa M, Aguiar CF, Bassi ÊJ, Correa-Silva R, Elias RM, Salvador F, Moraes-Vieira PM, Cenedeze MA, Reis MA, Hiyane MI, Pacheco-Silva Á, Gonçalves GM, Câmara NOS. TLR2, TLR4 and the MYD88 signaling pathway are crucial for neutrophil migration in acute kidney injury induced by sepsis. PLoS One 2012; 7:e37584. [PMID: 22655058 PMCID: PMC3360043 DOI: 10.1371/journal.pone.0037584] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Accepted: 04/22/2012] [Indexed: 01/01/2023] Open
Abstract
The aim of this study was to investigate the role of TLR2, TLR4 and MyD88 in sepsis-induced AKI. C57BL/6 TLR2−/−, TLR4−/− and MyD88−/− male mice were subjected to sepsis by cecal ligation and puncture (CLP). Twenty four hours later, kidney tissue and blood samples were collected for analysis. The TLR2−/−, TLR4−/− and MyD88−/− mice that were subjected to CLP had preserved renal morphology, and fewer areas of hypoxia and apoptosis compared with the wild-type C57BL/6 mice (WT). MyD88−/− mice were completely protected compared with the WT mice. We also observed reduced expression of proinflammatory cytokines in the kidneys of the knockout mice compared with those of the WT mice and subsequent inhibition of increased vascular permeability in the kidneys of the knockout mice. The WT mice had increased GR1+low cells migration compared with the knockout mice and decreased in GR1+high cells migration into the peritoneal cavity. The TLR2−/−, TLR4−/−, and MyD88−/− mice had lower neutrophil infiltration in the kidneys. Depletion of neutrophils in the WT mice led to protection of renal function and less inflammation in the kidneys of these mice. Innate immunity participates in polymicrobial sepsis-induced AKI, mainly through the MyD88 pathway, by leading to an increased migration of neutrophils to the kidney, increased production of proinflammatory cytokines, vascular permeability, hypoxia and apoptosis of tubular cells.
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Affiliation(s)
- Angela Castoldi
- Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
| | - Tárcio Teodoro Braga
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
| | - Matheus Correa-Costa
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
| | - Cristhiane Fávero Aguiar
- Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Ênio José Bassi
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
| | - Reinaldo Correa-Silva
- Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Rosa Maria Elias
- Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Fábia Salvador
- Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Pedro Manoel Moraes-Vieira
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
| | - Marcos Antônio Cenedeze
- Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | | | - Meire Ioshie Hiyane
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
| | - Álvaro Pacheco-Silva
- Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- IIEP, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Giselle Martins Gonçalves
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
| | - Niels Olsen Saraiva Câmara
- Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia, Universidade de São Paulo, São Paulo, Brazil
- * E-mail:
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Abstract
Acute kidney injury (AKI) is the leading cause of nephrology consultation and is associated with high mortality rates. The primary causes of AKI include ischemia, hypoxia, or nephrotoxicity. An underlying feature is a rapid decline in glomerular filtration rate (GFR) usually associated with decreases in renal blood flow. Inflammation represents an important additional component of AKI leading to the extension phase of injury, which may be associated with insensitivity to vasodilator therapy. It is suggested that targeting the extension phase represents an area potential of treatment with the greatest possible impact. The underlying basis of renal injury appears to be impaired energetics of the highly metabolically active nephron segments (i.e., proximal tubules and thick ascending limb) in the renal outer medulla, which can trigger conversion from transient hypoxia to intrinsic renal failure. Injury to kidney cells can be lethal or sublethal. Sublethal injury represents an important component in AKI, as it may profoundly influence GFR and renal blood flow. The nature of the recovery response is mediated by the degree to which sublethal cells can restore normal function and promote regeneration. The successful recovery from AKI depends on the degree to which these repair processes ensue and these may be compromised in elderly or chronic kidney disease (CKD) patients. Recent data suggest that AKI represents a potential link to CKD in surviving patients. Finally, earlier diagnosis of AKI represents an important area in treating patients with AKI that has spawned increased awareness of the potential that biomarkers of AKI may play in the future.
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Affiliation(s)
- David P Basile
- Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
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Leelahavanichkul A, Bocharov AV, Kurlander R, Baranova IN, Vishnyakova TG, Souza AC, Hu X, Doi K, Vaisman B, Amar M, Sviridov D, Chen Z, Remaley AT, Csako G, Patterson AP, Yuen PST, Star RA, Eggerman TL. Class B scavenger receptor types I and II and CD36 targeting improves sepsis survival and acute outcomes in mice. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2012; 188:2749-58. [PMID: 22327076 PMCID: PMC3859147 DOI: 10.4049/jimmunol.1003445] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Class B scavenger receptors (SR-Bs), such as SR-BI/II or CD36, bind lipoproteins but also mediate bacterial recognition and phagocytosis. In evaluating whether blocking receptors can prevent intracellular bacterial proliferation, phagocyte cytotoxicity, and proinflammatory signaling in bacterial infection/sepsis, we found that SR-BI/II- or CD36-deficient phagocytes are characterized by a reduced intracellular bacterial survival and a lower cytokine response and were protected from bacterial cytotoxicity in the presence of antibiotics. Mice deficient in either SR-BI/II or CD36 are protected from antibiotic-treated cecal ligation and puncture (CLP)-induced sepsis, with greatly increased peritoneal granulocytic phagocyte survival (8-fold), a drastic diminution in peritoneal bacteria counts, and a 50-70% reduction in systemic inflammation (serum levels of IL-6, TNF-α, and IL-10) and organ damage relative to CLP in wild-type mice. The survival rate of CD36-deficient mice after CLP was 58% compared with 17% in control mice. When compensated for mineralocorticoid and glucocorticoid deficiency, SR-BI/II-deficient mice had nearly a 50% survival rate versus 5% in mineralo-/glucocorticoid-treated controls. Targeting SR-B receptors with L-37pA, a peptide that functions as an antagonist of SR-BI/II and CD36 receptors, also increased peritoneal granulocyte counts, as well as reduced peritoneal bacteria and bacterium-induced cytokine secretion. In the CLP mouse sepsis model, L-37pA improved survival from 6 to 27%, reduced multiple organ damage, and improved kidney function. These results demonstrate that the reduction of both SR-BI/II- and CD36-dependent bacterial invasion and inflammatory response in the presence of antibiotic treatment results in granulocyte survival and local bacterial containment, as well as reduces systemic inflammation and organ damage and improves animal survival during severe infections.
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Affiliation(s)
- Asada Leelahavanichkul
- Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD 20892
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Alexander V. Bocharov
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD 20892
| | - Roger Kurlander
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD 20892
| | - Irina N. Baranova
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD 20892
| | - Tatyana G. Vishnyakova
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD 20892
| | - Ana C.P. Souza
- Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD 20892
| | - Xuzhen Hu
- Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD 20892
| | - Kent Doi
- Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD 20892
| | - Boris Vaisman
- National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20892
| | - Marcelo Amar
- National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20892
| | - Denis Sviridov
- National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20892
| | - Zhigang Chen
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD 20892
| | - Alan T. Remaley
- National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20892
| | - Gyorgy Csako
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD 20892
| | - Amy P. Patterson
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD 20892
- Office of Biotechnology Activities, Office of the Director, National Institutes of Health (NIH), Bethesda, MD 20892
| | - Peter S. T. Yuen
- Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD 20892
| | - Robert A Star
- Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD 20892
| | - Thomas L. Eggerman
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health (NIH), Bethesda, MD 20892
- Division of Diabetes, Endocrinology, and Metabolic Diseases, NIDDK, National Institutes of Health (NIH), Bethesda, MD 20892
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Mayeux PR, MacMillan-Crow LA. Pharmacological targets in the renal peritubular microenvironment: implications for therapy for sepsis-induced acute kidney injury. Pharmacol Ther 2012; 134:139-55. [PMID: 22274552 DOI: 10.1016/j.pharmthera.2012.01.004] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Accepted: 12/19/2011] [Indexed: 01/15/2023]
Abstract
One of the most frequent and serious complications to develop in septic patients is acute kidney injury (AKI), a disorder characterized by a rapid failure of the kidneys to adequately filter the blood, regulate ion and water balance, and generate urine. AKI greatly worsens the already poor prognosis of sepsis and increases cost of care. To date, therapies have been mostly supportive; consequently there has been little change in the mortality rates over the last decade. This is due, at least in part, to the delay in establishing clinical evidence of an infection and the associated presence of the systemic inflammatory response syndrome and thus, a delay in initiating therapy. A second reason is a lack of understanding regarding the mechanisms leading to renal injury, which has hindered the development of more targeted therapies. In this review, we summarize recent studies, which have examined the development of renal injury during sepsis and propose how changes in the peritubular capillary microenvironment lead to and then perpetuate microcirculatory failure and tubular epithelial cell injury. We also discuss a number of potential therapeutic targets in the renal peritubular microenvironment, which may prevent or lessen injury and/or promote recovery.
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Affiliation(s)
- Philip R Mayeux
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
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Hu YM, Pai MH, Yeh CL, Hou YC, Yeh SL. Glutamine administration ameliorates sepsis-induced kidney injury by downregulating the high-mobility group box protein-1-mediated pathway in mice. Am J Physiol Renal Physiol 2011; 302:F150-8. [PMID: 21921023 DOI: 10.1152/ajprenal.00246.2011] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Acute kidney injury (AKI) is a severe complication of sepsis. High-mobility group box (HMGB)-1 was implicated as a late mediator of lethal systemic inflammation in sepsis. Since glutamine (GLN) was shown to have anti-inflammatory and antioxidant properties, we hypothesized that GLN administration may downregulate an HMGB-1-mediated pathway and thus ameliorate sepsis-induced AKI. Mice were randomly assigned to a normal group (NC), a septic saline group (SS), or a septic GLN group (SG). Sepsis was induced by cecal ligation and puncture (CLP). The SS group was injected with saline, and the SG group was given 0.75 g GLN/kg body wt once via a tail vein 1 h after CLP. Mice were killed 2, 6, and 24 h after CLP, and blood and kidneys of the animals were harvested for further analysis. The results showed that sepsis resulted in higher mRNA and/or protein expressions of kidney HMGB-1, toll-like receptor (TLR) 4, myeloid differentiation primary-response protein (MyD) 88, and receptor of advanced glycation end products (RAGE) compared with normal mice. Septic mice with GLN administration exhibited decreased HMGB-1, TLR4, RAGE, and phosphorylated NF-κB p65 protein expressions and reduced nitrotyrosine levels in kidney tissues. The histological findings showed that damage to the kidneys was less severe, and survival improved in the SG group. These results indicated that a single dose of GLN administered after the initiation of sepsis plays a prophylactic role in downregulating the expressions of HMGB-1-related mediators and decreasing oxidative stress in the kidneys, which may consequently have ameliorated AKI induced by sepsis.
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Affiliation(s)
- Ya-Mei Hu
- School of Nutrition and Health Sciences, Taipei Medical Univ., 250 Wu-Hsing St., Taipei, 110 Taiwan
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Tran M, Tam D, Bardia A, Bhasin M, Rowe GC, Kher A, Zsengeller ZK, Akhavan-Sharif MR, Khankin EV, Saintgeniez M, David S, Burstein D, Karumanchi SA, Stillman IE, Arany Z, Parikh SM. PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice. J Clin Invest 2011; 121:4003-14. [PMID: 21881206 DOI: 10.1172/jci58662] [Citation(s) in RCA: 396] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2011] [Accepted: 07/13/2011] [Indexed: 01/16/2023] Open
Abstract
Sepsis-associated acute kidney injury (AKI) is a common and morbid condition that is distinguishable from typical ischemic renal injury by its paucity of tubular cell death. The mechanisms underlying renal dysfunction in individuals with sepsis-associated AKI are therefore less clear. Here we have shown that endotoxemia reduces oxygen delivery to the kidney, without changing tissue oxygen levels, suggesting reduced oxygen consumption by the kidney cells. Tubular mitochondria were swollen, and their function was impaired. Expression profiling showed that oxidative phosphorylation genes were selectively suppressed during sepsis-associated AKI and reactivated when global function was normalized. PPARγ coactivator-1α (PGC-1α), a major regulator of mitochondrial biogenesis and metabolism, not only followed this pattern but was proportionally suppressed with the degree of renal impairment. Furthermore, tubular cells had reduced PGC-1α expression and oxygen consumption in response to TNF-α; however, excess PGC-1α reversed the latter effect. Both global and tubule-specific PGC-1α-knockout mice had normal basal renal function but suffered persistent injury following endotoxemia. Our results demonstrate what we believe to be a novel mechanism for sepsis-associated AKI and suggest that PGC-1α induction may be necessary for recovery from this disorder, identifying a potential new target for future therapeutic studies.
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Affiliation(s)
- Mei Tran
- Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA
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Kalakeche R, Hato T, Rhodes G, Dunn KW, El-Achkar TM, Plotkin Z, Sandoval RM, Dagher PC. Endotoxin uptake by S1 proximal tubular segment causes oxidative stress in the downstream S2 segment. J Am Soc Nephrol 2011; 22:1505-16. [PMID: 21784899 DOI: 10.1681/asn.2011020203] [Citation(s) in RCA: 131] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Gram-negative sepsis carries high morbidity and mortality, especially when complicated by acute kidney injury (AKI). The mechanisms of AKI in sepsis remain poorly understood. Here we used intravital two-photon fluorescence microscopy to investigate the possibility of direct interactions between filtered endotoxin and tubular cells as a possible mechanism of AKI in sepsis. Using wild-type (WT), TLR4-knockout, and bone marrow chimeric mice, we found that endotoxin is readily filtered and internalized by S1 proximal tubules through local TLR4 receptors and through fluid-phase endocytosis. Only receptor-mediated interactions between endotoxin and S1 caused oxidative stress in neighboring S2 tubules. Despite significant endotoxin uptake, S1 segments showed no oxidative stress, possibly as a result of the upregulation of cytoprotective heme oxygenase-1 and sirtuin-1 (SIRT1). Conversely, S2 segments did not upregulate SIRT1 and exhibited severe structural and functional peroxisomal damage. Taken together, these data suggest that the S1 segment acts as a sensor of filtered endotoxin, which it takes up. Although this may limit the amount of endotoxin in the systemic circulation and the kidney, it results in severe secondary damage to the neighboring S2 segments.
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Affiliation(s)
- Rabih Kalakeche
- Department of Medicine, Division of Nephrology, Indiana University, Indianapolis, Indiana, USA
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Abstract
Acute kidney injury (AKI) is a common sequel of sepsis in the intensive care unit. It is being suggested that sepsis-induced AKI may have a distinct pathophysiology and identity. Availability of biomarkers now enable us to detect AKI as early as four hours after it's inception and may even help us to delineate sepsis-induced AKI. Protective strategies such as preferential use of vasopressin or prevention of intra-abdominal hypertension may help, in addition to the other global management strategies of sepsis. Pharmacologic interventions have had limited success, may be due to their delayed usage. Newer developments in extracorporeal blood purification techniques may proffer effects beyond simple replacement of renal function, such as metabolic functions of the kidney or modulation of the sepsis cascade.
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Gonçalves GM, Castoldi A, Braga TT, Câmara NOS. New roles for innate immune response in acute and chronic kidney injuries. Scand J Immunol 2011; 73:428-35. [PMID: 21272051 DOI: 10.1111/j.1365-3083.2011.02523.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The innate immune system plays an important role as a first response to tissue injury. This first response is carried out via germline-encoded receptors. They can recognize exogenous Pathogen-Associated Molecular Patterns and endogenous Dangers-Associated Molecular Patterns. The Toll-Like Receptor (TLR) family is well-studied, but more recently another family in the cytoplasmic compartment, called nod-like receptor (NLR), was discovered. In addition to being present in inflammatory cells, these receptors are widely distributed in various cell types, including renal tissue, where these receptors have an important role in triggering the inflammatory response during renal diseases. This review summarizes the present data regarding the role of TLRs and NLRs in the course and development of various kidney pathologies.
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Affiliation(s)
- G M Gonçalves
- Laboratory of Transplantation Immunobiology, Department of Immunology, Universidade de São Paulo, São Paulo, Brazil
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Abstract
Improved mechanistic understanding of renal cell death in acute kidney injury (AKI) has generated new therapeutic targets. Clearly, the classic lesion of acute tubular necrosis is not adequate to describe the consequences of renal ischemia, nephrotoxin exposure, or sepsis on glomerular filtration rate. Experimental evidence supports a pathogenic role for apoptosis in AKI. Interestingly, proximal tubule epithelial cells are highly susceptible to apoptosis, and injury at this site contributes to organ failure. During apoptosis, well-orchestrated events converge at the mitochondrion, the organelle that integrates life and death signals generated by the BCL2 (B-cell lymphoma 2) protein family. Death requires the 'perfect storm' for outer mitochondrial membrane injury to release its cellular 'executioners'. The complexity of this process affords new targets for effective interventions, both before and after renal insults. Inhibiting apoptosis appears to be critical, because circulating factors released by the injured kidney induce apoptosis and inflammation in distant organs including the heart, lung, liver, and brain, potentially contributing to the high morbidity and mortality associated with AKI. Manipulation of known stress kinases upstream of mitochondrial injury, induction of endogenous, anti-apoptotic proteins, and improved understanding of the timing and consequences of renal cell apoptosis will inevitably improve the outcome of human AKI.
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Affiliation(s)
- Andrea Havasi
- Renal Section, Department of Medicine, Boston University, Boston, Massachusetts 02118, USA
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