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Aalinkeel R, Quigg RJ, Alexander J. The complement system and kidney cancer: pathogenesis to clinical applications. J Clin Invest 2025; 135:e188351. [PMID: 40309765 PMCID: PMC12043091 DOI: 10.1172/jci188351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2025] Open
Abstract
Kidney cancer poses unique clinical challenges because of its resistance to conventional treatments and its tendency to metastasize. The kidney is particularly susceptible to dysfunction of the complement system, an immune network that tumors often exploit. Recent discoveries have highlighted that the complement system not only plays a crucial role in immune surveillance and defense in the circulatory system, but also functions intracellularly and autonomously. This concept has shifted the focus of investigation toward understanding how complement proteins influence cancer progression by regulating the tumor microenvironment (TME), cell signaling, proliferation, metabolism, and the immune response. With the complement system and its inhibitors emerging as a promising new class of immunotherapeutics and potential complement-targeted treatments advancing through development pipelines and clinical trials, this Review provides a timely examination of how harnessing the complement system could lead to effective tumor treatments and how to strategically combine complement inhibitors with other cancer treatments, offering renewed hope in the fight against kidney cancer.
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Wang JN, Suo XG, Yu JT, Luo QC, Ji ML, Zhang MM, Zhu Q, Cheng XR, Hou C, Chen X, Wang F, Xu CH, Li C, Xie SS, Wei J, Zhang DF, Zhang XR, Wang ZJ, Dong YH, Zhu S, Peng LJ, Li XY, Chen HY, Xu T, Jin J, Chen FX, Meng XM. NAT10 exacerbates acute renal inflammation by enhancing N4-acetylcytidine modification of the CCL2/CXCL1 axis. Proc Natl Acad Sci U S A 2025; 122:e2418409122. [PMID: 40261924 PMCID: PMC12054813 DOI: 10.1073/pnas.2418409122] [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: 09/12/2024] [Accepted: 03/08/2025] [Indexed: 04/24/2025] Open
Abstract
Inflammation plays an essential role in eliminating microbial pathogens and repairing tissues, while sustained inflammation accelerates kidney damage and disease progression. Therefore, understanding the mechanisms of the inflammatory response is vital for developing therapies for inflammatory kidney diseases like acute kidney injury (AKI), which currently lacks effective treatment. Here, we identified N-acetyltransferase 10 (NAT10) as an important regulator for acute inflammation. NAT10, the only known "writer" protein for N4-acetylcytidine (ac4C) acetylation, is elevated in renal tubules across various AKI models, human biopsies, and cultured tubular epithelial cells (TECs). Conditional knockout (cKO) of NAT10 in mouse kidneys attenuates renal dysfunction, inflammation, and infiltration of macrophages and neutrophils, whereas its conditional knock-in (cKI) exacerbates these effects. Mechanistically, our findings from ac4C-RIP-seq and RNA-seq analyses revealed that NAT10-mediated ac4C acetylation enhances the mRNA stability of a range of key chemokines, including C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 1(CXCL1), promoting macrophage and neutrophil recruitment and accelerating renal inflammation. Additionally, CCL2 and CXCL1 neutralizing antibodies or their receptor inhibitors, abrogated renal inflammation in NAT10-overexpression TECs or NAT10-cKI mice. Importantly, inhibiting NAT10, either through Adeno-associated virus 9 (AAV9)-mediated silencing or pharmacologically with our found inhibitor Cpd-155, significantly reduces renal inflammation and injury. Thus, targeting the NAT10/CCL2/CXCL1 axis presents a promising therapeutic strategy for treating inflammatory kidney diseases.
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Affiliation(s)
- Jia-nan Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Xiao-guo Suo
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Ju-tao Yu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Qi-chao Luo
- School of Basic Medicine, Anhui Medical University, Hefei230032, China
| | - Ming-lu Ji
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Meng-meng Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Qi Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Xin-ran Cheng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Chao Hou
- School of Basic Medicine, Anhui Medical University, Hefei230032, China
| | - Xin Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Fang Wang
- Department of Pharmacy, Lu’an Hospital of Anhui Medical University, Lu’an People’s Hospital of Anhui Province, Lu’an237006, China
| | - Chuan-hui Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Chao Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Shuai-shuai Xie
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Jie Wei
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei230601, Anhui, China
| | - Dan-feng Zhang
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei230601, Anhui, China
| | - Xin-ru Zhang
- School of Basic Medicine, Anhui Medical University, Hefei230032, China
| | - Zhi-juan Wang
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei230601, Anhui, China
| | - Yu-hang Dong
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Sai Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Li-jin Peng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Xiang-yu Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Hai-yong Chen
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong999077, Hong Kong
- Department of Chinese Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen518000, China
| | - Tao Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
| | - Juan Jin
- School of Basic Medicine, Anhui Medical University, Hefei230032, China
| | - Fei Xavier Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
- Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai200032, China
| | - Xiao-ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei230032, China
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Troise D, Allegra C, Cirolla LA, Mercuri S, Infante B, Castellano G, Stallone G. Exploring Potential Complement Modulation Strategies for Ischemia-Reperfusion Injury in Kidney Transplantation. Antioxidants (Basel) 2025; 14:66. [PMID: 39857400 PMCID: PMC11761266 DOI: 10.3390/antiox14010066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 01/03/2025] [Accepted: 01/06/2025] [Indexed: 01/27/2025] Open
Abstract
The complement system plays a crucial role in regulating the inflammatory responses in kidney transplantation, potentially contributing to early decline in kidney function. Ischemia-reperfusion injury (IRI) is among the factors affecting graft outcomes and a primary contributor to delayed graft function. Complement activation, particularly the alternative pathway, participates in the pathogenesis of IRI, involving all kidney compartments. In particular, tubular epithelial cells often acquire a dysfunctional phenotype that can exacerbate complement activation and kidney damage. Currently, complement-modulating drugs are under investigation for the treatment of kidney diseases. Many of these drugs have shown potential therapeutic benefits, but no effective clinical treatments for renal IRI have been identified yet. In this review, we will explore drugs that target complement factors, complement receptors, and regulatory proteins, aiming to highlight their potential value in improving the management of renal IRI.
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Affiliation(s)
- Dario Troise
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 141 52 Stockholm, Sweden
| | - Costanza Allegra
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Luciana Antonia Cirolla
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Silvia Mercuri
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Barbara Infante
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Giuseppe Castellano
- Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
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Yu SMW, King E, Fribourg M, Hartzell S, Tsou L, Gee L, D'Agati VD, Thurman JM, He JC, Cravedi P. A Newly Identified Protective Role of C5a Receptor 1 in Kidney Tubules against Toxin-Induced Acute Kidney Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:126-142. [PMID: 39427763 PMCID: PMC11686444 DOI: 10.1016/j.ajpath.2024.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 09/03/2024] [Accepted: 10/08/2024] [Indexed: 10/22/2024]
Abstract
Acute kidney injury (AKI) remains a major reason for hospitalization with limited therapeutic options. Although complement activation is implicated in AKI, the role of C5a receptor 1 (C5aR1) in kidney tubular cells is unclear. Herein, aristolochic acid nephropathy (AAN) and folic acid nephropathy (FAN) models were used to establish the role of C5aR1 in kidney tubules during AKI in germline C5ar1-/-, myeloid cell-specific, and kidney tubule-specific C5ar1 knockout mice. After aristolochic acid and folic acid injection, C5ar1-/- mice had increased AKI severity and a higher degree of tubular injury. Macrophage depletion in C5ar1-/- mice or myeloid cell-specific C5ar1 deletion did not affect the outcomes of aristolochic acid-induced AKI. RNA-sequencing data from renal tubular epithelial cells (RTECs) showed that C5ar1 deletion was associated with the down-regulation of mitochondrial metabolism and ATP production transcriptional pathways. Metabolic studies confirmed reduced mitochondrial membrane potential at baseline and increased mitochondrial oxidative stress after injury in C5ar1-/- RTECs. Moreover, C5ar1-/- RTECs had enhanced glycolysis, glucose uptake, and lactate production on injury, corroborated by metabolomics analysis of kidneys from AAN mice. Kidney tubule-specific C5ar1 knockout mice recapitulated exacerbated AKI observed in C5ar1-/- mice in AAN and FAN. These data indicate that C5aR1 signaling in kidney tubules exerts renoprotective effects against toxin-induced AKI by limiting overt glycolysis and maintaining mitochondrial function, thereby revealing a novel link between the complement system and tubular cell metabolism.
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Affiliation(s)
- Samuel Mon-Wei Yu
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York.
| | - Emily King
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York
| | - Miguel Fribourg
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York
| | - Susan Hartzell
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York
| | - Liam Tsou
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York
| | - Logan Gee
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York
| | - Vivette D D'Agati
- Department of Pathology and Cell Biology, Columbia University, New York, New York
| | - Joshua M Thurman
- Medicine-Renal Med Diseases/Hypertension, Colorado University, Aurora, Colorado
| | - John Cijiang He
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York; James J. Peters Department of Veterans Affairs Medical Center, New York, New York
| | - Paolo Cravedi
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York.
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de Boer E, Sokolova M, Jager NM, Schjalm C, Weiss MG, Liavåg OM, Maassen H, van Goor H, Thorgersen EB, Pettersen K, Christiansen D, Ludviksen JK, Jespersen B, Mollnes TE, Leuvenink HGD, Pischke SE. Normothermic Machine Perfusion Reconstitutes Porcine Kidney Tissue Metabolism But Induces an Inflammatory Response, Which Is Reduced by Complement C5 Inhibition. Transpl Int 2024; 37:13348. [PMID: 39606689 PMCID: PMC11598510 DOI: 10.3389/ti.2024.13348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 11/05/2024] [Indexed: 11/29/2024]
Abstract
Normothermic machine perfusion (NMP) is a clinical strategy to reduce renal ischemia-reperfusion injury (IRI). Optimal NMP should restore metabolism and minimize IRI induced inflammatory responses. Microdialysis was used to evaluate renal metabolism. This study aimed to assess the effect of complement inhibition on NMP induced inflammatory responses. Twenty-two pig kidneys underwent 18 h of static cold storage (SCS) followed by 4 h of NMP using a closed-circuit system. Kidneys were randomized to receive a C5-inhibitor or placebo during SCS and NMP. Perfusion resulted in rapidly stabilized renal flow, low renal resistance, and urine production. During SCS, tissue microdialysate levels of glucose and pyruvate decreased significantly, whereas glycerol increased (p < 0.001). In the first hour of NMP, glucose and pyruvate increased while glycerol decreased (p < 0.001). After 4 h, all metabolites had returned to baseline. Inflammatory markers C3a, soluble C5b-9, TNF, IL-6, IL-1β, IL-8, and IL-10 increased significantly during NMP in perfusate and kidney tissue. C5-inhibition significantly decreased perfusate and urine soluble C5b-9 (p < 0.001; p = 0.002, respectively), and tissue IL-1β (p = 0.049), but did not alter other inflammatory markers. Microdialysis can accurately monitor the effect of NMP on renal metabolism. Closed-circuit NMP induces inflammation, which appeared partly complement-mediated. Targeting additional immune inhibitors should be the next step.
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Affiliation(s)
- Eline de Boer
- Department of Immunology, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Marina Sokolova
- Department of Immunology, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Neeltina M. Jager
- Department of Surgery, Division of Organ Donation and Transplantation, University Medical Center Groningen, Groningen, Netherlands
| | - Camilla Schjalm
- Department of Immunology, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Marc G. Weiss
- Department of Medicine and Nephrology, Aarhus University Hospital, Aarhus, Denmark
| | - Olav M. Liavåg
- Section for Transplantation Surgery, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Hanno Maassen
- Department of Surgery, Division of Organ Donation and Transplantation, University Medical Center Groningen, Groningen, Netherlands
- Department of Pathology and Medical Biology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, Netherlands
| | - Harry van Goor
- Department of Pathology and Medical Biology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, Netherlands
| | - Ebbe Billmann Thorgersen
- Department of Immunology, Oslo University Hospital, Oslo, Norway
- Department of Gastroenterological Surgery, Oslo University Hospital the Radium Hospital, Oslo, Norway
| | | | | | | | - Bente Jespersen
- Department of Medicine and Nephrology, Aarhus University Hospital, Aarhus, Denmark
| | - Tom E. Mollnes
- Department of Immunology, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Research Laboratory, Nordland Hospital, Bodø, Norway
- Center of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway
| | - Henri G. D. Leuvenink
- Department of Surgery, Division of Organ Donation and Transplantation, University Medical Center Groningen, Groningen, Netherlands
- Department of Medicine and Nephrology, Aarhus University Hospital, Aarhus, Denmark
| | - Søren E. Pischke
- Department of Immunology, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Division of Emergencies and Critical Care, Oslo University Hospital Rikshospitalet, Oslo, Norway
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Yuan Y, Cui Y, Zhao D, Yuan Y, Zhao Y, Li D, Jiang X, Zhao G. Complement networks in gene-edited pig xenotransplantation: enhancing transplant success and addressing organ shortage. J Transl Med 2024; 22:324. [PMID: 38566098 PMCID: PMC10986007 DOI: 10.1186/s12967-024-05136-4] [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: 12/26/2023] [Accepted: 03/27/2024] [Indexed: 04/04/2024] Open
Abstract
The shortage of organs for transplantation emphasizes the urgent need for alternative solutions. Xenotransplantation has emerged as a promising option due to the greater availability of donor organs. However, significant hurdles such as hyperacute rejection and organ ischemia-reperfusion injury pose major challenges, largely orchestrated by the complement system, and activated immune responses. The complement system, a pivotal component of innate immunity, acts as a natural barrier for xenotransplantation. To address the challenges of immune rejection, gene-edited pigs have become a focal point, aiming to shield donor organs from human immune responses and enhance the overall success of xenotransplantation. This comprehensive review aims to illuminate strategies for regulating complement networks to optimize the efficacy of gene-edited pig xenotransplantation. We begin by exploring the impact of the complement system on the effectiveness of xenotransplantation. Subsequently, we delve into the evaluation of key complement regulators specific to gene-edited pigs. To further understand the status of xenotransplantation, we discuss preclinical studies that utilize gene-edited pigs as a viable source of organs. These investigations provide valuable insights into the feasibility and potential success of xenotransplantation, offering a bridge between scientific advancements and clinical application.
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Affiliation(s)
- Yinglin Yuan
- Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuanyuan Cui
- Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Dayue Zhao
- Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuan Yuan
- Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yanshuang Zhao
- Department of Pharmacy, The People's Hospital of Leshan, Leshan, China
| | - Danni Li
- Department of Pharmacy, Longquanyi District of Chengdu Maternity & Child Health Care Hospital, Chengdu, China
| | - Xiaomei Jiang
- Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Gaoping Zhao
- Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
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Wen Z, Sun C, Lou Y, Kong J. Vitamin D/Vitamin D receptor mitigates cisplatin-induced acute kidney injury by down-regulating C5aR. J Immunotoxicol 2023; 20:2248267. [PMID: 37667858 DOI: 10.1080/1547691x.2023.2248267] [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: 06/25/2023] [Accepted: 08/09/2023] [Indexed: 09/06/2023] Open
Abstract
Cisplatin (DDP) is a potent chemotherapeutic; however, it can also cause acute kidney injury (AKI). Because of the complexity of the toxicity it induces, few effective methods exist for ameliorating any form of DDP-induced AKI. Recent research has suggested that the complement system is a potential molecular target for such amelioration. In the study here, in vivo (male ICR mice) and in vitro (HK-2 cells) models of DDP-induced AKI were established to investigate the potential therapeutic effects of Vitamin D (VD) against this form of AKI. Endpoints assessed in vivo/in vitro included overall renal function, degree of renal damage, and complement receptor C5aR expression using histology, immunohistochemistry, immunofluorescence, RT-PCR, and Western blots. The data indicated that the use of VD treatment could reduce renal pathological damage along with expression of TNFα, IL-1β, IL-18, and C5aR; however, an over-expression of C5aR weakened the protective effects of VD/VD receptor (VDR) against oxidative damage and inflammatory cell infiltration. Using a luciferase reporter gene assay and ChIP analysis, it was demonstrated that C5aR was transcriptionally inhibited by VDR. In conclusion, VD/VDR could delay DDP-induced AKI by inhibiting the expression of C5aR through transcriptional regulation and reducing the production of downstream pro-inflammatory cytokines. The present study revealed the regulatory mechanism of VD/VDR in acute renal inflammation and provides new insights into its therapeutic function in DDP-induced AKI.
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Affiliation(s)
- Zhouyu Wen
- Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang, China
| | - Can Sun
- Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yan Lou
- Department of Computer Science, School of Intelligent Medicine, China Medical University, Shenyang, China
| | - Juan Kong
- Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang, China
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Golshayan D, Schwotzer N, Fakhouri F, Zuber J. Targeting the Complement Pathway in Kidney Transplantation. J Am Soc Nephrol 2023; 34:1776-1792. [PMID: 37439664 PMCID: PMC10631604 DOI: 10.1681/asn.0000000000000192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 07/02/2023] [Indexed: 07/14/2023] Open
Abstract
The complement system is paramount in the clearance of pathogens and cell debris, yet is increasingly recognized as a key component in several pathways leading to allograft injury. There is thus a growing interest in new biomarkers to assess complement activation and guide tailored therapies after kidney transplantation (KTx). C5 blockade has revolutionized post-transplant management of atypical hemolytic uremic syndrome, a paradigm of complement-driven disease. Similarly, new drugs targeting the complement amplification loop hold much promise in the treatment and prevention of recurrence of C3 glomerulopathy. Although unduly activation of the complement pathway has been described after brain death and ischemia reperfusion, any clinical attempts to mitigate the ensuing renal insults have so far provided mixed results. However, the intervention timing, strategy, and type of complement blocker need to be optimized in these settings. Furthermore, the fast-moving field of ex vivo organ perfusion technology opens new avenues to deliver complement-targeted drugs to kidney allografts with limited iatrogenic risks. Complement plays also a key role in the pathogenesis of donor-specific ABO- and HLA-targeted alloantibodies. However, C5 blockade failed overall to improve outcomes in highly sensitized patients and prevent the progression to chronic antibody-mediated rejection (ABMR). Similarly, well-conducted studies with C1 inhibitors in sensitized recipients yielded disappointing results so far, in part, because of subtherapeutic dosage used in clinical studies. The emergence of new complement blockers raises hope to significantly reduce the negative effect of ischemia reperfusion, ABMR, and nephropathy recurrence on outcomes after KTx.
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Affiliation(s)
- Dela Golshayan
- Transplantation Center, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Nora Schwotzer
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Fadi Fakhouri
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Julien Zuber
- Service de Transplantation rénale adulte, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France
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9
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Gibson B, Connelly C, Moldakhmetova S, Sheerin NS. Complement activation and kidney transplantation; a complex relationship. Immunobiology 2023; 228:152396. [PMID: 37276614 DOI: 10.1016/j.imbio.2023.152396] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/14/2023] [Accepted: 05/15/2023] [Indexed: 06/07/2023]
Abstract
Although kidney transplantation is the best treatment for end stage kidney disease, the benefits are limited by factors such as the short fall in donor numbers, the burden of immunosuppression and graft failure. Although there have been improvements in one-year outcomes, the annual rate of graft loss beyond the first year has not significantly improved, despite better therapies to control the alloimmune response. There is therefore a need to develop alternative strategies to limit kidney injury at all stages along the transplant pathway and so improve graft survival. Complement is primarily part of the innate immune system, but is also known to enhance the adaptive immune response. There is increasing evidence that complement activation occurs at many stages during transplantation and can have deleterious effects on graft outcome. Complement activation begins in the donor and occurs again on reperfusion following a period of ischemia. Complement can contribute to the development of the alloimmune response and may directly contribute to graft injury during acute and chronic allograft rejection. The complexity of the relationship between complement activation and allograft outcome is further increased by the capacity of the allograft to synthesise complement proteins, the contribution complement makes to interstitial fibrosis and complement's role in the development of recurrent disease. The better we understand the role played by complement in kidney transplant pathology the better placed we will be to intervene. This is particularly relevant with the rapid development of complement therapeutics which can now target different the different pathways of the complement system. Combining our basic understanding of complement biology with preclinical and observational data will allow the development and delivery of clinical trials which have best chance to identify any benefit of complement inhibition.
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Affiliation(s)
- B Gibson
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK
| | - C Connelly
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK
| | - S Moldakhmetova
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK
| | - N S Sheerin
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK.
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10
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Zhang Q, Ye J, Zhang Z, Hu Y, Wang X, Jiang W, Guo X, Chen L, Cheng S, Li J, Zhang L. Aristolocholic acid I promotes renal tubular epithelial fibrosis by upregulating matrix metalloproteinase-9 expression via activating the C3a/C3aR axis of macrophages. Toxicol Lett 2023; 381:27-35. [PMID: 37084829 DOI: 10.1016/j.toxlet.2023.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 02/17/2023] [Accepted: 04/18/2023] [Indexed: 04/23/2023]
Abstract
Aristolochic acid I (AAI) can cause nephrotoxicity and is characterized by interstitial fibrosis. The C3a/C3aR axis of macrophages and matrix metalloproteinase-9 (MMP-9) play important roles in fibrosis, but whether they are involved in AAI-induced renal interstitial fibrosis and are related remains to be elucidated. In this study, we investigated whether C3a/C3aR axis of macrophages promotes renal interstitial fibrosis by regulating MMP-9 in aristolochic acid nephropathy (AAN). Intraperitoneal injection of AAI for 28 days successfully induced AAN in C57bl/6 mice. The content of C3a in the kidney of AAN mice was increased, and there was a significant distribution of macrophages in the renal tubules. The same results were observed in the in vitro experiment. We also explored the role and mechanism of macrophages after AAI administration in the epithelial-mesenchymal transformation (EMT) of renal tubular epithelial cells (RTECs) and found that AAI could activate the C3a/C3aR axis of macrophages to upregulate p65 expression in macrophages. p65 upregulated MMP-9 expression in macrophages not only directly but also by promoting the secretion if interleukin-6 by macrophages and then activating STAT3 in RTECs. The upregulation of MMP-9 expression could promote the EMT of RTECs. Taken together, our study demonstrated that the AAI-activated the C3a/C3aR axis of macrophages, which induced MMP-9 production, was one of the causes of renal interstitial fibrosis. Therefore, targeting the C3a/C3aR axis of macrophages is an effective therapeutic strategy for the prevention and treatment of renal interstitial fibrosis in AAN.
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Affiliation(s)
- Qi Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jing Ye
- School of Life Science, Nanjing University, Nanjing 210023, China
| | - Zhaofeng Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yongkang Hu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xian Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Wenjuan Jiang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xinlong Guo
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Langqun Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Siyu Cheng
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jian Li
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China; Jinling Pharmaceutical Co., Ltd., Nanjing, 210009, China.
| | - Liang Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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11
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Santarsiero D, Aiello S. The Complement System in Kidney Transplantation. Cells 2023; 12:cells12050791. [PMID: 36899927 PMCID: PMC10001167 DOI: 10.3390/cells12050791] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 02/24/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Kidney transplantation is the therapy of choice for patients who suffer from end-stage renal diseases. Despite improvements in surgical techniques and immunosuppressive treatments, long-term graft survival remains a challenge. A large body of evidence documented that the complement cascade, a part of the innate immune system, plays a crucial role in the deleterious inflammatory reactions that occur during the transplantation process, such as brain or cardiac death of the donor and ischaemia/reperfusion injury. In addition, the complement system also modulates the responses of T cells and B cells to alloantigens, thus playing a crucial role in cellular as well as humoral responses to the allograft, which lead to damage to the transplanted kidney. Since several drugs that are capable of inhibiting complement activation at various stages of the complement cascade are emerging and being developed, we will discuss how these novel therapies could have potential applications in ameliorating outcomes in kidney transplantations by preventing the deleterious effects of ischaemia/reperfusion injury, modulating the adaptive immune response, and treating antibody-mediated rejection.
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12
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Gibson BG, Cox TE, Marchbank KJ. Contribution of animal models to the mechanistic understanding of Alternative Pathway and Amplification Loop (AP/AL)-driven Complement-mediated Diseases. Immunol Rev 2023; 313:194-216. [PMID: 36203396 PMCID: PMC10092198 DOI: 10.1111/imr.13141] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
This review aimed to capture the key findings that animal models have provided around the role of the alternative pathway and amplification loop (AP/AL) in disease. Animal models, particularly mouse models, have been incredibly useful to define the role of complement and the alternative pathway in health and disease; for instance, the use of cobra venom factor and depletion of C3 provided the initial insight that complement was essential to generate an appropriate adaptive immune response. The development of knockout mice have further underlined the importance of the AP/AL in disease, with the FH knockout mouse paving the way for the first anti-complement drugs. The impact from the development of FB, properdin, and C3 knockout mice closely follows this in terms of mechanistic understanding in disease. Indeed, our current understanding that complement plays a role in most conditions at one level or another is rooted in many of these in vivo studies. That C3, in particular, has roles beyond the obvious in innate and adaptive immunity, normal physiology, and cellular functions, with or without other recognized AP components, we would argue, only extends the reach of this arm of the complement system. Humanized mouse models also continue to play their part. Here, we argue that the animal models developed over the last few decades have truly helped define the role of the AP/AL in disease.
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Affiliation(s)
- Beth G. Gibson
- Complement Therapeutics Research Group and Newcastle University Translational and Clinical Research InstituteFaculty of Medical ScienceNewcastle‐upon‐TyneUK
- National Renal Complement Therapeutics CentreaHUS ServiceNewcastle upon TyneUK
| | - Thomas E. Cox
- Complement Therapeutics Research Group and Newcastle University Translational and Clinical Research InstituteFaculty of Medical ScienceNewcastle‐upon‐TyneUK
- National Renal Complement Therapeutics CentreaHUS ServiceNewcastle upon TyneUK
| | - Kevin J. Marchbank
- Complement Therapeutics Research Group and Newcastle University Translational and Clinical Research InstituteFaculty of Medical ScienceNewcastle‐upon‐TyneUK
- National Renal Complement Therapeutics CentreaHUS ServiceNewcastle upon TyneUK
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13
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Wang H, Ideguchi H, Kajikawa T, Mastellos DC, Lambris JD, Hajishengallis G. Complement Is Required for Microbe-Driven Induction of Th17 and Periodontitis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:1370-1378. [PMID: 36028293 PMCID: PMC9530003 DOI: 10.4049/jimmunol.2200338] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/27/2022] [Indexed: 12/29/2022]
Abstract
In both mice and humans, complement and Th17 cells have been implicated in periodontitis, an oral microbiota-driven inflammatory disease associated with systemic disorders. A recent clinical trial showed that a complement C3 inhibitor (AMY-101) causes sustainable resolution of periodontal inflammation, the main effector of tissue destruction in this oral disease. Although both complement and Th17 are required for periodontitis, it is uncertain how these immune components cooperate in disease development. In this study, we dissected the complement-Th17 relationship in the setting of ligature-induced periodontitis (LIP), a model that previously established that microbial dysbiosis drives Th17 cell expansion and periodontal bone loss. Complement was readily activated in the periodontal tissue of LIP-subjected mice but not when the mice were placed on broad-spectrum antibiotics. Microbiota-induced complement activation generated critical cytokines, IL-6 and IL-23, which are required for Th17 cell expansion. These cytokines as well as Th17 accumulation and IL-17 expression were significantly suppressed in LIP-subjected C3-deficient mice relative to wild-type controls. As IL-23 has been extensively studied in periodontitis, we focused on IL-6 and showed that LIP-induced IL-17 and bone loss required intact IL-6 receptor signaling in the periodontium. LIP-induced IL-6 was predominantly produced by gingival epithelial cells that upregulated C3a receptor upon LIP challenge. Experiments in human gingival epithelial cells showed that C3a upregulated IL-6 production in cooperation with microbial stimuli that upregulated C3a receptor expression in ERK1/2- and JNK-dependent manner. In conclusion, complement links the periodontal microbiota challenge to Th17 cell accumulation and thus integrates complement- and Th17-driven immunopathology in periodontitis.
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Affiliation(s)
- Hui Wang
- Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA
| | - Hidetaka Ideguchi
- Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA
- Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Tetsuhiro Kajikawa
- Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA
- Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Dimitrios C Mastellos
- Division of Biodiagnostic Science and Technologies, The Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, National Center for Scientific Research "Demokritos," Athens, Greece; and
| | - John D Lambris
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - George Hajishengallis
- Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA;
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14
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Juncos LA, Wieruszewski PM, Kashani K. Pathophysiology of Acute Kidney Injury in Critical Illness: A Narrative Review. Compr Physiol 2022; 12:3767-3780. [PMID: 36073750 DOI: 10.1002/cphy.c210028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Acute kidney injury (AKI) is a syndrome that entails a rapid decline in kidney function with or without injury. The consequences of AKI among acutely ill patients are dire and lead to higher mortality, morbidity, and healthcare cost. To prevent AKI and its short and long-term repercussions, understanding its pathophysiology is essential. Depending on the baseline kidney histology and function reserves, the number of kidney insults, and the intensity of each insult, the clinical presentation of AKI may differ. While many factors are capable of inducing renal injury, they can be categorized into a few processes. The three primary processes reported in the literature are hemodynamic changes, inflammatory reactions, and nephrotoxicity. The majority of patients with AKI will suffer from more than one during their development and/or progression of AKI. Moreover, the development of one usually leads to the instigation of another. Thus, the interactions and progression between these mechanisms may determine the severity and duration of the AKI. Other factors such as organ crosstalk and how our concurrent therapies interact with these mechanisms complicate the pathophysiology of the progression of the AKI even further. In this narrative review article, we describe these three main pathophysiological processes that lead to the development and progression of AKI. © 2022 American Physiological Society. Compr Physiol 12: 1-14, 2022.
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Affiliation(s)
- Luis A Juncos
- Division of Nephrology, Central Arkansas Veterans' Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Patrick M Wieruszewski
- Division of Hospital Pharmacy, Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA
| | - Kianoush Kashani
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
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15
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Neves JCF, Ibiapina HNS, Magalhães-Gama F, Sachett JAG, Silva IM, Coelho KF, Alves EC, Tarragô AM, de Lima Ferreira LC, Malheiro A, Monteiro WM, Costa AG. CCL-2 and CXCL-8: Potential Prognostic Biomarkers of Acute Kidney Injury after a Bothrops atrox Snakebite. Mediators Inflamm 2022; 2022:8285084. [PMID: 36117588 PMCID: PMC9473908 DOI: 10.1155/2022/8285084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 08/10/2022] [Accepted: 08/23/2022] [Indexed: 11/17/2022] Open
Abstract
In the Brazilian Amazon, the snake Bothrops atrox is the primary cause of snakebites. B. atrox (BaV) venom can cause systemic pathophysiological changes such as acute kidney injury (AKI), which leads to the production of chemokines and cytokines in response to the envenomation. These soluble immunological molecules act by modulating the inflammatory response; however, the mechanisms associated with the development of AKI are still poorly understood. Here, we characterize the profile of these soluble immunological molecules as possible predictive biomarkers of the development of AKI. The study involved 34 patients who had been victims of snakebites by Bothrops sp. These were categorized into two groups according to the development of AKI (AKI(-)/AKI(+)), using healthy donors as the control (HD). Peripheral blood samples were collected at three-time points: before antivenom administration (T0) and at 24 and 48 hours after antivenom (T1 and T2, respectively). The soluble immunological molecules (CXCL-8, CCL-5, CXCL-9, CCL-2, CXCL-10, IL-6, TNF, IL-2, IL-10, IFN-γ, IL-4, and IL-17A) were quantified using cytometric bead array. Our results demonstrated an increase in CXCL-9, CXCL-10, IL-6, IL-2, IL-10, and IL-17A molecules in the groups of patients who suffered Bothrops snakebites (AKI(-) and AKI(+)) before antivenom administration, when compared to HD. In the AKI(+) group, levels of CXCL-8 and CCL-2 molecules were elevated on admission and progressively decreased during the clinical evolution of patients after antivenom administration. In addition, in the signature analysis, these were produced exclusively by the group AKI(+) at T0. Thus, these chemokines may be related to the initiation and extension of AKI after envenomation by Bothrops and present themselves as two potential biomarkers of AKI at T0.
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Affiliation(s)
- Juliana Costa Ferreira Neves
- Post-graduate Program in Tropical Medicine, Amazonas State University (UEA), Manaus, AM, Brazil
- Carlos Borborema Clinical Research Institute, Tropical Medicine Foundation Doctor Heitor Vieira Dourado (FMT-HVD), Manaus, AM, Brazil
| | - Hiochelson Najibe Santos Ibiapina
- Post-graduate Program in Tropical Medicine, Amazonas State University (UEA), Manaus, AM, Brazil
- Carlos Borborema Clinical Research Institute, Tropical Medicine Foundation Doctor Heitor Vieira Dourado (FMT-HVD), Manaus, AM, Brazil
| | - Fábio Magalhães-Gama
- Post-Graduate Program in Basic and Applied Immunology, Federal University of Amazonas (UFAM), Manaus, AM, Brazil
- Post-Graduate Program in Health Sciences, René Rachou Institute, Oswaldo Cruz Foundation (FIOCRUZ-Minas), Minas Gerais, Belo Horizonte, Brazil
- Directorate of Teaching and Research, Hematology and Hemotherapy Foundation of Amazonas (HEMOAM), Manaus, AM, Brazil
| | - Jacqueline Almeida Gonçalves Sachett
- Post-graduate Program in Tropical Medicine, Amazonas State University (UEA), Manaus, AM, Brazil
- Carlos Borborema Clinical Research Institute, Tropical Medicine Foundation Doctor Heitor Vieira Dourado (FMT-HVD), Manaus, AM, Brazil
- Department of Education and Research, Alfredo da Matta Foundation (FUAM), Manaus, AM, Brazil
| | - Iran Mendonça Silva
- Carlos Borborema Clinical Research Institute, Tropical Medicine Foundation Doctor Heitor Vieira Dourado (FMT-HVD), Manaus, AM, Brazil
| | - Kerolaine Fonseca Coelho
- Post-graduate Program in Tropical Medicine, Amazonas State University (UEA), Manaus, AM, Brazil
- Carlos Borborema Clinical Research Institute, Tropical Medicine Foundation Doctor Heitor Vieira Dourado (FMT-HVD), Manaus, AM, Brazil
| | - Eliane Campos Alves
- Post-graduate Program in Tropical Medicine, Amazonas State University (UEA), Manaus, AM, Brazil
- Carlos Borborema Clinical Research Institute, Tropical Medicine Foundation Doctor Heitor Vieira Dourado (FMT-HVD), Manaus, AM, Brazil
| | - Andréa Monteiro Tarragô
- Post-Graduate Program in Basic and Applied Immunology, Federal University of Amazonas (UFAM), Manaus, AM, Brazil
- Directorate of Teaching and Research, Hematology and Hemotherapy Foundation of Amazonas (HEMOAM), Manaus, AM, Brazil
- Post-Graduate Program in Sciences Applied to Hematology, UEA, Manaus, AM, Brazil
| | - Luiz Carlos de Lima Ferreira
- Post-graduate Program in Tropical Medicine, Amazonas State University (UEA), Manaus, AM, Brazil
- Carlos Borborema Clinical Research Institute, Tropical Medicine Foundation Doctor Heitor Vieira Dourado (FMT-HVD), Manaus, AM, Brazil
| | - Adriana Malheiro
- Post-graduate Program in Tropical Medicine, Amazonas State University (UEA), Manaus, AM, Brazil
- Post-Graduate Program in Basic and Applied Immunology, Federal University of Amazonas (UFAM), Manaus, AM, Brazil
- Directorate of Teaching and Research, Hematology and Hemotherapy Foundation of Amazonas (HEMOAM), Manaus, AM, Brazil
- Post-Graduate Program in Sciences Applied to Hematology, UEA, Manaus, AM, Brazil
| | - Wuelton Marcelo Monteiro
- Post-graduate Program in Tropical Medicine, Amazonas State University (UEA), Manaus, AM, Brazil
- Carlos Borborema Clinical Research Institute, Tropical Medicine Foundation Doctor Heitor Vieira Dourado (FMT-HVD), Manaus, AM, Brazil
| | - Allyson Guimarães Costa
- Post-graduate Program in Tropical Medicine, Amazonas State University (UEA), Manaus, AM, Brazil
- Carlos Borborema Clinical Research Institute, Tropical Medicine Foundation Doctor Heitor Vieira Dourado (FMT-HVD), Manaus, AM, Brazil
- Post-Graduate Program in Basic and Applied Immunology, Federal University of Amazonas (UFAM), Manaus, AM, Brazil
- Post-Graduate Program in Health Sciences, René Rachou Institute, Oswaldo Cruz Foundation (FIOCRUZ-Minas), Minas Gerais, Belo Horizonte, Brazil
- Directorate of Teaching and Research, Hematology and Hemotherapy Foundation of Amazonas (HEMOAM), Manaus, AM, Brazil
- Post-Graduate Program in Sciences Applied to Hematology, UEA, Manaus, AM, Brazil
- Nursing School of Manaus, UFAM, Manaus, AM, Brazil
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16
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Fernandez-Ruiz R, Belmont HM. The role of anticomplement therapy in lupus nephritis. Transl Res 2022; 245:1-17. [PMID: 35158097 DOI: 10.1016/j.trsl.2022.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 02/03/2022] [Accepted: 02/07/2022] [Indexed: 10/19/2022]
Abstract
The complement system plays crucial roles in homeostasis and host defense against microbes. Deficiency of early complement cascade components has been associated with increased susceptibility to systemic lupus erythematosus (SLE), whereas excessive complement consumption is a hallmark of this disease. Although enhanced classical pathway activation by immune complexes was initially thought to be the main contributor to lupus nephritis (LN) pathogenesis, an increasing body of evidence has suggested the alternative and the lectin pathways are also involved. Therapeutic agents targeting complement activation have been used in LN patients and clinical trials are ongoing. We review the mechanisms by which complement system dysregulation contributes to renal injury in SLE and summarize the latest evidence on the use of anticomplement agents to manage this condition.
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Affiliation(s)
- Ruth Fernandez-Ruiz
- Division of Rheumatology, NYU Grossman School of Medicine, New York, New York
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17
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The Importance of CXCL1 in the Physiological State and in Noncancer Diseases of the Oral Cavity and Abdominal Organs. Int J Mol Sci 2022; 23:ijms23137151. [PMID: 35806156 PMCID: PMC9266754 DOI: 10.3390/ijms23137151] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 06/23/2022] [Accepted: 06/25/2022] [Indexed: 02/06/2023] Open
Abstract
CXCL1 is a CXC chemokine, CXCR2 ligand and chemotactic factor for neutrophils. In this paper, we present a review of the role of the chemokine CXCL1 in physiology and in selected major non-cancer diseases of the oral cavity and abdominal organs (gingiva, salivary glands, stomach, liver, pancreas, intestines, and kidneys). We focus on the importance of CXCL1 on implantation and placentation as well as on human pluripotent stem cells. We also show the significance of CXCL1 in selected diseases of the abdominal organs, including the gastrointestinal tract and oral cavity (periodontal diseases, periodontitis, Sjögren syndrome, Helicobacter pylori infection, diabetes, liver cirrhosis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), HBV and HCV infection, liver ischemia and reperfusion injury, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), obesity and overweight, kidney transplantation and ischemic-reperfusion injury, endometriosis and adenomyosis).
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18
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Luo S, Xu H, Gong X, Shen J, Chen X, Wu Z. The complement C3a‑C3aR and C5a‑C5aR pathways promote viability and inflammation of human retinal pigment epithelium cells by targeting NF‑κB signaling. Exp Ther Med 2022; 24:493. [PMID: 35837068 PMCID: PMC9257899 DOI: 10.3892/etm.2022.11420] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 04/08/2022] [Indexed: 11/05/2022] Open
Abstract
Retinal detachment (RD) and its special form of rhegmatogenous RD associated with choroidal detachment (RRDCD) feature similar pathological alterations, including enhanced retinal cell inflammation. Although the importance of the complement components C3a and C5a and their corresponding receptors in retinal maintenance has been demonstrated, the relevance of these molecules to the pathogenesis of RD or RRDCD remains to be investigated. The contents of C3a, C5a and inflammatory factors, such as TNF-α, IL-1β, IL-6 and prostaglandin (PG)E2, in related clinical samples were examined by ELISA. Subsequently, human retinal pigment epithelial (HRPE) cells were subjected to challenge with the C3a and C5a recombinant proteins with or without C3a and C5a antagonists and NF-κB inhibitor, and the cell viability and inflammatory cytokines were then determined by a Cell Counting Kit-8 assay and ELISA, respectively. In addition, reverse transcription-quantitative PCR and western blot analyses were utilized to examine the mRNA or/and protein levels of C3a and its receptor C3aR, as well as C5a and its receptor C5aR, and NF-κB. In addition, the correlation of C3a and C5a with the aforementioned inflammatory factors was analyzed. The inflammatory factor levels of C3a and C5a were considerably elevated in patients with RRDCD compared to those in the controls. Consistently, C3a and C5a treatment led to increased cell viability and aggravated inflammation in HRPE cells. Accordingly, C3a and C5a induced upregulation of their corresponding receptors C3aR and C5aR, which was in turn observed to be linked to the activation of the NF-κB signaling pathway. Furthermore, there was a positive correlation of the complements C3a and C5a with individual TNF-α, IL-1β, IL-6 and PGE2. Taken together, the C3a-C3aR and C5a-C5aR pathways were indicated to promote cell viability and inflammation of HRPE cells by targeting the NF-κB signaling pathway.
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Affiliation(s)
- Shasha Luo
- Department of Ophthalmology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Huiyan Xu
- Department of Ophthalmology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Xuechun Gong
- Department of Ophthalmology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Jinyan Shen
- Department of Ophthalmology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Xuan Chen
- Department of Ophthalmology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Zhifeng Wu
- Department of Ophthalmology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
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19
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Buelli S, Locatelli M, Carminati CE, Corna D, Cerullo D, Imberti B, Perico L, Brigotti M, Abbate M, Zoja C, Benigni A, Remuzzi G, Morigi M. Shiga Toxin 2 Triggers C3a-Dependent Glomerular and Tubular Injury through Mitochondrial Dysfunction in Hemolytic Uremic Syndrome. Cells 2022; 11:cells11111755. [PMID: 35681450 PMCID: PMC9179250 DOI: 10.3390/cells11111755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/13/2022] [Accepted: 05/23/2022] [Indexed: 11/16/2022] Open
Abstract
Shiga toxin (Stx)-producing Escherichia coli is the predominant offending agent of post-diarrheal hemolytic uremic syndrome (HUS), a rare disorder of microvascular thrombosis and acute kidney injury possibly leading to long-term renal sequelae. We previously showed that C3a has a critical role in the development of glomerular damage in experimental HUS. Based on the evidence that activation of C3a/C3a receptor (C3aR) signaling induces mitochondrial dysregulation and cell injury, here we investigated whether C3a caused podocyte and tubular injury through induction of mitochondrial dysfunction in a mouse model of HUS. Mice coinjected with Stx2/LPS exhibited glomerular podocyte and tubular C3 deposits and C3aR overexpression associated with cell damage, which were limited by C3aR antagonist treatment. C3a promoted renal injury by affecting mitochondrial wellness as demonstrated by data showing that C3aR blockade reduced mitochondrial ultrastructural abnormalities and preserved mitochondrial mass and energy production. In cultured podocytes and tubular cells, C3a caused altered mitochondrial fragmentation and distribution, and reduced anti-oxidant SOD2 activity. Stx2 potentiated the responsiveness of renal cells to the detrimental effects of C3a through increased C3aR protein expression. These results indicate that C3aR may represent a novel target in Stx-associated HUS for the preservation of renal cell integrity through the maintenance of mitochondrial function.
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Affiliation(s)
- Simona Buelli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy; (M.L.); (C.E.C.); (D.C.); (D.C.); (B.I.); (L.P.); (M.A.); (C.Z.); (A.B.); (G.R.); (M.M.)
- Correspondence: ; Tel.: +39-035-42131; Fax: +39-035-319-331
| | - Monica Locatelli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy; (M.L.); (C.E.C.); (D.C.); (D.C.); (B.I.); (L.P.); (M.A.); (C.Z.); (A.B.); (G.R.); (M.M.)
| | - Claudia Elisa Carminati
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy; (M.L.); (C.E.C.); (D.C.); (D.C.); (B.I.); (L.P.); (M.A.); (C.Z.); (A.B.); (G.R.); (M.M.)
| | - Daniela Corna
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy; (M.L.); (C.E.C.); (D.C.); (D.C.); (B.I.); (L.P.); (M.A.); (C.Z.); (A.B.); (G.R.); (M.M.)
| | - Domenico Cerullo
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy; (M.L.); (C.E.C.); (D.C.); (D.C.); (B.I.); (L.P.); (M.A.); (C.Z.); (A.B.); (G.R.); (M.M.)
| | - Barbara Imberti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy; (M.L.); (C.E.C.); (D.C.); (D.C.); (B.I.); (L.P.); (M.A.); (C.Z.); (A.B.); (G.R.); (M.M.)
| | - Luca Perico
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy; (M.L.); (C.E.C.); (D.C.); (D.C.); (B.I.); (L.P.); (M.A.); (C.Z.); (A.B.); (G.R.); (M.M.)
| | - Maurizio Brigotti
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40126 Bologna, Italy;
| | - Mauro Abbate
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy; (M.L.); (C.E.C.); (D.C.); (D.C.); (B.I.); (L.P.); (M.A.); (C.Z.); (A.B.); (G.R.); (M.M.)
| | - Carlamaria Zoja
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy; (M.L.); (C.E.C.); (D.C.); (D.C.); (B.I.); (L.P.); (M.A.); (C.Z.); (A.B.); (G.R.); (M.M.)
| | - Ariela Benigni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy; (M.L.); (C.E.C.); (D.C.); (D.C.); (B.I.); (L.P.); (M.A.); (C.Z.); (A.B.); (G.R.); (M.M.)
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy; (M.L.); (C.E.C.); (D.C.); (D.C.); (B.I.); (L.P.); (M.A.); (C.Z.); (A.B.); (G.R.); (M.M.)
| | - Marina Morigi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy; (M.L.); (C.E.C.); (D.C.); (D.C.); (B.I.); (L.P.); (M.A.); (C.Z.); (A.B.); (G.R.); (M.M.)
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20
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Qi R, Qin W. Role of Complement System in Kidney Transplantation: Stepping From Animal Models to Clinical Application. Front Immunol 2022; 13:811696. [PMID: 35281019 PMCID: PMC8913494 DOI: 10.3389/fimmu.2022.811696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/31/2022] [Indexed: 12/23/2022] Open
Abstract
Kidney transplantation is a life-saving strategy for patients with end-stage renal diseases. Despite the advances in surgical techniques and immunosuppressive agents, the long-term graft survival remains a challenge. Growing evidence has shown that the complement system, part of the innate immune response, is involved in kidney transplantation. Novel insights highlighted the role of the locally produced and intracellular complement components in the development of inflammation and the alloreactive response in the kidney allograft. In the current review, we provide the updated understanding of the complement system in kidney transplantation. We will discuss the involvement of the different complement components in kidney ischemia-reperfusion injury, delayed graft function, allograft rejection, and chronic allograft injury. We will also introduce the existing and upcoming attempts to improve allograft outcomes in animal models and in the clinical setting by targeting the complement system.
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Affiliation(s)
| | - Weijun Qin
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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21
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Howard MC, Nauser CL, Farrar CA, Sacks SH. Complement in ischaemia-reperfusion injury and transplantation. Semin Immunopathol 2021; 43:789-797. [PMID: 34757496 PMCID: PMC8579729 DOI: 10.1007/s00281-021-00896-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 09/22/2021] [Indexed: 01/08/2023]
Abstract
Until recently, the only known condition in which complement could mediate transplant injury was the rare occurrence of antibody-mediated rejection, in which the original concept of antibody immunity against the transplant was supported by complementary proteins present in the serum. This has changed within the last two decades because of evidence that the processes of ischaemia–reperfusion injury followed by T cell–mediated rejection are also critically dependent on components generated by the complement system. We now have a clearer understanding of the complement triggers and effectors that mediate injury, and a detailed map of their local sites of production and activation in the kidney. This is providing helpful guidelines as to how these harmful processes that restrict transplant outcomes can be targeted for therapeutic benefit. Here we review some of the recent advances highlighting relevant therapeutic targets.
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Affiliation(s)
- Mark C Howard
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
| | - Christopher L Nauser
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK
| | - Conrad A Farrar
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK
| | - Steven H Sacks
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK
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22
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Cantarelli C, Leventhal J, Cravedi P. Complement in Lupus: Biomarker, Therapeutic Target, or a Little Bit of Both? Kidney Int Rep 2021; 6:2031-2032. [PMID: 34386652 PMCID: PMC8344109 DOI: 10.1016/j.ekir.2021.06.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Chiara Cantarelli
- UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Jeremy Leventhal
- Division of Nephrology, White Plains Hospital, White Plains, New York, USA
| | - Paolo Cravedi
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
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23
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[Therapeutics for acute tubular necrosis in 2020]. Nephrol Ther 2021; 17:92-100. [PMID: 33483244 DOI: 10.1016/j.nephro.2020.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 10/24/2020] [Accepted: 11/03/2020] [Indexed: 11/23/2022]
Abstract
Acute kidney injury is a major cause of in-hospital morbidity and mortality because of the serious nature of the underlying illnesses and the high incidence of complications. The two major causes of acute kidney injury that occur in the hospital are prerenal disease and acute tubular necrosis. Acute tubular necrosis has a histological definition, even if a kidney biopsy is rarely performed. Kidney injuries occurring during acute tubular necrosis are underlined by different pathophysiological mechanisms that emphasize the role of hypoxia on the tubular cells such as apoptosis, cytoskeleton disruption, mitochondrial function and the inflammation mediated by innate immune cells. The microcirculation and the endothelial cells are also the targets of hypoxia-mediated impairment. Repair mechanisms are sometimes inadequate because of pro-fibrotic factors that will lead to chronic kidney disease. Despite all the potential therapeutic targets highlighted by the pathophysiological knowledge, further works remain necessary to find a way to prevent these injuries.
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24
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Thurman JM, Laskowski J, Nemenoff RA. Complement and Cancer-A Dysfunctional Relationship? Antibodies (Basel) 2020; 9:antib9040061. [PMID: 33167384 PMCID: PMC7709115 DOI: 10.3390/antib9040061] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 09/08/2020] [Accepted: 11/03/2020] [Indexed: 12/13/2022] Open
Abstract
Although it was long believed that the complement system helps the body to identify and remove transformed cells, it is now clear that complement activation contributes to carcinogenesis and can also help tumors to escape immune-elimination. Complement is activated by several different mechanisms in various types of cancer, and complement activation fragments have multiple different downstream effects on cancer cells and throughout the tumor microenvironment. Thus, the role of complement activation in tumor biology may vary among different types of cancer and over time within a single tumor. In multiple different pre-clinical models, however, complement activation has been shown to recruit immunosuppressive myeloid cells into the tumor microenvironment. These cells, in turn, suppress anti-tumor T cell immunity, enabling the tumor to grow. Based on extensive pre-clinical work, therapeutic complement inhibitors hold great promise as a new class of immunotherapy. A greater understanding of the role of complement in tumor biology will improve our ability to identify those patients most likely to benefit from this treatment and to rationally combine complement inhibitors with other cancer therapies.
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25
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Gao S, Cui Z, Zhao MH. The Complement C3a and C3a Receptor Pathway in Kidney Diseases. Front Immunol 2020; 11:1875. [PMID: 32973774 PMCID: PMC7461857 DOI: 10.3389/fimmu.2020.01875] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 07/13/2020] [Indexed: 12/23/2022] Open
Abstract
The pathogenesis of some kidney diseases is closely associated with complement activation, where the C3a/C3a receptor (C3aR) might play a crucial role. C3a/C3aR has dual roles and may exert anti-inflammatory or pro-inflammatory effects depending on different cell types and diseases. In the kidneys, C3aR is primarily expressed on the tubular epithelium and less in glomerular podocytes. C3aR expression is enhanced and the levels of C3a in the plasma and urine are increased in kidney diseases of several types, and are associated with disease progression and severity. The C3a/C3aR pathway facilitates the progression of glomerular and tubulointerstitial diseases, while it has opposite effects on urinary tract infections. Clinical trials targeting C3a/C3aR in kidney diseases are lacking. Here, we reviewed the studies on the C3a/C3aR pathway in kidney disease, with the aim of understanding in-depth its controversial roles and its potential therapeutic value.
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Affiliation(s)
- Shuang Gao
- Renal Division, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China
| | - Zhao Cui
- Renal Division, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China
| | - Ming-Hui Zhao
- Renal Division, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
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26
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Thurman JM. Complement and the Kidney: An Overview. Adv Chronic Kidney Dis 2020; 27:86-94. [PMID: 32553250 DOI: 10.1053/j.ackd.2019.10.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/10/2019] [Accepted: 10/10/2019] [Indexed: 12/12/2022]
Abstract
The complement cascade was first recognized as a downstream effector system of antibody-mediated cytotoxicity. Consistent with this view, it was discovered in the 1960s that complement is activated in the glomeruli of patients with immune complex glomerulonephritis. More recently, research has shown that complement system has many additional functions relating to regulation of the immune response, homeostasis, and metabolism. It has also become clear that the complement system is important to the pathogenesis of many non-immune complex mediated kidney diseases. In fact, in atypical hemolytic uremic syndrome and C3 glomerulopathy, uncontrolled complement activation is the primary driver of disease. Complement activation generates multiple pro-inflammatory fragments, and if not properly controlled it can cause fulminant tissue injury. Furthermore, the mechanisms of complement activation and complement-mediated injury vary from disease to disease. Many new drugs that target the complement cascade are in clinical development, so it is important to fully understand the biology of the complement system and its role in disease.
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27
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Frid MG, McKeon BA, Thurman JM, Maron BA, Li M, Zhang H, Kumar S, Sullivan T, Laskowsky J, Fini MA, Hu S, Tuder RM, Gandjeva A, Wilkins MR, Rhodes CJ, Ghataorhe P, Leopold JA, Wang RS, Holers VM, Stenmark KR. Immunoglobulin-driven Complement Activation Regulates Proinflammatory Remodeling in Pulmonary Hypertension. Am J Respir Crit Care Med 2020; 201:224-239. [PMID: 31545648 PMCID: PMC6961733 DOI: 10.1164/rccm.201903-0591oc] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 09/20/2019] [Indexed: 01/18/2023] Open
Abstract
Rationale: Pulmonary hypertension (PH) is a life-threatening cardiopulmonary disorder in which inflammation and immunity have emerged as critical early pathogenic elements. Although proinflammatory processes in PH and pulmonary arterial hypertension (PAH) are the focus of extensive investigation, the initiating mechanisms remain elusive.Objectives: We tested whether activation of the complement cascade is critical in regulating proinflammatory and pro-proliferative processes in the initiation of experimental hypoxic PH and can serve as a prognostic biomarker of outcome in human PAH.Methods: We used immunostaining of lung tissues from experimental PH models and patients with PAH, analyses of genetic murine models lacking specific complement components or circulating immunoglobulins, cultured human pulmonary adventitial fibroblasts, and network medicine analysis of a biomarker risk panel from plasma of patients with PAH.Measurements and Main Results: Pulmonary perivascular-specific activation of the complement cascade was identified as a consistent critical determinant of PH and PAH in experimental animal models and humans. In experimental hypoxic PH, proinflammatory and pro-proliferative responses were dependent on complement (alternative pathway and component 5), and immunoglobulins, particularly IgG, were critical for activation of the complement cascade. We identified Csf2/GM-CSF as a primary complement-dependent inflammatory mediator. Furthermore, using network medicine analysis of a biomarker risk panel from plasma of patients with PAH, we demonstrated that complement signaling can serve as a prognostic factor for clinical outcome in PAH.Conclusions: This study establishes immunoglobulin-driven dysregulated complement activation as a critical pathobiological mechanism regulating proinflammatory and pro-proliferative processes in the initiation of experimental hypoxic PH and demonstrates complement signaling as a critical determinant of clinical outcome in PAH.
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Affiliation(s)
- Maria G. Frid
- Division of Critical Care Medicine and Cardiovascular Pulmonary Research, Departments of Pediatrics and Medicine
| | - B. Alexandre McKeon
- Division of Critical Care Medicine and Cardiovascular Pulmonary Research, Departments of Pediatrics and Medicine
| | | | - Bradley A. Maron
- Division of Cardiovascular Medicine, Department of Medicine, School of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Min Li
- Division of Critical Care Medicine and Cardiovascular Pulmonary Research, Departments of Pediatrics and Medicine
| | - Hui Zhang
- Division of Critical Care Medicine and Cardiovascular Pulmonary Research, Departments of Pediatrics and Medicine
| | - Sushil Kumar
- Division of Critical Care Medicine and Cardiovascular Pulmonary Research, Departments of Pediatrics and Medicine
| | - Timothy Sullivan
- Division of Critical Care Medicine and Cardiovascular Pulmonary Research, Departments of Pediatrics and Medicine
| | | | - Mehdi A. Fini
- Division of Critical Care Medicine and Cardiovascular Pulmonary Research, Departments of Pediatrics and Medicine
| | - Samantha Hu
- Division of Critical Care Medicine and Cardiovascular Pulmonary Research, Departments of Pediatrics and Medicine
| | - Rubin M. Tuder
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, and
| | - Aneta Gandjeva
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, and
| | - Martin R. Wilkins
- Department of Medicine and National Heart and Lung Institute, Imperial College London, London, United Kingdom; and
| | - Christopher J. Rhodes
- Department of Medicine and National Heart and Lung Institute, Imperial College London, London, United Kingdom; and
| | - Pavandeep Ghataorhe
- Department of Medicine and National Heart and Lung Institute, Imperial College London, London, United Kingdom; and
| | - Jane A. Leopold
- Division of Cardiovascular Medicine, Department of Medicine, School of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Rui-Sheng Wang
- Channing Division of Network Medicine, Department of Medicine, School of Medicine, Brigham Health Brigham and Women’s Hospital, Boston, Massachusetts
| | - V. Michael Holers
- Division of Rheumatology, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Kurt R. Stenmark
- Division of Critical Care Medicine and Cardiovascular Pulmonary Research, Departments of Pediatrics and Medicine
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28
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Winnicki W, Pichler P, Mechtler K, Imre R, Steinmacher I, Sengölge G, Knafl D, Beilhack G, Wagner L. A novel approach to immunoapheresis of C3a/C3 and proteomic identification of associates. PeerJ 2019; 7:e8218. [PMID: 31871840 PMCID: PMC6921979 DOI: 10.7717/peerj.8218] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 11/15/2019] [Indexed: 02/06/2023] Open
Abstract
Background Complement factor C3 represents the central component of the complement cascade and its activation split product C3a plays an important role in inflammation and disease. Many human disorders are linked to dysregulation of the complement system and alteration in interaction molecules. Therefore, various therapeutic approaches to act on the complement system have been initiated. Methods and Results Aiming to develop a tool to eliminate C3a/C3 from the circulation, in a first step a high affine murine monoclonal antibody (mAb) (3F7E2-mAb) was generated against complement factor C3 and selected for binding to the C3a region to serve as immunoaffinity reagent. Functional testing of the 3F7E2-mAb revealed an inhibition of Zymosan-induced cleavage of C3a from C3. Subsequently, a C3a/C3 specific 3F7E2-immunoaffinity column was developed and apheresis of C3a/C3 and associates was performed. Finally, a proteomic analysis was carried out for identification of apheresis products. C3a/C3 was liberated from the 3F7E2-column together with 278 proteins. C3a/C3 interaction specificity was validated by using a haptoglobin immunoaffinity column as control and biostatistic analysis revealed 39 true C3a/C3 interactants. Conclusion A novel and functionally active mAb was developed against complement factor C3a/C3 and used in a specific immunoaffinity column that allows apheresis of C3a/C3 and associates and their identification by proteomic analysis. This methodological approach of developing specific antibodies that can be used as immunoaffinity reagents to design immunoaffinity columns for elimination and further identification of associated proteins could open new avenues for the development of tailored immunotherapy in various complement-mediated or autoimmune diseases.
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Affiliation(s)
- Wolfgang Winnicki
- Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Peter Pichler
- Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Karl Mechtler
- ProtChem Facility, Research Institute of Molecular Pathology, Vienna, Austria
| | - Richard Imre
- ProtChem Facility, Research Institute of Molecular Pathology, Vienna, Austria
| | - Ines Steinmacher
- ProtChem Facility, Research Institute of Molecular Pathology, Vienna, Austria
| | - Gürkan Sengölge
- Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Daniela Knafl
- Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Georg Beilhack
- Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Ludwig Wagner
- Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
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29
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Liu P, Li X, Lv W, Xu Z. Inhibition of CXCL1-CXCR2 axis ameliorates cisplatin-induced acute kidney injury by mediating inflammatory response. Biomed Pharmacother 2019; 122:109693. [PMID: 31812015 DOI: 10.1016/j.biopha.2019.109693] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 11/11/2019] [Accepted: 11/22/2019] [Indexed: 12/15/2022] Open
Abstract
One of the limiting side effects of cisplatin use in cancer chemotherapy is nephrotoxicity. Inflammation is now believed to play a major role in the pathogenesis of cisplatin-induced acute kidney injury (AKI), and the mediators of inflammation contribute to it. CXCL1 was recently reported to be involved in renal physiology and pathology in ischemia mouse model; however, its roles and mechanisms in cisplatin-induced AKI are completely unknown. We observed that CXCL1 and CXCR2 expression in the kidney was markedly increased on day 7 after cisplatin treatment. Subsequently, we demonstrate that inhibition of CXCL1-CXCR2 signaling axis, using genetic and pharmacological approaches, reduces renal damage following cisplatin treatment as compared with control mice. Specifically, deficiency of CXCL1 or CXCR2 extensively preserved the renal histology and maintained the kidney functions after cisplatin treatment, which was associated with reduced expression of the pro-inflammatory cytokines and infiltration of neutrophils in the kidneys as compared. Furthermore, inhibition of CXCR2 by intragastric administration of repertaxin in mice with AKI reduces kidney injury associated with a reduction of inflammatory cytokines and neutrophils infiltration. Finally, we found that CXCL1/CXCR2 regulated cisplatin-induced inflammatory responses via the P38 and NF-κB signaling pathways in vitro and in vivo. In conclusion, our results indicate that CXCL1-CXCR2 signaling axis plays a crucial role in the pathogenesis of cisplatin-induced AKI through regulation of inflammatory response and maybe a novel therapeutic target for cisplatin-induced AKI.
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Affiliation(s)
- Peng Liu
- Department of Intensive Care Unit, Hwamei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Xinxiu Li
- Department of Experimental Medical Science, Hwamei Hospital, University of Chinese Academy of Sciences, Ningbo, China; Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo, China.
| | - Weixing Lv
- Department of Intensive Care Unit, Hwamei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Zhaojun Xu
- Department of Intensive Care Unit, Hwamei Hospital, University of Chinese Academy of Sciences, Ningbo, China.
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30
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Grafals M, Thurman JM. The Role of Complement in Organ Transplantation. Front Immunol 2019; 10:2380. [PMID: 31636644 PMCID: PMC6788431 DOI: 10.3389/fimmu.2019.02380] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 09/23/2019] [Indexed: 12/17/2022] Open
Abstract
The current immunosuppressive protocols used in transplant recipients have improved short-term outcomes, but long-term allograft failure remains an important clinical problem. Greater understanding of the immunologic mechanisms that cause allograft failure are needed, as well as new treatment strategies for protecting transplanted organs. The complement cascade is an important part of the innate immune system. Studies have shown that complement activation contributes to allograft injury in several clinical settings, including ischemia/reperfusion injury and antibody mediated rejection. Furthermore, the complement system plays critical roles in modulating the responses of T cells and B cells to antigens. Therapeutic complement inhibitors, therefore, may be effective for protecting transplanted organs from several causes of inflammatory injury. Although several anti-complement drugs have shown promise in selected patients, the role of these drugs in transplantation medicine requires further study.
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Affiliation(s)
- Monica Grafals
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
| | - Joshua M Thurman
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
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The role of complement activation in rhabdomyolysis-induced acute kidney injury. PLoS One 2018; 13:e0192361. [PMID: 29466390 PMCID: PMC5821337 DOI: 10.1371/journal.pone.0192361] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 01/20/2018] [Indexed: 12/25/2022] Open
Abstract
Rhabdomyolysis (RM) may cause kidney damage and results primarily in acute kidney injury (AKI). Complement is implicated in the pathogenesis of renal diseases and ischemia-reperfusion injury (IRI), but the role of complement, especially its activation pathway(s) and its effect in RM-induced AKI, is not clear. This study established a rat model of AKI induced by RM via intramuscular treatment with glycerol. Cobra venom factor (CVF) was administered via tail vein injection to deplete complement 12 h prior to intramuscular injection of glycerol. We found that the complement components, including complement 3 (C3), C1q, MBL-A, factor B(fB), C5a, C5b-9, and CD59, were significantly increased in rat kidneys after intramuscular glycerol administration. However, the levels of serum BUN and Cr, renal tubular injury scores, and the number of TUNEL-positive cells decreased significantly in the CVF+AKI group. These results suggest that complement plays an important role in RM-induced AKI and that complement depletion may improve renal function and decrease renal tissue damage by reducing the inflammatory response and apoptosis.
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32
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Urbschat A, Baer P, Zacharowski K, Sprunck V, Scheller B, Raimann F, Maier TJ, Hegele A, Hofmann R, Mersmann J. Systemic TLR2 Antibody Application in Renal Ischaemia and Reperfusion Injury Decreases AKT Phosphorylation and Increases Apoptosis in the Mouse Kidney. Basic Clin Pharmacol Toxicol 2017; 122:223-232. [PMID: 28857508 DOI: 10.1111/bcpt.12896] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 08/21/2017] [Indexed: 12/27/2022]
Abstract
Acute kidney injury remains an important cause of renal dysfunction. In this context, Toll-like receptors have been demonstrated to play a critical role in the induction of innate and inflammatory responses. Among these, Toll-like receptor 2 (TLR2) is constitutively expressed in tubular epithelial cells (TECs) of the kidney and is also known to mediate ischaemia reperfusion (IR) injury. Adult male C57BL/6JRj mice were randomized into seven groups (n = 8): a non-operative control group (CTRL) and six interventional groups in which mice were subjected to a 30 min. bilateral renal ischaemia. Immediately before reperfusion, mice were treated either with saline or with TLR2 antibody (clone T2.5) and harvested after ischaemia and reperfusion for 3, 24 and 48 hr. Analysed kidney homogenates of TLR2 antibody-treated mice displayed significantly decreased levels of TLR2 protein after 3 hr of IR compared to saline-treated mice. Accordingly, the degree of AKT phosphorylation was significantly decreased after 3 hr of IR compared to saline-treated animals. TUNEL staining revealed significantly higher apoptosis rates in TLR2 antibody-treated animals compared to saline-treated mice after 3 and 24 hr of IR. Further, a positive correlation between TLR2 protein expression and phosphorylation of AKT as well as a negative correlation with the number of TUNEL-positive cells could be observed. Inhibition of TLR2 and its signalling pathway by a single application of TLR2 antibody results in reduced phosphorylation of AKT and consecutively increased apoptosis.
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Affiliation(s)
- Anja Urbschat
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.,Clinic of Urology and Pediatric Urology, Medical School, Philipps-University Marburg, Marburg, Germany
| | - Patrick Baer
- Clinic of Internal Medicine III, Division of Nephrology, Goethe-University Hospital, Frankfurt am Main, Germany
| | - Kai Zacharowski
- Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe-University Hospital, Frankfurt am Main, Germany
| | - Vera Sprunck
- Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe-University Hospital, Frankfurt am Main, Germany
| | - Bertram Scheller
- Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe-University Hospital, Frankfurt am Main, Germany
| | - Florian Raimann
- Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe-University Hospital, Frankfurt am Main, Germany
| | - Thorsten Jürgen Maier
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.,Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe-University Hospital, Frankfurt am Main, Germany
| | - Axel Hegele
- Clinic of Urology and Pediatric Urology, Medical School, Philipps-University Marburg, Marburg, Germany
| | - Rainer Hofmann
- Clinic of Urology and Pediatric Urology, Medical School, Philipps-University Marburg, Marburg, Germany
| | - Jan Mersmann
- Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe-University Hospital, Frankfurt am Main, Germany
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Sheen JH, Strainic MG, Liu J, Zhang W, Yi Z, Medof ME, Heeger PS. TLR-Induced Murine Dendritic Cell (DC) Activation Requires DC-Intrinsic Complement. THE JOURNAL OF IMMUNOLOGY 2017; 199:278-291. [PMID: 28539427 DOI: 10.4049/jimmunol.1700339] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 05/04/2017] [Indexed: 01/04/2023]
Abstract
Induction of proinflammatory T cell immunity is augmented by innate dendritic cell (DC) maturation commonly initiated by TLR signaling. We demonstrate that ligation of TLR3, TLR4, and TLR9 induces murine DC production of complement components and local production of the anaphylatoxin C5a. In vitro, ex vivo, and in vivo analyses show that TLR-induced DC maturation, as assessed by surface phenotype, expression profiling by gene array, and functional ability to stimulate T cell responses, requires autocrine C3a receptor and C5a receptor (C3ar1/C5ar1) signaling. Studies using bone marrow chimeric animals and Foxp3-GFP/ERT2-Cre/dTomato fate-mapping mice show that TLR-initiated DC autocrine C3ar1/C5ar1 signaling causes expansion of effector T cells and instability of regulatory T cells and contributes to T cell-dependent transplant rejection. Together, our data position immune cell-derived complement production and autocrine/paracrine C3ar1/C5ar1 signaling as crucial intermediary processes that link TLR stimulation to DC maturation and the subsequent development of effector T cell responses.
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Affiliation(s)
- Joong-Hyuk Sheen
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.,Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.,Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; and
| | - Michael G Strainic
- Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106
| | - Jinbo Liu
- Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106
| | - Weijia Zhang
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.,Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Zhengzi Yi
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.,Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - M Edward Medof
- Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106
| | - Peter S Heeger
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029; .,Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.,Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; and
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Abstract
The clinical category of acute kidney injury includes a wide range of completely different disorders, many with their own pathomechanisms and treatment targets. In this review we focus on the role of inflammation in the pathogenesis of acute tubular necrosis (ATN). We approach this topic by first discussing the role of the immune system in the different phases of ATN (ie, early and late injury phase, recovery phase, and the long-term outcome phase of an ATN episode). A more detailed discussion focuses on putative therapeutic targets among the following mechanisms and mediators: oxidative stress and reactive oxygen species-related necroinflammation, regulated cell death-related necroinflammation, immunoregulatory lipid mediators, cytokines and cytokine signaling, chemokines and chemokine signaling, neutrophils and neutrophils extracellular traps (NETs) associated neutrophil cell death, called NETosis, extracellular histones, proinflammatory mononuclear phagocytes, humoral mediators such as complement, pentraxins, and natural antibodies. Any prioritization of these targets has to take into account the intrinsic differences between rodent models and human ATN, the current acute kidney injury definitions, and the timing of clinical decision making. Several conceptual problems need to be solved before anti-inflammatory drugs that are efficacious in rodent ATN may become useful therapeutics for human ATN.
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Affiliation(s)
- Shrikant R Mulay
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Alexander Holderied
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Santhosh V Kumar
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Hans-Joachim Anders
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
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Abou-El-Hassan H, Zaraket H. Viral-derived complement inhibitors: current status and potential role in immunomodulation. Exp Biol Med (Maywood) 2016; 242:397-410. [PMID: 27798122 DOI: 10.1177/1535370216675772] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The complement system is one of the body's major innate immune defense mechanisms in vertebrates. Its function is to detect foreign bodies and promote their elimination through opsonisation or lysis. Complement proteins play an important role in the immunopathogenesis of several disorders. However, excessive complement activation does not confer more protection but instead leads to several autoimmune and inflammatory diseases. With inappropriate activation of the complement system, activated complement proteins and glycoproteins may damage both healthy and diseased tissues. Development of complement inhibitors represents an effective approach in controlling dysregulated complement activity and reducing disease severity, yet few studies have investigated the nature and role of novel complement inhibitory proteins of viral origin. Viral complement inhibitors have important implications in understanding the importance of complement inhibition and their role as a promising novel therapeutic approach in diseases caused by dysregulated complement function. In this review, we discuss the role and importance of complement inhibitors derived from several viruses in the scope of human inflammatory and autoimmune diseases.
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Affiliation(s)
- Hadi Abou-El-Hassan
- 1 Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon.,2 Center for Infectious Diseases Research, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Hassan Zaraket
- 2 Center for Infectious Diseases Research, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.,3 Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Abstract
The complement (C) cascade is an ancient system of proteins whose primary role is to initiate and modulate immune responses. During C activation, circulating proteins are cleaved and nascent cleavage fragments participate in a broad range of downstream innate and adaptive immune functions. Although the majority of these functions are either homeostatic or protective, a large body of experimental and clinical evidence also highlights a central role for the C system in the pathogenesis of many types of glomerular disease. From classic pathway activation in lupus nephritis to alternative pathway dysregulation in C3 glomerulopathy, our understanding of the spectrum of C involvement in kidney disease has expanded greatly in recent years. However, the characteristics that make the glomerulus so uniquely susceptible to C-mediated injury are not fully understood, and this remains an area of ongoing investigation. Several C inhibitors have been approved for clinical use, and additional C inhibitory drugs are in development. The use of these drugs in patients with kidney disease will expand our understanding of the benefits and limitations of C inhibition.
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Affiliation(s)
- Joshua M. Thurman
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado; and
| | - Carla M. Nester
- Stead Family Department of Pediatrics and
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa
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Thurman JM, Le Quintrec M. Targeting the complement cascade: novel treatments coming down the pike. Kidney Int 2016; 90:746-52. [PMID: 27325183 DOI: 10.1016/j.kint.2016.04.018] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 03/09/2016] [Accepted: 04/07/2016] [Indexed: 12/19/2022]
Abstract
The complement cascade is a vital component of both the innate and adaptive immune systems. Complement activation also contributes to the pathogenesis of many diseases, however, and the kidney is particularly susceptible to complement-mediated injury. Drugs that block complement activation can rapidly reduce tissue inflammation and also attenuate the adaptive immune response to foreign and tissue antigens. Eculizumab is a monoclonal antibody that prevents the cleavage of C5. It has been approved for the treatment of atypical hemolytic uremic syndrome, and it has been used in selected patients with other kidney diseases. Many additional drugs are also in development for blocking the complement cascade, including new monoclonal antibodies, recombinant proteins, small molecules, and small interfering RNA agents. Validation of these new drugs as effective treatments for kidney diseases faces several challenges. Many complement-mediated kidney diseases are rare, so it is not feasible to test all of the new drugs in numerous different rare diseases. The onset and course of the diseases are heterogeneous; many of these diseases also carry a lifelong risk of recurrence, and it is not clear how long complement inhibition must be maintained. In spite of these challenges, new therapeutic options for targeting the complement system will likely become available in the near future and may prove useful for treating patients with kidney disease.
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Affiliation(s)
- Joshua M Thurman
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA.
| | - Moglie Le Quintrec
- Department of Nephrology and Renal Transplantation, Lapeyronnie Hospital and INSERM U1183, Institute of Regenerative Medicine and Biotherapies, Montpellier, France
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Grootjans J, Lenaerts K, Buurman WA, Dejong CHC, Derikx JPM. Life and death at the mucosal-luminal interface: New perspectives on human intestinal ischemia-reperfusion. World J Gastroenterol 2016; 22:2760-2770. [PMID: 26973414 PMCID: PMC4777998 DOI: 10.3748/wjg.v22.i9.2760] [Citation(s) in RCA: 106] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 09/24/2015] [Accepted: 12/14/2015] [Indexed: 02/06/2023] Open
Abstract
Intestinal ischemia is a frequently observed phenomenon. Morbidity and mortality rates are extraordinarily high and did not improve over the past decades. This is in part attributable to limited knowledge on the pathophysiology of intestinal ischemia-reperfusion (IR) in man, the paucity in preventive and/or therapeutic options and the lack of early diagnostic markers for intestinal ischemia. To improve our knowledge and solve clinically important questions regarding intestinal IR, we developed a human experimental intestinal IR model. With this model, we were able to gain insight into the mechanisms that allow the human gut to withstand short periods of IR without the development of severe inflammatory responses. The purpose of this review is to overview the most relevant recent advances in our understanding of the pathophysiology of human intestinal IR, as well as the (potential) future clinical implications.
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Hattori Y, Kim H, Tsuboi N, Yamamoto A, Akiyama S, Shi Y, Katsuno T, Kosugi T, Ueda M, Matsuo S, Maruyama S. Therapeutic Potential of Stem Cells from Human Exfoliated Deciduous Teeth in Models of Acute Kidney Injury. PLoS One 2015; 10:e0140121. [PMID: 26509261 PMCID: PMC4625005 DOI: 10.1371/journal.pone.0140121] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 09/21/2015] [Indexed: 12/15/2022] Open
Abstract
Background Acute kidney injury (AKI) is a critical condition associated with high mortality. However, the available treatments for AKI are limited. Stem cells from human exfoliated deciduous teeth (SHED) have recently gained attention as a novel source of stem cells. The purpose of this study was to clarify whether SHED have a therapeutic effect on AKI induced by ischemia-reperfusion injury. Methods The left renal artery and vein of the mice were clamped for 20 min to induce ischemia. SHED, bone marrow derived mesenchymal stem cells (BMMSC) or phosphate-buffered saline (control) were administered into the subrenal capsule. To confirm the potency of SHED in vitro, H2O2 stimulation assays and scratch assays were performed. Results The serum creatinine and blood urea nitrogen levels of the SHED group were significantly lower than those of the control group, while BMMSC showed no therapeutic effect. Infiltration of macrophages and neutrophils in the kidney was significantly attenuated in mice treated with SHED. Cytokine levels (MIP-2, IL-1β, and MCP-1) in mice kidneys were significantly reduced in the SHED group. In in vitro experiments, SHED significantly decreased MCP-1 secretion in tubular epithelial cells (TEC) stimulated with H2O2. In addition, SHED promoted wound healing in the scratch assays, which was blunted by anti-HGF antibodies. Discussion SHED attenuated the levels of inflammatory cytokines and improved kidney function in AKI induced by IRI. SHED secreted factors reduced MCP-1 and increased HGF expression, which promoted wound healing. These results suggest that SHED might provide a novel stem cell resource, which can be applied for the treatment of ischemic kidney injury.
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Affiliation(s)
- Yuka Hattori
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan
| | - Hangsoo Kim
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan
| | - Naotake Tsuboi
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan
| | - Akihito Yamamoto
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan
| | - Shinichi Akiyama
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan
| | - Yiqin Shi
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan
| | - Takayuki Katsuno
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan
| | - Tomoki Kosugi
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan
| | - Minoru Ueda
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan
| | - Seiichi Matsuo
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan
- * E-mail:
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Schraufstatter IU, Khaldoyanidi SK, DiScipio RG. Complement activation in the context of stem cells and tissue repair. World J Stem Cells 2015; 7:1090-1108. [PMID: 26435769 PMCID: PMC4591784 DOI: 10.4252/wjsc.v7.i8.1090] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 07/27/2015] [Indexed: 02/06/2023] Open
Abstract
The complement pathway is best known for its role in immune surveillance and inflammation. However, its ability of opsonizing and removing not only pathogens, but also necrotic and apoptotic cells, is a phylogenetically ancient means of initiating tissue repair. The means and mechanisms of complement-mediated tissue repair are discussed in this review. There is increasing evidence that complement activation contributes to tissue repair at several levels. These range from the chemo-attraction of stem and progenitor cells to areas of complement activation, to increased survival of various cell types in the presence of split products of complement, and to the production of trophic factors by cells activated by the anaphylatoxins C3a and C5a. This repair aspect of complement biology has not found sufficient appreciation until recently. The following will examine this aspect of complement biology with an emphasis on the anaphylatoxins C3a and C5a.
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Piechota-Polanczyk A, Jozkowicz A, Nowak W, Eilenberg W, Neumayer C, Malinski T, Huk I, Brostjan C. The Abdominal Aortic Aneurysm and Intraluminal Thrombus: Current Concepts of Development and Treatment. Front Cardiovasc Med 2015; 2:19. [PMID: 26664891 PMCID: PMC4671358 DOI: 10.3389/fcvm.2015.00019] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 04/10/2015] [Indexed: 01/09/2023] Open
Abstract
The pathogenesis of the abdominal aortic aneurysm (AAA) shows several hallmarks of atherosclerotic and atherothrombotic disease, but comprises an additional, predominant feature of proteolysis resulting in the degradation and destabilization of the aortic wall. This review aims to summarize the current knowledge on AAA development, involving the accumulation of neutrophils in the intraluminal thrombus and their central role in creating an oxidative and proteolytic environment. Particular focus is placed on the controversial role of heme oxygenase 1/carbon monoxide and nitric oxide synthase/peroxynitrite, which may exert both protective and damaging effects in the development of the aneurysm. Treatment indications as well as surgical and pharmacological options for AAA therapy are discussed in light of recent reports.
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Affiliation(s)
- Aleksandra Piechota-Polanczyk
- Department of Surgery, Medical University of Vienna , Vienna , Austria ; Department of Biochemistry, Medical University of Lodz , Lodz , Poland
| | - Alicja Jozkowicz
- Department of Medical Biotechnology, Jagiellonian University , Krakow , Poland
| | - Witold Nowak
- Department of Medical Biotechnology, Jagiellonian University , Krakow , Poland
| | - Wolf Eilenberg
- Department of Surgery, Medical University of Vienna , Vienna , Austria
| | | | - Tadeusz Malinski
- Department of Chemistry and Biochemistry, Ohio University , Athens, OH , USA
| | - Ihor Huk
- Department of Surgery, Medical University of Vienna , Vienna , Austria
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Diverse Cell Populations Involved in Regeneration of Renal Tubular Epithelium following Acute Kidney Injury. Stem Cells Int 2015; 2015:964849. [PMID: 26089922 PMCID: PMC4452180 DOI: 10.1155/2015/964849] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 12/06/2014] [Indexed: 12/17/2022] Open
Abstract
Renal tubular epithelium has the capacity to regenerate, repair, and reepithelialize in response to a variety of insults. Previous studies with several kidney injury models demonstrated that various growth factors, transcription factors, and extracellular matrices are involved in this process. Surviving tubular cells actively proliferate, migrate, and differentiate in the kidney regeneration process after injury, and some cells express putative stem cell markers or possess stem cell properties. Using fate mapping techniques, bone marrow-derived cells and endothelial progenitor cells have been shown to transdifferentiate into tubular components in vivo or ex vivo. Similarly, it has been demonstrated that, during tubular cell regeneration, several inflammatory cell populations migrate, assemble around tubular cells, and interact with tubular cells during the repair of tubular epithelium. In this review, we describe recent advances in understanding the regeneration mechanisms of renal tubules, particularly the characteristics of various cell populations contributing to tubular regeneration, and highlight the targets for the development of regenerative medicine for treating kidney diseases in humans.
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Abstract
Understanding innate immune responses and their correlation to alloimmunity after solid organ transplantation is key to optimizing long term graft outcome. While Ischemia/Reperfusion injury (IRI) has been well studied, new insight into central mechanisms of innate immune activation, i.e. chemokine mediated cell trafficking and the role of Toll-like receptors have evolved recently. The mechanistic implications of Neutrophils, Macrophages/Monocytes, NK-cells, Dendritic cells in renal IRI has been proven by selective depletion of these cell types, thereby offering novel therapeutic interventions. At the same time, the multi-faceted role of different T-cell subsets in IRI has gained interest, highlighting the dichotomous effects of differentiated T-cells and suggesting more selective therapeutic approaches. Targeting innate immune cells and their activation and migration pathways, respectively, has been promising in experimental models holding translational potential. This review will summarize the effects of innate immune activation and potential strategies to interfere with the immunological cascade following renal IRI.
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Kumar D, Singla SK, Puri V, Puri S. The restrained expression of NF-kB in renal tissue ameliorates folic acid induced acute kidney injury in mice. PLoS One 2015; 10:e115947. [PMID: 25559736 PMCID: PMC4283964 DOI: 10.1371/journal.pone.0115947] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Accepted: 11/27/2014] [Indexed: 01/13/2023] Open
Abstract
The Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) represent family of structurally-related eukaryotic transcription factors which regulate diverse array of cellular processes including immunological responses, inflammation, apoptosis, growth & development. Increased expression of NF-kB has often been seen in many diverse diseases, suggesting the importance of genomic deregulation to disease pathophysiology. In the present study we focused on acute kidney injury (AKI), which remains one of the major risk factor showing a high rate of mortality and morbidity. The pathology associated with it, however, remains incompletely known though inflammation has been reported to be one of the major risk factor in the disease pathophysiology. The role of NF-kB thus seemed pertinent. In the present study we show that high dose of folic acid (FA) induced acute kidney injury (AKI) characterized by elevation in levels of blood urea nitrogen & serum creatinine together with extensive tubular necrosis, loss of brush border and marked reduction in mitochondria. One of the salient observations of this study was a coupled increase in the expression of renal, relA, NF-kB2, and p53 genes and proteins during folic acid induced AKI (FA AKI). Treatment of mice with NF-kB inhibitor, pyrrolidine dithio-carbamate ammonium (PDTC) lowered the expression of these transcription factors and ameliorated the aberrant renal function by decreasing serum creatinine levels. In conclusion, our results suggested that NF-kB plays a pivotal role in maintaining renal function that also involved regulating p53 levels during FA AKI.
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Affiliation(s)
- Dev Kumar
- Department of Biochemistry, Panjab University, Chandigarh, India
| | | | - Veena Puri
- Centre for Systems Biology & Bioinformatics, Panjab University, Chandigarh, India
| | - Sanjeev Puri
- Biotechnology Branch, University Institute of Engineering & Technology, Panjab University, Chandigarh, India
- Centre for Stem Cell & Tissue Engineering, Panjab University, Chandigarh, India
- * E-mail:
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Reid RC, Yau MK, Singh R, Hamidon JK, Lim J, Stoermer MJ, Fairlie DP. Potent Heterocyclic Ligands for Human Complement C3a Receptor. J Med Chem 2014; 57:8459-70. [DOI: 10.1021/jm500956p] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Robert C. Reid
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Mei-Kwan Yau
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Ranee Singh
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Johan K. Hamidon
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Junxian Lim
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Martin J. Stoermer
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - David P. Fairlie
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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Abstract
Acute kidney injury is common, dangerous and costly, affecting around one in five patients emergency admissions to hospital. Although survival decreases as disease worsens, it is now apparent that even modest degrees of dysfunction are not only associated with higher mortality but are an independent risk factor for death. This review focuses on the pathophysiology of acute kidney injury secondary to ischaemia - its commonest aetiology. The haemodynamic disturbances, endothelial injury, epithelial cell injury and immunological mechanisms underpinning its initiation and extension will be discussed along with the considerable and complex interplay between these factors that lead to an intense, pro-inflammatory state. Mechanisms of tubular recovery will be discussed but also the pathophysiology of abnormal repair with its direct consequences for long-term renal function. Finally, the concept of 'organ cross-talk' will be introduced as a potential explanation for the higher mortality observed with acute kidney injury that might be deemed modest in conventional biochemical terms.
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Affiliation(s)
- Nigel Suren Kanagasundaram
- Renal Services, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, High Heaton, Newcastle upon Tyne, UK
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Kawa MP, Machalinska A, Roginska D, Machalinski B. Complement system in pathogenesis of AMD: dual player in degeneration and protection of retinal tissue. J Immunol Res 2014; 2014:483960. [PMID: 25276841 PMCID: PMC4168147 DOI: 10.1155/2014/483960] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 07/18/2014] [Accepted: 08/01/2014] [Indexed: 12/25/2022] Open
Abstract
Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly, especially in Western countries. Although the prevalence, risk factors, and clinical course of the disease are well described, its pathogenesis is not entirely elucidated. AMD is associated with a variety of biochemical abnormalities, including complement components deposition in the retinal pigment epithelium-Bruch's membrane-choriocapillaris complex. Although the complement system (CS) is increasingly recognized as mediating important roles in retinal biology, its particular role in AMD pathogenesis has not been precisely defined. Unrestricted activation of the CS following injury may directly damage retinal tissue and recruit immune cells to the vicinity of active complement cascades, therefore detrimentally causing bystander damage to surrounding cells and tissues. On the other hand, recent evidence supports the notion that an active complement pathway is a necessity for the normal maintenance of the neurosensory retina. In this scenario, complement activation appears to have beneficial effect as it promotes cell survival and tissue remodeling by facilitating the rapid removal of dying cells and resulting cellular debris, thus demonstrating anti-inflammatory and neuroprotective activities. In this review, we discuss both the beneficial and detrimental roles of CS in degenerative retina, focusing on the diverse aspects of CS functions that may promote or inhibit macular disease.
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Affiliation(s)
- Milosz P. Kawa
- Department of General Pathology, Pomeranian Medical University, Al. Powstancow Wlkp. 72, 70-111 Szczecin, Poland
| | - Anna Machalinska
- Department of Ophthalmology, Pomeranian Medical University, Al. Powstancow Wlkp. 72, 70-111 Szczecin, Poland
- Department of Histology and Embryology, Pomeranian Medical University, Al. Powstancow Wlkp. 72, 70-111 Szczecin, Poland
| | - Dorota Roginska
- Department of General Pathology, Pomeranian Medical University, Al. Powstancow Wlkp. 72, 70-111 Szczecin, Poland
| | - Boguslaw Machalinski
- Department of General Pathology, Pomeranian Medical University, Al. Powstancow Wlkp. 72, 70-111 Szczecin, Poland
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Prieto-Moure B, Carabén-Redaño A, Aliena-Valero A, Cejalvo D, Toledo AH, Flores-Bellver M, Martínez-Gil N, Toledo-Pereyra LH, Lloris Carsí JM. Allopurinol in Renal Ischemia. J INVEST SURG 2014; 27:304-16. [DOI: 10.3109/08941939.2014.911395] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Abstract
Complement is an important component of the innate immune system that is crucial for defense from microbial infections and for clearance of immune complexes and injured cells. In normal conditions complement is tightly controlled by a number of fluid-phase and cell surface proteins to avoid injury to autologous tissues. When complement is hyperactivated, as occurs in autoimmune diseases or in subjects with dysfunctional regulatory proteins, it drives a severe inflammatory response in numerous organs. The kidney appears to be particularly vulnerable to complement-mediated inflammatory injury. Injury may derive from deposition of circulating active complement fragments in glomeruli, but complement locally produced and activated in the kidney also may have a role. Many kidney disorders have been linked to abnormal complement activation, including immune-complex–mediated glomerulonephritis and rare genetic kidney diseases, but also tubulointerstitial injury associated with progressive proteinuric diseases or ischemia-reperfusion.
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50
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The regulation of inflammatory mediators in acute kidney injury via exogenous mesenchymal stem cells. Mediators Inflamm 2014; 2014:261697. [PMID: 24839354 PMCID: PMC4009277 DOI: 10.1155/2014/261697] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 03/07/2014] [Accepted: 03/20/2014] [Indexed: 12/31/2022] Open
Abstract
Acute kidney injury (AKI) remains to be an independent risk factor for mortality and morbidity. Inflammation is believed to play a major role in the pathophysiology of AKI. Exogenous mesenchymal stem cells (MSCs) are now under extensive investigation as a potential therapy for AKI. Various preclinical studies indicated the beneficial effects of MSCs in alleviating renal injury and accelerating tissue repair. However the mechanisms responsible for these effects are incompletely understood. In the recent years, anti-inflammatory/immunoregulatory properties of MSCs have become one of the important issues in the treatment of AKI. This review will summarize the current literature on the regulation of inflammatory mediators via exogenous MSCs contributing to the recovery from AKI.
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