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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] [Academic Contribution 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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Kakuta Y, Miyagawa S, Matsumura S, Higa-Maegawa Y, Fukae S, Tanaka R, Nakazawa S, Yamanaka K, Kawamura T, Saito S, Miyagawa S, Nonomura N. Complement and complement regulatory protein in allogeneic and xenogeneic kidney transplantation. Transplant Rev (Orlando) 2025; 39:100885. [PMID: 39536474 DOI: 10.1016/j.trre.2024.100885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/25/2024] [Revised: 10/31/2024] [Accepted: 11/03/2024] [Indexed: 11/16/2024]
Abstract
Kidney transplantation is the most optimal treatment for patients with end-stage renal disease, offering significant improvements in patient outcomes over dialysis. However, the potential for immune rejection, where the recipient's immune system attacks the transplanted kidney, can compromise transplant success. The complement system, a key component of the immune response, plays a crucial role in both acute and chronic rejection, including T-cell- and antibody-mediated rejection. Understanding and controlling the complement system is essential for managing rejection and enhancing graft survival and overall success of kidney transplantation. In allogeneic transplantation, complement activation through various pathways contributes to graft damage and failure. Recent advancements in genetic engineering enable the development of transgenic pigs expressing human complement regulatory proteins, which display potential for reducing rejection in xenotransplantation. Despite these advances, the complex mechanisms of complement activation and regulation are not fully understood, necessitating further research. This review examines the role of the complement system in kidney transplantation, explores the latest developments in complement regulatory strategies, and discusses potential therapeutic approaches to improve transplant outcomes.
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Affiliation(s)
- Yoichi Kakuta
- Department of Urology, Osaka University Graduate School of Medicine, Japan
| | - Shuji Miyagawa
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Japan.
| | - Soichi Matsumura
- Department of Urology, Osaka University Graduate School of Medicine, Japan
| | - Yoko Higa-Maegawa
- Department of Urology, Osaka University Graduate School of Medicine, Japan
| | - Shota Fukae
- Department of Urology, Osaka University Graduate School of Medicine, Japan
| | - Ryo Tanaka
- Department of Urology, Osaka University Graduate School of Medicine, Japan
| | - Shigeaki Nakazawa
- Department of Urology, Osaka University Graduate School of Medicine, Japan
| | - Kazuaki Yamanaka
- Department of Urology, Osaka University Graduate School of Medicine, Japan
| | - Takuji Kawamura
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Japan
| | - Shunsuke Saito
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Japan
| | - Shigeru Miyagawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Japan
| | - Norio Nonomura
- Department of Urology, Osaka University Graduate School of Medicine, Japan
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Stepanova G, Manzéger A, Mózes MM, Kökény G. Renal Epithelial Complement C3 Expression Affects Kidney Fibrosis Progression. Int J Mol Sci 2024; 25:12551. [PMID: 39684261 DOI: 10.3390/ijms252312551] [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] [Academic Contribution Register] [Received: 09/24/2024] [Revised: 11/16/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024] Open
Abstract
Kidney fibrosis is a hallmark of chronic kidney diseases. Evidence shows that genetic variability and complement component 3 (C3) might influence tubulointerstitial fibrosis. Still, the role of renal C3 production in the epithelial-to-mesenchymal transition (EMT) and genetically determined fibrosis progression remains undiscovered. The kidneys of fibrosis-resistant C57Bl/6J (B6) and fibrosis-prone CBA/J (CBA) and BALB/cJ (BalbC) mice (n = 4-8/group) were subjected to unilateral ureteral obstruction (UUO) and analyzed after 1, 3, and 7 days, along with human focal glomerular sclerotic (FSGS) and healthy kidneys. Mouse primary tubular epithelial cells (PTECs) were investigated after 24 h of treatment with transforming growth factor β (TGFβ) or complement anaphylatoxin 3a (C3a) agonist (n = 4/group). UUO resulted in delayed kidney injury in fibrosis-resistant B6 mice, but very early renal C3 messenger RNA (mRNA) induction in fibrosis-prone CBA and BalbC mice, along with collagen I (Col1a1) and collagen III (Col3a1). CBA depicted the fastest fibrosis progression with the highest C3, lipocalin-2 (Lcn2), Tgfb1, and chemokine (C-C motif) ligand 2 (Ccl2) expression. Human FSGS kidneys depicted C3 mRNA over-expression and strong tubular C3 immunostaining. In PTECs, C3a agonist treatment induced pro-fibrotic early growth response protein 1 (EGR1) expression and the EMT, independent of TGFβ signaling. We conclude that de novo renal tubular C3 synthesis is associated with the genetically determined kidney fibrosis progression rate in mice and the pathogenesis of FSGS in humans. This tubular C3 overproduction can, through local pro-fibrotic effects, influence the progression of chronic kidney disease.
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Affiliation(s)
- Ganna Stepanova
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary
| | - Anna Manzéger
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary
- International Nephrology Research and Training Center, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary
| | - Miklós M Mózes
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary
- International Nephrology Research and Training Center, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary
| | - Gábor Kökény
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary
- International Nephrology Research and Training Center, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary
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Montenegro F, Giannuzzi F, Picerno A, Cicirelli A, Stea ED, Di Leo V, Sallustio F. How Stem and Progenitor Cells Can Affect Renal Diseases. Cells 2024; 13:1460. [PMID: 39273032 PMCID: PMC11393889 DOI: 10.3390/cells13171460] [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] [Academic Contribution Register] [Received: 07/14/2024] [Revised: 08/26/2024] [Accepted: 08/27/2024] [Indexed: 09/15/2024] Open
Abstract
Stem and progenitor cells have been observed to contribute to regenerative processes in acute renal failure and chronic kidney disease. Recent research has delved into the intricate mechanisms by which stem and progenitor cells exert their influence on kidney diseases. Understanding how these cells integrate with the existing renal architecture and their response to injury could pave the way for innovative treatment strategies aimed at promoting kidney repair and regeneration. Overall, the role of stem and progenitor cells in kidney diseases is multifaceted, with their ability to contribute to tissue regeneration, immune modulation, and the maintenance of renal homeostasis. Here, we review the studies that we have available today about the involvement of stem and progenitor cells both in regenerative therapies and in the causes of renal diseases, as well as in natural healing mechanisms, taking into account the main kidney disorders, such as IgA nephropathy, lupus nephritis, diabetic nephropathy, C3 glomerulopathy, focal segmental glomerulosclerosis, idiopathic membranous nephropathy, anti-glomerular basement membrane glomerulonephritis, and ANCA-associated crescentic glomerulonephritis. Moreover, based on the comprehensive data available in the framework of the specific kidney diseases on stem cells and renal progenitors, we hypothesize a possible role of adult renal progenitors in exacerbating or recovering the illness.
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Affiliation(s)
- Francesca Montenegro
- Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy; (F.M.); (F.G.); (A.P.); (A.C.); (V.D.L.)
| | - Francesca Giannuzzi
- Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy; (F.M.); (F.G.); (A.P.); (A.C.); (V.D.L.)
| | - Angela Picerno
- Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy; (F.M.); (F.G.); (A.P.); (A.C.); (V.D.L.)
| | - Antonella Cicirelli
- Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy; (F.M.); (F.G.); (A.P.); (A.C.); (V.D.L.)
| | - Emma Diletta Stea
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy;
| | - Vincenzo Di Leo
- Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy; (F.M.); (F.G.); (A.P.); (A.C.); (V.D.L.)
| | - Fabio Sallustio
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy;
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Abstract
The complement cascade comprises soluble and cell surface proteins and is an important arm of the innate immune system. Once activated, the complement system rapidly generates large quantities of protein fragments that are potent mediators of inflammatory, vasoactive and metabolic responses. Although complement is crucial to host defence and homeostasis, its inappropriate or uncontrolled activation can also drive tissue injury. For example, the complement system has been known for more than 50 years to be activated by glomerular immune complexes and to contribute to autoimmune kidney disease. Notably, the latest research shows that complement is also activated in kidney diseases that are not traditionally thought of as immune-mediated, including haemolytic-uraemic syndrome, diabetic kidney disease and focal segmental glomerulosclerosis. Several complement-targeted drugs have been approved for the treatment of kidney disease, and additional anti-complement agents are being investigated in clinical trials. These drugs are categorically different from other immunosuppressive agents and target pathological processes that are not effectively inhibited by other classes of immunosuppressants. The development of these new drugs might therefore have considerable benefits in the treatment of kidney disease.
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Affiliation(s)
- Vojtech Petr
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Joshua M Thurman
- University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
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Manzéger A, Garmaa G, Mózes MM, Hansmann G, Kökény G. Pioglitazone Protects Tubular Epithelial Cells during Kidney Fibrosis by Attenuating miRNA Dysregulation and Autophagy Dysfunction Induced by TGF-β. Int J Mol Sci 2023; 24:15520. [PMID: 37958504 PMCID: PMC10649561 DOI: 10.3390/ijms242115520] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/05/2023] [Revised: 10/20/2023] [Accepted: 10/21/2023] [Indexed: 11/15/2023] Open
Abstract
Excessive renal TGF-β production and pro-fibrotic miRNAs are important drivers of kidney fibrosis that lack any efficient treatment. Dysfunctional autophagy might play an important role in the pathogenesis. We aimed to study the yet unknown effects of peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone (Pio) on renal autophagy and miRNA dysregulation during fibrosis. Mouse primary tubular epithelial cells (PTEC) were isolated, pre-treated with 5 µM pioglitazone, and then stimulated with 10 ng/mL TGF-β1 for 24 h. Male 10-week-old C57Bl6 control (CTL) and TGF-β overexpressing mice were fed with regular chow (TGF) or Pio-containing chow (20 mg/kg/day) for 5 weeks (TGF + Pio). PTEC and kidneys were evaluated for mRNA and protein expression. In PTEC, pioglitazone attenuated (p < 0.05) the TGF-β-induced up-regulation of Col1a1 (1.4-fold), Tgfb1 (2.2-fold), Ctgf (1.5-fold), Egr2 (2.5-fold) mRNAs, miR-130a (1.6-fold), and miR-199a (1.5-fold), inhibited epithelial-to-mesenchymal transition, and rescued autophagy function. In TGF mice, pioglitazone greatly improved kidney fibrosis and related dysfunctional autophagy (increased LC3-II/I ratio and reduced SQSTM1 protein content (p < 0.05)). These were accompanied by 5-fold, 3-fold, 12-fold, and 2-fold suppression (p < 0.05) of renal Ccl2, Il6, C3, and Lgals3 mRNA expression, respectively. Our results implicate that pioglitazone counteracts multiple pro-fibrotic processes in the kidney, including autophagy dysfunction and miRNA dysregulation.
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Affiliation(s)
- Anna Manzéger
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary; (A.M.); (G.G.); (M.M.M.)
- International Nephrology Research and Training Center, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary
| | - Gantsetseg Garmaa
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary; (A.M.); (G.G.); (M.M.M.)
| | - Miklós M. Mózes
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary; (A.M.); (G.G.); (M.M.M.)
- International Nephrology Research and Training Center, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary
| | - Georg Hansmann
- Department of Pediatric Cardiology and Critical Care, Hannover Medical School, 30625 Hannover, Germany;
| | - Gábor Kökény
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary; (A.M.); (G.G.); (M.M.M.)
- International Nephrology Research and Training Center, Semmelweis University, Nagyvárad tér 4, 1089 Budapest, Hungary
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7
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KUNIYOSHI N, HANADA S, ANDO R, YUSTINASARI LR, KURATOMI M, KAGAWA S, IMAI H, KUSAKABE KT. Expression dynamics of Crry at the implantation sites in normal pregnancy and response against miscarriage induction. J Vet Med Sci 2023; 85:92-98. [PMID: 36450590 PMCID: PMC9887214 DOI: 10.1292/jvms.22-0286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/21/2022] [Accepted: 11/07/2022] [Indexed: 12/02/2022] Open
Abstract
In mammals, immune tolerance against fetal tissue has been established for normal pregnancy progression. It is known that Crry regulates complemental activity to prevent injury of the mouse embryo and extra-embryonic tissue. This study aimed to examine the expression appearance and normal localization sites of Crry in the mouse placenta. Also, the emergency responses of Crry were verified at the time of experimental miscarriage induction. Moreover, we investigated an existing similar protein of Crry in animal placentas other than mice. Crry expression level showed a peak at day 8.5 of pregnancy. Trophoblast giant cells and decidual cells indicated a positive reaction to anti-Crry antibody. After treatments of interferon-γ, Crry expression was increased significantly in the survived implantation sites as compared with the controls. However, there was no significant difference in the miscarriage-initiated sites. It disclosed that Crry distributes from the early to middle periods of the placentas and involves complement regulation at the extraembryonic tissue and decidua basalis. Crry also showed an ability to respond to risk against external initiation for urgent miscarriage. Finally, we found anti-mouse Crry antibody-bound proteins in the placenta of many animals. It suggests a potency of Crry to make an environment of immune tolerance in many types of mammal placentas.
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Affiliation(s)
- Nobue KUNIYOSHI
- Laboratory of Basic Veterinary Science, The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan
| | - Saki HANADA
- Laboratory of Veterinary Anatomy, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Reina ANDO
- Laboratory of Veterinary Anatomy, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Lita Rakhma YUSTINASARI
- Laboratory of Basic Veterinary Science, Joint Graduate School of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
- Division of Veterinary Anatomy, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Maria KURATOMI
- Laboratory of Veterinary Anatomy, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Seizaburo KAGAWA
- Laboratory of Veterinary Anatomy, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Hiroyuki IMAI
- Laboratory of Veterinary Anatomy, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
- Laboratory of Basic Veterinary Science, Joint Graduate School of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Ken Takeshi KUSAKABE
- Laboratory of Basic Veterinary Science, The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan
- Laboratory of Veterinary Anatomy, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
- Laboratory of Basic Veterinary Science, Joint Graduate School of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
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Kemper C, Ferreira VP, Paz JT, Holers VM, Lionakis MS, Alexander JJ. Complement: The Road Less Traveled. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:119-125. [PMID: 36596217 PMCID: PMC10038130 DOI: 10.4049/jimmunol.2200540] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 07/25/2022] [Accepted: 09/11/2022] [Indexed: 01/04/2023]
Abstract
The complement field has recently experienced a strong resurgence of interest because of the unexpected discovery of new complement functions extending complement's role beyond immunity and pathogen clearance, a growing list of diseases in which complement plays a role, and the proliferation of complement therapeutics. Importantly, although the majority of complement components in the circulation are generated by the liver and activated extracellularly, complement activation unexpectedly also occurs intracellularly across a broad range of cells. Such cell-autonomous complement activation can engage intracellular complement receptors, which then drive noncanonical cell-specific effector functions. Thus, much remains to be discovered about complement biology. In this brief review, we focus on novel noncanonical activities of complement in its "classic areas of operation" (kidney and brain biology, infection, and autoimmunity), with an outlook on the next generation of complement-targeted therapeutics.
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Affiliation(s)
- Claudia Kemper
- Complement and Inflammation Research Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Viviana P Ferreira
- Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, OH
| | - Jeanne T Paz
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco CA
- Department of Neurology, University of California, San Francisco, San Francisco, CA
- Neurosciences Graduate Program, University of California, San Francisco, San Francisco, CA
| | - V Michael Holers
- Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Michail S Lionakis
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; and
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9
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Nauser CL, Sacks SH. Local complement synthesis-A process with near and far consequences for ischemia reperfusion injury and transplantation. Immunol Rev 2023; 313:320-326. [PMID: 36200881 DOI: 10.1111/imr.13144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/20/2023]
Abstract
The model of the solid organ as a target for circulating complement deposited at the site of injury, for many years concealed the broader influence of complement in organ transplantation. The study of locally synthesized complement especially in transplantation cast new light on complement's wider participation in ischaemia-reperfusion injury, the presentation of donor antigen and finally rejection. The lack of clarity, however, has persisted as to which complement activation pathways are involved and how they are triggered, and above all whether the distinction is relevant. In transplantation, the need for clarity is heightened by the quest for precision therapies in patients who are already receiving potent immunosuppressives, and because of the opportunity for well-timed intervention. This review will present new evidence for the emerging role of the lectin pathway, weighed alongside the longer established role of the alternative pathway as an amplifier of the complement system, and against contributions from the classical pathway. It is hoped this understanding will contribute to the debate on precisely targeted versus broadly acting therapeutic innovation within the aim to achieve safe long term graft acceptance.
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10
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Quaglia M, Merlotti G, Colombatto A, Bruno S, Stasi A, Franzin R, Castellano G, Grossini E, Fanelli V, Cantaluppi V. Stem Cell-Derived Extracellular Vesicles as Potential Therapeutic Approach for Acute Kidney Injury. Front Immunol 2022; 13:849891. [PMID: 35359949 PMCID: PMC8960117 DOI: 10.3389/fimmu.2022.849891] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/06/2022] [Accepted: 02/15/2022] [Indexed: 12/12/2022] Open
Abstract
Acute kidney injury is a frequent complication of hospitalized patients and significantly increases morbidity and mortality, worsening costs and length of hospital stay. Despite this impact on healthcare system, treatment still remains only supportive (dialysis). Stem cell-derived extracellular vesicles are a promising option as they recapitulate stem cells properties, overcoming safety issues related to risks or rejection or aberrant differentiation. A growing body of evidence based on pre-clinical studies suggests that extracellular vesicles may be effective to treat acute kidney injury and to limit fibrosis through direct interference with pathogenic mechanisms of vascular and tubular epithelial cell damage. We herein analyze the state-of-the-art knowledge of therapeutic approaches with stem cell-derived extracellular vesicles for different forms of acute kidney injury (toxic, ischemic or septic) dissecting their cytoprotective, regenerative and immunomodulatory properties. We also analyze the potential impact of extracellular vesicles on the mechanisms of transition from acute kidney injury to chronic kidney disease, with a focus on the pivotal role of the inhibition of complement cascade in this setting. Despite some technical limits, nowadays the development of therapies based on stem cell-derived extracellular vesicles holds promise as a new frontier to limit acute kidney injury onset and progression.
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Affiliation(s)
- Marco Quaglia
- Nephrology and Kidney Transplantation Unit, "Maggiore della Carità" University Hospital, Department of Translational Medicine, Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
| | - Guido Merlotti
- Nephrology and Kidney Transplantation Unit, "Maggiore della Carità" University Hospital, Department of Translational Medicine, Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
| | - Andrea Colombatto
- Nephrology and Kidney Transplantation Unit, "Maggiore della Carità" University Hospital, Department of Translational Medicine, Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
| | - Stefania Bruno
- Department of Medical Sciences, University of Torino, Torino, Italy
| | - Alessandra Stasi
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Rossana Franzin
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Kidney Transplantation Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Elena Grossini
- Laboratory of Physiology, Department of Translational Medicine, Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale, Novara, Italy
| | - Vito Fanelli
- Department of Anesthesiology and Intensive Care, University of Torino, Torino, Italy
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplantation Unit, "Maggiore della Carità" University Hospital, Department of Translational Medicine, Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
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11
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Freiwald T, Afzali B. Renal diseases and the role of complement: Linking complement to immune effector pathways and therapeutics. Adv Immunol 2021; 152:1-81. [PMID: 34844708 PMCID: PMC8905641 DOI: 10.1016/bs.ai.2021.09.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/29/2022]
Abstract
The complement system is an ancient and phylogenetically conserved key danger sensing system that is critical for host defense against pathogens. Activation of the complement system is a vital component of innate immunity required for the detection and removal of pathogens. It is also a central orchestrator of adaptive immune responses and a constituent of normal tissue homeostasis. Once complement activation occurs, this system deposits indiscriminately on any cell surface in the vicinity and has the potential to cause unwanted and excessive tissue injury. Deposition of complement components is recognized as a hallmark of a variety of kidney diseases, where it is indeed associated with damage to the self. The provenance and the pathophysiological role(s) played by complement in each kidney disease is not fully understood. However, in recent years there has been a renaissance in the study of complement, with greater appreciation of its intracellular roles as a cell-intrinsic system and its interplay with immune effector pathways. This has been paired with a profusion of novel therapeutic agents antagonizing complement components, including approved inhibitors against complement components (C)1, C3, C5 and C5aR1. A number of clinical trials have investigated the use of these more targeted approaches for the management of kidney diseases. In this review we present and summarize the evidence for the roles of complement in kidney diseases and discuss the available clinical evidence for complement inhibition.
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Affiliation(s)
- Tilo Freiwald
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, MD, United States; Department of Nephrology, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany
| | - Behdad Afzali
- Department of Nephrology, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany.
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12
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Stewart T, Zea A, Aviles D. Expression of the IL-2R in Human Podocytes and the Effect of Activation on Autophagy and Apoptosis. Fetal Pediatr Pathol 2021; 40:369-377. [PMID: 31971468 DOI: 10.1080/15513815.2019.1710793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 10/25/2022]
Abstract
Interleukin 2 (IL-2) treatment is associated with proteinuria. Materials and Methods: A conditionally immortalized human podocyte cell line was used to investigate expression of the podocyte specific marker podocin, IL-2R alpha (IL-2Rα), apoptosis marker Bax, and autophagy markers LC3I AND LC3II, determined by quantitative immunoblotting, following 24, 48, and 72 hours of IL-2 stimulation, comparing them to unstimulated cells. Results: Podocin was expressed at all time points. IL-2Rα expression was increased after 24 and 72 hrs (p = 0.0014, p = 0.0139) and decreased after 48 hours (p = 0.0445). Bax, LC3I, and LC3II were increased after 24 hrs (p = 0.0094, p = 0.0016, p = 0.0004) and 48 hrs (p = 0.0072, p = 0.0024, p = 0.0087). Conclusion: Human podocytes express the IL-2R and activation results in increased autophagy and apoptosis.
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Affiliation(s)
- Tyrus Stewart
- LSU Health Sciences Center, Department of Pediatrics, New Orleans, USA
| | - Arnold Zea
- LSU Health Sciences Center New Orleans, New Orleans, USA
| | - Diego Aviles
- LSU Health Sciences Center, Department of Pediatrics, New Orleans, USA
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13
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Lo S, Jiang L, Stacks S, Lin H, Parajuli N. Aberrant activation of the complement system in renal grafts is mediated by cold storage. Am J Physiol Renal Physiol 2021; 320:F1174-F1190. [PMID: 33998295 DOI: 10.1152/ajprenal.00670.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/22/2022] Open
Abstract
Aberrant complement activation leads to tissue damage during kidney transplantation, and it is recognized as an important target for therapeutic intervention. However, it is not clear whether cold storage (CS) triggers the complement pathway in transplanted kidneys. The goal of the present study was to determine the impact of CS on complement activation in renal transplants. Male Lewis and Fischer rats were used, and donor rat kidneys were exposed to 4 h or 18 h of CS followed by transplantation (CS + transplant). To study CS-induced effects, a group with no CS was included in which the kidney was removed and transplanted back to the same rat [autotransplantation (ATx)]. Complement proteins (C3 and C5b-9) were evaluated with Western blot analysis (reducing and nonreducing conditions) and immunostaining. Western blot analysis of renal extracts or serum indicated that the levels of C3 and C5b-9 increased after CS + transplant compared with ATx. Quite strikingly, intracellular C3 was profoundly elevated within renal tubules after CS + transplant but was absent in sham or ATx groups, which showed only extratubular C3. Similarly, C5b-9 immunofluorescence staining of renal sections showed an increase in C5b-9 deposits in kidneys after CS + transplant. Real-time PCR (SYBR green) showed increased expression of CD11b and CD11c, components of complement receptors 3 and 4, respectively, as well as inflammatory markers such as TNF-α. In addition, recombinant TNF-α significantly increased C3 levels in renal cells. Collectively, these results demonstrate that CS mediates aberrant activation of the complement system in renal grafts following transplantation.NEW & NOTEWORTHY This study highlights cold storage-mediated aberrant activation of complement components in renal allografts following transplantation. Specifically, the results demonstrate, for the first time, that cold storage functions in exacerbation of C5b-9, a terminal cytolytic membrane attack complex, in renal grafts following transplantation. In addition, the results indicated that cold storage induces local C3 biogenesis in renal proximal cells/tubules and that TNF-α promotes C3 biogenesis and activation in renal proximal tubular cells.
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Affiliation(s)
- Sorena Lo
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Li Jiang
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Savannah Stacks
- Arkansas Children's Research Institute, Little Rock, Arkansas
| | - Haixia Lin
- Arkansas Children's Nutrition Center, Little Rock, Arkansas
| | - Nirmala Parajuli
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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14
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Wang X, Wilkinson R, Kildey K, Ungerer JPJ, Hill MM, Shah AK, Mohamed A, Dutt M, Molendijk J, Healy H, Kassianos AJ. Molecular and functional profiling of apical versus basolateral small extracellular vesicles derived from primary human proximal tubular epithelial cells under inflammatory conditions. J Extracell Vesicles 2021; 10:e12064. [PMID: 33643548 PMCID: PMC7886702 DOI: 10.1002/jev2.12064] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/18/2020] [Revised: 01/08/2021] [Accepted: 01/13/2021] [Indexed: 12/14/2022] Open
Abstract
Proximal tubular epithelial cells (PTEC) are central players in inflammatory kidney diseases. However, the complex signalling mechanism/s via which polarized PTEC mediate disease progression are poorly understood. Small extracellular vesicles (sEV), including exosomes, are recognized as fundamental components of cellular communication and signalling courtesy of their molecular cargo (lipids, microRNA, proteins). In this study, we examined the molecular content and function of sEV secreted from the apical versus basolateral surfaces of polarized human primary PTEC under inflammatory diseased conditions. PTEC were cultured under normal and inflammatory conditions on Transwell inserts to enable separate collection and isolation of apical/basolateral sEV. Significantly increased numbers of apical and basolateral sEV were secreted under inflammatory conditions compared with equivalent normal conditions. Multi‐omics analysis revealed distinct molecular profiles (lipids, microRNA, proteins) between inflammatory and normal conditions for both apical and basolateral sEV. Biological pathway analyses of significantly differentially expressed molecules associated apical inflammatory sEV with processes of cell survival and immunological disease, while basolateral inflammatory sEV were linked to pathways of immune cell trafficking and cell‐to‐cell signalling. In line with this mechanistic concept, functional assays demonstrated significantly increased production of chemokines (monocyte chemoattractant protein‐1, interleukin‐8) and immuno‐regulatory cytokine interleukin‐10 by peripheral blood mononuclear cells activated with basolateral sEV derived from inflammatory PTEC. We propose that the distinct molecular composition of sEV released from the apical versus basolateral membranes of human inflammatory PTEC may reflect specialized functional roles, with basolateral‐derived sEV pivotal in modulating tubulointerstitial inflammatory responses observed in many immune‐mediated kidney diseases. These findings provide a rationale to further evaluate these sEV‐mediated inflammatory pathways as targets for biomarker and therapeutic development.
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Affiliation(s)
- Xiangju Wang
- Conjoint Internal Medicine Laboratory, Chemical Pathology Pathology Queensland Brisbane Queensland Australia.,Kidney Health Service Royal Brisbane and Women's Hospital Brisbane Queensland Australia
| | - Ray Wilkinson
- Conjoint Internal Medicine Laboratory, Chemical Pathology Pathology Queensland Brisbane Queensland Australia.,Kidney Health Service Royal Brisbane and Women's Hospital Brisbane Queensland Australia.,Institute of Health and Biomedical Innovation Queensland University of Technology Brisbane Queensland Australia.,Faculty of Medicine University of Queensland Brisbane Queensland Australia
| | - Katrina Kildey
- Conjoint Internal Medicine Laboratory, Chemical Pathology Pathology Queensland Brisbane Queensland Australia.,Kidney Health Service Royal Brisbane and Women's Hospital Brisbane Queensland Australia
| | - Jacobus P J Ungerer
- Conjoint Internal Medicine Laboratory, Chemical Pathology Pathology Queensland Brisbane Queensland Australia.,Faculty of Medicine University of Queensland Brisbane Queensland Australia
| | - Michelle M Hill
- QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
| | - Alok K Shah
- QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
| | - Ahmed Mohamed
- QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
| | - Mriga Dutt
- QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
| | - Jeffrey Molendijk
- QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
| | - Helen Healy
- Conjoint Internal Medicine Laboratory, Chemical Pathology Pathology Queensland Brisbane Queensland Australia.,Kidney Health Service Royal Brisbane and Women's Hospital Brisbane Queensland Australia.,Faculty of Medicine University of Queensland Brisbane Queensland Australia
| | - Andrew J Kassianos
- Conjoint Internal Medicine Laboratory, Chemical Pathology Pathology Queensland Brisbane Queensland Australia.,Kidney Health Service Royal Brisbane and Women's Hospital Brisbane Queensland Australia.,Institute of Health and Biomedical Innovation Queensland University of Technology Brisbane Queensland Australia.,Faculty of Medicine University of Queensland Brisbane Queensland Australia
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15
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Huang WC, Hashimoto M, Shih YL, Wu CC, Lee MF, Chen YL, Wu JJ, Wang MC, Lin WH, Hong MY, Teng CH. Peptidoglycan Endopeptidase Spr of Uropathogenic Escherichia coli Contributes to Kidney Infections and Competitive Fitness During Bladder Colonization. Front Microbiol 2021; 11:586214. [PMID: 33391204 PMCID: PMC7774453 DOI: 10.3389/fmicb.2020.586214] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/22/2020] [Accepted: 11/25/2020] [Indexed: 11/27/2022] Open
Abstract
Uropathogenic Escherichia coli (UPEC) is the most common pathogen of urinary tract infections (UTIs). Antibiotic therapy is the conventional measure to manage such infections. However, the rapid emergence of antibiotic resistance has reduced the efficacy of antibiotic treatment. Given that the bacterial factors required for the full virulence of the pathogens are potential therapeutic targets, identifying such factors may facilitate the development of novel therapeutic strategies against UPEC UTIs. The peptidoglycan (PG) endopeptidase Spr (also named MepS) is required for PG biogenesis in E. coli. In the present study, we found that Spr deficiency attenuated the ability of UPEC to infect kidneys and induced a fitness defect during bladder colonization in a mouse model of UTI. Based on the liquid chromatography (LC)/mass spectrometry (MS)/MS analysis of the bacterial envelope, spr deletion changed the levels of some envelope-associated proteins, suggesting that Spr deficiency interfere with the components of the bacterial structure. Among the proteins, FliC was significantly downregulated in the spr mutant, which is resulted in reduced motility. Lack of Spr might hinder the function of the flagellar transcriptional factor FlhDC to decrease FliC expression. The motility downregulation contributed to the reduced fitness in urinary tract colonization. Additionally, spr deletion compromised the ability of UPEC to evade complement-mediated attack and to resist intracellular killing of phagocytes, consequently decreasing UPEC bloodstream survival. Spr deficiency also interfered with the UPEC morphological switch from bacillary to filamentous shapes during UTI. It is known that bacterial filamentation protects UPEC from phagocytosis by phagocytes. In conclusion, Spr deficiency was shown to compromise multiple virulence properties of UPEC, leading to attenuation of the pathogen in urinary tract colonization and bloodstream survival. These findings indicate that Spr is a potential antimicrobial target for further studies attempting to develop novel strategies in managing UPEC UTIs.
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Affiliation(s)
- Wen-Chun Huang
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Masayuki Hashimoto
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Ling Shih
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Chia-Ching Wu
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Mei-Feng Lee
- Department of Biotechnology, National Kaohsiung Normal University, Kaohsiung, Taiwan
| | - Ya-Lei Chen
- Department of Biotechnology, National Kaohsiung Normal University, Kaohsiung, Taiwan
| | - Jiunn-Jong Wu
- Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang Ming University, Taipei, Taiwan
| | - Ming-Cheng Wang
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wei-Hung Lin
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ming-Yuan Hong
- Department of Emergency Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ching-Hao Teng
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
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16
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Ort M, Dingemanse J, van den Anker J, Kaufmann P. Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway. Front Immunol 2020; 11:599417. [PMID: 33362783 PMCID: PMC7758461 DOI: 10.3389/fimmu.2020.599417] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/27/2020] [Accepted: 11/09/2020] [Indexed: 12/15/2022] Open
Abstract
The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.
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Affiliation(s)
- Marion Ort
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.,Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland
| | - Jasper Dingemanse
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - John van den Anker
- Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland.,Division of Clinical Pharmacology, Children's National Hospital, Washington, DC, United States
| | - Priska Kaufmann
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
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17
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Le Fournis C, Jeanneau C, Roumani S, Giraud T, About I. Pulp Fibroblast Contribution to the Local Control of Pulp Inflammation via Complement Activation. J Endod 2020; 46:S26-S32. [PMID: 32950192 DOI: 10.1016/j.joen.2020.06.029] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 10/23/2022]
Abstract
Upon traumatic injuries or carious lesions, the elimination of bacteria infiltrating the pulp is recognized as a prerequisite for initiating the regeneration process. Complement is a major system involved in initiating the inflammatory reaction and the subsequent bacteria elimination. This plasma system of above 35 proteins is synthesized by the liver and some immune cells. It is activated by 3 pathways: the classical, alternative, and lectin pathways that can be triggered by physical injuries, infection, and biomaterials. Recent data have shown that the pulp fibroblast represents a unique nonimmune cell type able to synthesize Complement proteins. Indeed, after physical injuries/bacteria stimulation, the pulp fibroblast has been shown to synthesize and to activate the complement system leading to the production of biologically active molecules such as C5a, C3b, and the membrane attack complex. This local secretion represents a rapid and efficient mechanism for eliminating bacteria invading the pulp, thus supporting complement activation from the plasma. Pulp fibroblast-secreted Complement proteins allow cariogenic bacteria direct lysis via membrane attack complex formation on their surface, phagocytic cell recruitment by producing C5a and cariogenic bacteria opsonization by C3b fixation on their surface, stimulating cariogenic bacteria phagocytosis. Overall, this review highlights that, in addition to initiating the inflammatory reaction, pulp fibroblasts also provide a powerful control of this inflammation via local Complement activation. The pathogen elimination capacity by fibroblast-produced complement demonstrates that this system is a strong local actor in arresting bacterial progression into the dental pulp.
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Affiliation(s)
- Chloé Le Fournis
- Aix-Marseille University, Centre National de la Recherche Scientifique, Institut des Sciences du Mouvement, Marseille, France
| | - Charlotte Jeanneau
- Aix-Marseille University, Centre National de la Recherche Scientifique, Institut des Sciences du Mouvement, Marseille, France
| | - Sandra Roumani
- Aix-Marseille University, Centre National de la Recherche Scientifique, Institut des Sciences du Mouvement, Marseille, France
| | - Thomas Giraud
- Aix-Marseille University, Centre National de la Recherche Scientifique, Institut des Sciences du Mouvement, Marseille, France; Assistance Publique-Hôpitaux de Marseille, Hôpital Timone, Service d'Odontologie, Marseille, France
| | - Imad About
- Aix-Marseille University, Centre National de la Recherche Scientifique, Institut des Sciences du Mouvement, Marseille, France.
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18
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Huang WC, Liao YJ, Hashimoto M, Chen KF, Chu C, Hsu PC, Wang S, Teng CH. cjrABC-senB hinders survival of extraintestinal pathogenic E. coli in the bloodstream through triggering complement-mediated killing. J Biomed Sci 2020; 27:86. [PMID: 32762693 PMCID: PMC7412671 DOI: 10.1186/s12929-020-00677-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/27/2019] [Accepted: 07/28/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Extraintestinal pathogenic E. coli (ExPEC) is a common gram-negative organism causing various infections, including urinary tract infections (UTIs), bacteremia, and neonatal meningitis. The cjrABC-senB gene cluster of E. coli contributes to ExPEC virulence in the mouse model of UTIs. Consistently, the distribution of cjrABC-senB is epidemiologically associated with human UTIs caused by E. coli. cjrABC-senB, which has previously been proposed to encode an iron uptake system, may facilitate ExPEC survival in the iron availability-restricted urinary tract. Given that the bloodstream is also an iron limited environment to invading bacteria, the pathogenic role of cjrABC-senB in ExPEC bacteremia, however, remains to be investigated. METHODS The ability of ExPEC RS218 strains with and without cjrABC-senB to survive in the mouse bloodstream and human serum was evaluated. Subsequently, the role of this gene cluster in the ExPEC interaction with the complement system was evaluated. Finally, the distribution of cjrABC-senB in human clinical E. coli isolates was determined by PCR. The frequency of cjrABC-senB in bacteremia isolates that were not associated with UTIs (non-UTI bacteremia isolates) was compared with that in UTI-associated isolates and fecal isolates. RESULTS Expression of cjrABC-senB attenuated the survival of RS218 in the mouse bloodstream and human serum. The cjrABC-senB-harboring strains triggered enhanced classical- and alternative-complement pathway activation and became more vulnerable to complement-mediated killing in serum. cjrA was identified as the major gene responsible for the attenuated serum survival. Expressing cjrABC-senB and cjrA increased bacterial susceptibility to detergent and induced periplasmic protein leakage, suggesting that the expression of these genes compromises the integrity of the outer membrane of ExPEC. In addition, the frequency of cjrABC-senB in non-UTI bacteremia isolates was significantly lower than that in UTI-associated isolates, while the frequencies in non-UTI bacteremia isolates and fecal isolates showed no significant difference. Consistently, this epidemiological investigation suggests that cjrABC-senB does not contribute to E. coli bacteremia in humans. CONCLUSION The contribution of cjrABC-senB to the pathogenesis of ExPEC is niche dependent and contradictory because the genes facilitate ExPEC UTIs but hinder bacteremia. The contradictory niche-dependent characteristic may benefit the development of novel strategies against E. coli-caused infections.
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Affiliation(s)
- Wen-Chun Huang
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, 4th F, 367 Sheng Li Road, North District, Tainan City, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Yi-Jyun Liao
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, 4th F, 367 Sheng Li Road, North District, Tainan City, Taiwan
| | - Masayuki Hashimoto
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, 4th F, 367 Sheng Li Road, North District, Tainan City, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan City, Taiwan
| | - Kuan-Fu Chen
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, 4th F, 367 Sheng Li Road, North District, Tainan City, Taiwan
| | - Chishih Chu
- Department of Microbiology, Immunology, and Biopharmaceuticals, National Chiayi University, Chiayi City, Taiwan
| | - Po-Chuen Hsu
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, 4th F, 367 Sheng Li Road, North District, Tainan City, Taiwan
| | - Shuying Wang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan City, Taiwan
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan City, Taiwan
| | - Ching-Hao Teng
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, 4th F, 367 Sheng Li Road, North District, Tainan City, Taiwan.
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan.
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan City, Taiwan.
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19
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Franzin R, Stasi A, Fiorentino M, Stallone G, Cantaluppi V, Gesualdo L, Castellano G. Inflammaging and Complement System: A Link Between Acute Kidney Injury and Chronic Graft Damage. Front Immunol 2020; 11:734. [PMID: 32457738 PMCID: PMC7221190 DOI: 10.3389/fimmu.2020.00734] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/02/2019] [Accepted: 03/31/2020] [Indexed: 12/13/2022] Open
Abstract
The aberrant activation of complement system in several kidney diseases suggests that this pillar of innate immunity has a critical role in the pathophysiology of renal damage of different etiologies. A growing body of experimental evidence indicates that complement activation contributes to the pathogenesis of acute kidney injury (AKI) such as delayed graft function (DGF) in transplant patients. AKI is characterized by the rapid loss of the kidney's excretory function and is a complex syndrome currently lacking a specific medical treatment to arrest or attenuate progression in chronic kidney disease (CKD). Recent evidence suggests that independently from the initial trigger (i.e., sepsis or ischemia/reperfusions injury), an episode of AKI is strongly associated with an increased risk of subsequent CKD. The AKI-to-CKD transition may involve a wide range of mechanisms including scar-forming myofibroblasts generated from different sources, microvascular rarefaction, mitochondrial dysfunction, or cell cycle arrest by the involvement of epigenetic, gene, and protein alterations leading to common final signaling pathways [i.e., transforming growth factor beta (TGF-β), p16 ink4a , Wnt/β-catenin pathway] involved in renal aging. Research in recent years has revealed that several stressors or complications such as rejection after renal transplantation can lead to accelerated renal aging with detrimental effects with the establishment of chronic proinflammatory cellular phenotypes within the kidney. Despite a greater understanding of these mechanisms, the role of complement system in the context of the AKI-to-CKD transition and renal inflammaging is still poorly explored. The purpose of this review is to summarize recent findings describing the role of complement in AKI-to-CKD transition. We will also address how and when complement inhibitors might be used to prevent AKI and CKD progression, therefore improving graft function.
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Affiliation(s)
- Rossana Franzin
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
- Department Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Alessandra Stasi
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Marco Fiorentino
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Vincenzo Cantaluppi
- Department Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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20
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Nauser CL, Howard MC, Fanelli G, Farrar CA, Sacks S. Collectin-11 (CL-11) Is a Major Sentinel at Epithelial Surfaces and Key Pattern Recognition Molecule in Complement-Mediated Ischaemic Injury. Front Immunol 2018; 9:2023. [PMID: 30237800 PMCID: PMC6136055 DOI: 10.3389/fimmu.2018.02023] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/29/2018] [Accepted: 08/16/2018] [Indexed: 12/31/2022] Open
Abstract
The complement system is a dynamic subset of the innate immune system, playing roles in host defense, clearance of immune complexes and cell debris, and priming the adaptive immune response. Over the last 40 years our understanding of the complement system has evolved from identifying its presence and recognizing its role in the blood to now focusing on understanding the role of local complement synthesis in health and disease. In particular, the local synthesis of complement was found to have an involvement in mediating ischaemic injury, including following transplantation. Recent work on elucidating the triggers of local complement synthesis and activation in renal tissue have led to the finding that Collectin-11 (CL-11) engages with L-fucose at the site of ischaemic stress, namely at the surface of the proximal tubular epithelial cells. What remains unknown is the precise structure of the damage-associated ligand that participates in CL-11 binding and subsequent complement activation. In this article, we will discuss our hypothesis regarding the role of CL-11 as an integral tissue-based pattern recognition molecule which we postulate has a significant contributory role in complement-mediated ischaemic injury.
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Affiliation(s)
- Christopher L Nauser
- MRC Centre for Transplantation, School of Immunology and Microbial Sciences, King's College London, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
| | - Mark C Howard
- MRC Centre for Transplantation, School of Immunology and Microbial Sciences, King's College London, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
| | - Giorgia Fanelli
- MRC Centre for Transplantation, School of Immunology and Microbial Sciences, King's College London, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
| | - Conrad A Farrar
- MRC Centre for Transplantation, School of Immunology and Microbial Sciences, King's College London, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
| | - Steven Sacks
- MRC Centre for Transplantation, School of Immunology and Microbial Sciences, King's College London, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom
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21
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Song Y, Wu KY, Wu W, Duan ZY, Gao YF, Zhang LD, Chong T, Garstka MA, Zhou W, Li K. Epithelial C5aR1 Signaling Enhances Uropathogenic Escherichia coli Adhesion to Human Renal Tubular Epithelial Cells. Front Immunol 2018; 9:949. [PMID: 29765378 PMCID: PMC5938350 DOI: 10.3389/fimmu.2018.00949] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/04/2018] [Accepted: 04/17/2018] [Indexed: 12/22/2022] Open
Abstract
Recent work in a murine model of ascending urinary tract infection has suggested that C5a/C5aR1 interactions play a pathogenic role in the development of renal infection through enhancement of bacterial adhesion/colonization to renal tubular epithelial cells (RTECs). In the present study, we extended these observations to human. We show that renal tubular epithelial C5aR1 signaling is involved in promoting uropathogenic Escherichia coli (UPEC) adhesion/invasion of host cells. Stimulation of primary cultures of RTEC with C5a resulted in significant increases in UPEC adhesion/invasion of the RTEC. This was associated with enhanced expression of terminal α-mannosyl residues (Man) (a ligand for type 1 fimbriae of E. coli) in the RTEC following C5a stimulation. Mechanism studies revealed that C5aR1-mediated activation of ERK1/2/NF-κB and upregulation of proinflammatory cytokine production (i.e., TNF-α) is at least partly responsible for the upregulation of Man expression and bacterial adhesion. Clinical sample studies showed that C5aR1 and Man were clearly detected in the renal tubular epithelium of normal human kidney biopsies, and UPEC bound to the epithelium in a d-mannose-dependent manner. Additionally, C5a levels were significantly increased in urine of urinary tract infection patients compared with healthy controls. Our data therefore demonstrate that, in agreement with observations in mice, human renal tubular epithelial C5aR1 signaling can upregulate Man expression in RTEC, which enhances UPEC adhesion to and invasion of RTEC. It also suggests the in vivo relevance of upregulation of Man expression in renal tubular epithelium by C5a/C5aR1 interactions and its potential impact on renal infection.
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Affiliation(s)
- Yun Song
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Kun-Yi Wu
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Weiju Wu
- Medical Research Council (MRC) Centre for Transplantation, King's College London, Guy's Hospital, London, United Kingdom
| | - Zhao-Yang Duan
- Department of Nephrology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Ya-Feng Gao
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Liang-Dong Zhang
- Department of Urology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Tie Chong
- Department of Urology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Malgorzata A Garstka
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Wuding Zhou
- Medical Research Council (MRC) Centre for Transplantation, King's College London, Guy's Hospital, London, United Kingdom
| | - Ke Li
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
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Magyarlaki T, Mosolits S, Baranyay F, Buzogány I. Immunohistochemistry of Complement Response on Human Renal Cell Carcinoma Biopsies. TUMORI JOURNAL 2018; 82:473-9. [PMID: 9063527 DOI: 10.1177/030089169608200513] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/17/2022]
Abstract
The goal of the study was to characterize the complement humoral and cellular antitumor responses on primary renal cell carcinoma biopsies. As an original observation, complement activation was found on 11/22 cases. Classical complement pathway activation was characterized by tumor C1q complement protein and IgG deposition (5/22 cases). Alternative or nonimmune complement pathway activation was seen as tissue deposition of C3 (6/22 cases). The membrane attack complex was present in cases with alternative complement pathway activation at the sites of tumor necrosis. Renal cell carcinomas with complement activation overexpressed at least one of the complement regulatory factors (membrane cofactor protein, decay accelerating factor, membrane attack complex inhibitor) and major histocompatibility complex class II molecules. Tumor infiltrating lymphocytes were present in most of the renal cell carcinomas with complement activation (8/11). However, the number of tumor-infiltrating lymphocytes was correlated with the intensity of major histocompatibility complex-ll expression in 18/22 cases. Detection of complement activation and immune cell infiltrates on renal cell carcinoma primary biopsies may serve as a new predictive factor for immunotherapy.
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Affiliation(s)
- T Magyarlaki
- Department of Pathology, University Medical School of Pécs, Hungary
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23
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Complement activation in patients with diabetic nephropathy. DIABETES & METABOLISM 2018; 45:248-253. [PMID: 29729954 DOI: 10.1016/j.diabet.2018.04.001] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 01/03/2018] [Revised: 03/15/2018] [Accepted: 04/07/2018] [Indexed: 01/10/2023]
Abstract
AIM Emerging evidence has indicated a role of the complement system in the pathogenesis of diabetic nephropathy (DN), although the pathways of complement activation and their clinicopathological relevance in DN are as yet unclear. The present study aimed to investigate levels of various complement components in plasma and urine of DN patients, and their correlation with clinicopathological parameters. METHODS A total of 68 biopsy-proven DN patients with plasma samples were recruited, including 50 patients who also had urine samples available. Seven complement components (C1q, MBL, Bb, C4d, C3a, C5a, soluble C5b-9) were measured by enzyme-linked immunosorbent assay (Elisa), and any associations between their levels and clinicopathological parameters were then investigated. RESULTS In DN patients, plasma levels of C1q, MBL, Bb, C4d, C3a, C5a and sC5b-9 were significantly higher than in diabetes patients without renal involvement, as were also urinary levels except for C1q, which showed no significant differences between the two groups. Also, urinary levels of C3a and C5a were significantly correlated with serum creatinine, urinary protein and estimated glomerular filtration rate, whereas urinary sC5b-9 was significantly correlated with the latter two (and not serum creatinine). In addition, urinary levels of MBL, Bb and C4d were significantly correlated with urinary protein, while C3a, C4d and Bb significantly correlated with the classification of glomerular lesions in DN. CONCLUSION In DN patients, the complement system is activated and, of the three possible complement pathways, activation of the lectin and alternative pathways is associated with renal damage.
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Wang XL, Hou L, Zhao CG, Tang Y, Zhang B, Zhao JY, Wu YB. Screening of genes involved in epithelial-mesenchymal transition and differential expression of complement-related genes induced by PAX2 in renal tubules. Nephrology (Carlton) 2018; 24:263-271. [PMID: 29280536 PMCID: PMC6585862 DOI: 10.1111/nep.13216] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Accepted: 12/15/2017] [Indexed: 01/09/2023]
Abstract
Aim The aim of the present study was to screen and verify downstream genes involved in the epithelial mesenchymal transition (EMT) induced by paired box 2 (PAX2) in NRK‐52E cells. Methods NRK‐52E cells were transfected with lentivirus carrying PAX2 gene or no‐load virus respectively. Total RNA was isolated 72 h after transfection from PAX2‐overexpressing cells and control cells. Isolated RNA was then hybridized with the Rat OneArray Plus expression profile chip. The chips were examined by Agilent 0.1 XDR to screen for differentially expressed genes, which were further analyzed to investigate complement‐related genes as genes of interest. Results In NRK‐52E cells, PAX2 overexpression promoted EMT followed by upregulation of 298 genes and downregulation of 293 genes. KEGG analysis indicated the differential expression of genes related to cytokines and their receptors, extracellular matrix (ECM), MAPKs, local adhesion, cancer, the complement cascade, and coagulation. Gene oncology analysis screened out genes related to molecular functions (e.g., hydrolase activity, phospholipase activity, components of the ECM) and biological processes (e.g., cell development, signal transduction, phylogeny), and cell components (e.g., cytoplasm, cell membrane, and ECM). Analysis of the complement system revealed upregulation of C3 and downregulation of CD55 and complement regulator factor H (CFH). Conclusion PAX2 overexpression upregulates EMT in vitro and may regulate C3, CD55, and CFH. This molecular analysis examines the effect of overexpressing paired box 2 (PAX2) in a tubule epithelial cell line. Results establish a link between pax2 and both epithelial‐mesenchymal transition (EMT) and the complement pathway.
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Affiliation(s)
- Xiu-Li Wang
- Department of Pediatric Nephrology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ling Hou
- Department of Pediatric Nephrology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Cheng-Guang Zhao
- Department of Pediatric Nephrology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ying Tang
- Department of Pediatric Nephrology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Bo Zhang
- Department of Pediatric Nephrology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jing-Ying Zhao
- Department of Pediatric Nephrology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yu-Bin Wu
- Department of Pediatric Nephrology, Shengjing Hospital of China Medical University, Shenyang, China
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Liu BC, Tang TT, Lv LL, Lan HY. Renal tubule injury: a driving force toward chronic kidney disease. Kidney Int 2018; 93:568-579. [DOI: 10.1016/j.kint.2017.09.033] [Citation(s) in RCA: 260] [Impact Index Per Article: 37.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/28/2017] [Revised: 08/17/2017] [Accepted: 09/06/2017] [Indexed: 12/13/2022]
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26
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Loeschenberger B, Niess L, Würzner R, Schwelberger H, Eder IE, Puhr M, Guenther J, Troppmair J, Rudnicki M, Neuwirt H. Calcineurin inhibitor-induced complement system activation via ERK1/2 signalling is inhibited by SOCS-3 in human renal tubule cells. Eur J Immunol 2017; 48:330-343. [PMID: 29143318 DOI: 10.1002/eji.201747135] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/17/2017] [Revised: 09/12/2017] [Accepted: 11/03/2017] [Indexed: 12/22/2022]
Abstract
One factor that significantly contributes to renal allograft loss is chronic calcineurin inhibitor (CNI) nephrotoxicity (CIN). Among other factors, the complement (C-) system has been proposed to be involved CIN development. Hence, we investigated the impact of CNIs on intracellular signalling and the effects on the C-system in human renal tubule cells. In a qPCR array, CNI treatment upregulated C-factors and downregulated SOCS-3 and the complement inhibitors CD46 and CD55. Additionally, ERK1/-2 was required for these regulations. Following knock-down and overexpression of SOCS-3, we found that SOCS-3 inhibits ERK1/-2 signalling. Finally, we assessed terminal complement complex formation, cell viability and apoptosis. Terminal complement complex formation was induced by CNIs. Cell viability was significantly decreased, whereas apoptosis was increased. Both effects were reversed under complement component-depleted conditions. In vivo, increased ERK1/-2 phosphorylation and SOCS-3 downregulation were observed at the time of transplantation in renal allograft patients who developed a progressive decline of renal function in the follow-up compared to stable patients. The progressive cohort also had lower total C3 levels, suggesting higher complement activity at baseline. In conclusion, our data suggest that SOCS-3 inhibits CNI-induced ERK1/-2 signalling, thereby blunting the negative control of C-system activation.
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Affiliation(s)
| | - Lea Niess
- Department of Internal Medicine IV, Innsbruck Medical University, Innsbruck, Austria
| | - Reinhard Würzner
- Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria
| | - Hubert Schwelberger
- Molecular Biology Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - Iris E Eder
- Department of Urology, Division of Experimental Urology, Innsbruck Medical University, Innsbruck, Austria
| | - Martin Puhr
- Department of Urology, Division of Experimental Urology, Innsbruck Medical University, Innsbruck, Austria
| | - Julia Guenther
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant- and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - Jakob Troppmair
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant- and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - Michael Rudnicki
- Department of Internal Medicine IV, Innsbruck Medical University, Innsbruck, Austria
| | - Hannes Neuwirt
- Department of Internal Medicine IV, Innsbruck Medical University, Innsbruck, Austria
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Angeletti A, Reyes-Bahamonde J, Cravedi P, Campbell KN. Complement in Non-Antibody-Mediated Kidney Diseases. Front Med (Lausanne) 2017; 4:99. [PMID: 28748184 PMCID: PMC5506082 DOI: 10.3389/fmed.2017.00099] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/02/2017] [Accepted: 06/21/2017] [Indexed: 12/15/2022] Open
Abstract
The complement system is part of the innate immune response that plays important roles in protecting the host from foreign pathogens. The complement components and relative fragment deposition have long been recognized to be strongly involved also in the pathogenesis of autoantibody-related kidney glomerulopathies, leading to direct glomerular injury and recruitment of infiltrating inflammation pathways. More recently, unregulated complement activation has been shown to be associated with progression of non-antibody-mediated kidney diseases, including focal segmental glomerulosclerosis, C3 glomerular disease, thrombotic microangiopathies, or general fibrosis generation in progressive chronic kidney diseases. Some of the specific mechanisms associated with complement activation in these diseases were recently clarified, showing a dominant role of alternative activation pathway. Over the last decade, a growing number of anticomplement agents have been developed, and some of them are being approved for clinical use or already in use. Therefore, anticomplement therapies represent a realistic choice of therapeutic approaches for complement-related diseases. Herein, we review the complement system activation, regulatory mechanisms, their involvement in non-antibody-mediated glomerular diseases, and the recent advances in complement-targeting agents as potential therapeutic strategies.
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Affiliation(s)
- Andrea Angeletti
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, St Orsola Hospital, University of Bologna, Bologna, Italy
| | - Joselyn Reyes-Bahamonde
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Paolo Cravedi
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Kirk N Campbell
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Generation of complement protein C3 deficient pigs by CRISPR/Cas9-mediated gene targeting. Sci Rep 2017; 7:5009. [PMID: 28694465 PMCID: PMC5503937 DOI: 10.1038/s41598-017-05400-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/18/2017] [Accepted: 06/23/2017] [Indexed: 12/26/2022] Open
Abstract
Complement protein C3 is the pivotal component of the complement system. Previous studies have demonstrated that C3 has implications in various human diseases and exerts profound functions under certain conditions. However, the delineation of pathological and physiological roles of C3 has been hampered by the insufficiency of suitable animal models. In the present study, we applied the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system to target the C3 gene in porcine fetal fibroblasts. Our results indicated that CRISPR/Cas9 targeting efficiency was as high as 84.7%, and the biallelic mutation efficiency reached at 45.7%. The biallelic modified colonies were used as donor for somatic cell nuclear transfer (SCNT) technology to generate C3 targeted piglets. A total of 19 C3 knockout (KO) piglets were produced and their plasma C3 protein was undetectable by western blot analysis and ELISA. The hemolytic complement activity and complement-dependent cytotoxicity assay further confirmed that C3 was disrupted in these piglets. These C3 KO pigs could be utilized as a valuable large animal model for the elucidation of the roles of C3.
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29
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Jager NM, Poppelaars F, Daha MR, Seelen MA. Complement in renal transplantation: The road to translation. Mol Immunol 2017; 89:22-35. [PMID: 28558950 DOI: 10.1016/j.molimm.2017.05.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/25/2017] [Revised: 05/17/2017] [Accepted: 05/19/2017] [Indexed: 02/08/2023]
Abstract
Renal transplantation is the treatment of choice for patients with end-stage renal disease. The vital role of the complement system in renal transplantation is widely recognized. This review discusses the role of complement in the different phases of renal transplantation: in the donor, during preservation, in reperfusion and at the time of rejection. Here we examine the current literature to determine the importance of both local and systemic complement production and how complement activation contributes to the pathogenesis of renal transplant injury. In addition, we dissect the complement pathways involved in the different phases of renal transplantation. We also review the therapeutic strategies that have been tested to inhibit complement during the kidney transplantation. Several clinical trials are currently underway to evaluate the therapeutic potential of complement inhibition for the treatment of brain death-induced renal injury, renal ischemia-reperfusion injury and acute rejection. We conclude that it is expected that in the near future, complement-targeted therapeutics will be used clinically in renal transplantation. This will hopefully result in improved renal graft function and increased graft survival.
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Affiliation(s)
- Neeltina M Jager
- Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
| | - Felix Poppelaars
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Mohamed R Daha
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Nephrology, Leiden University Medical Center, University of Leiden, Leiden, The Netherlands
| | - Marc A Seelen
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Li X, Ding F, Zhang X, Li B, Ding J. The Expression Profile of Complement Components in Podocytes. Int J Mol Sci 2016; 17:471. [PMID: 27043537 PMCID: PMC4848927 DOI: 10.3390/ijms17040471] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/29/2016] [Revised: 03/14/2016] [Accepted: 03/23/2016] [Indexed: 01/10/2023] Open
Abstract
Podocytes are critical for maintaining the glomerular filtration barrier and are injured in many renal diseases, especially proteinuric kidney diseases. Recently, reports suggested that podocytes are among the renal cells that synthesize complement components that mediate glomerular diseases. Nevertheless, the profile and extent of complement component expression in podocytes remain unclear. This study examined the expression profile of complement in podocytes under physiological conditions and in abnormal podocytes induced by multiple stimuli. In total, 23/32 complement component components were detected in podocyte by conventional RT-PCR. Both primary cultured podocytes and immortalized podocytes expressed the complement factors C1q, C1r, C2, C3, C7, MASP, CFI, DAF, CD59, C4bp, CD46, Protein S, CR2, C1qR, C3aR, C5aR, and Crry (17/32), whereas C4, CFB, CFD, C5, C6, C8, C9, MBL1, and MBL2 (9/32) complement factors were not expressed. C3, Crry, and C1q-binding protein were detected by tandem mass spectrometry. Podocyte complement gene expression was affected by several factors (puromycin aminonucleoside (PAN), angiotensin II (Ang II), interleukin-6 (IL-6), and transforming growth factor-β (TGF-β)). Representative complement components were detected using fluorescence confocal microscopy. In conclusion, primary podocytes express various complement components at the mRNA and protein levels. The complement gene expressions were affected by several podocyte injury factors.
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Affiliation(s)
- Xuejuan Li
- Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
| | - Fangrui Ding
- Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
| | - Xiaoyan Zhang
- Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
| | - Baihong Li
- Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
| | - Jie Ding
- Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
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31
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van Es LA. Moh Daha, a successful scientist with a strong personality, who loves to stimulate and support his colleagues. Mol Immunol 2016; 68:2-5. [PMID: 26597198 DOI: 10.1016/j.molimm.2015.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/27/2015] [Revised: 06/06/2015] [Accepted: 06/08/2015] [Indexed: 11/18/2022]
Abstract
Mohammed R. Daha is a successful and very productive scientist. He is internationally recognised for his expertise of Complement. In addition, he contributed to many other fields of Immunology, in particular Clinical Immunology within Internal Medicine. He did not only contribute to Nephrology and Transplantation, but also to Rheumatology, Infectious diseases and Pulmonology. He enjoyed teaching and he was also appreciated for his guidance of biomedical and clinical PhD's.
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Affiliation(s)
- Leendert A van Es
- Leiden University Medical Center, Department of Pathology, The Netherlands.
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32
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Fearn A, Sheerin NS. Complement activation in progressive renal disease. World J Nephrol 2015; 4:31-40. [PMID: 25664245 PMCID: PMC4317626 DOI: 10.5527/wjn.v4.i1.31] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/02/2014] [Revised: 11/14/2014] [Accepted: 12/10/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD) is common and the cause of significant morbidity and mortality. The replacement of functioning nephrons by fibrosis is characteristic of progressive disease. The pathways that lead to fibrosis are not fully understood, although chronic non-resolving inflammation in the kidney is likely to drive the fibrotic response that occurs. In patients with progressive CKD there is histological evidence of inflammation in the interstitium and strategies that reduce inflammation reduce renal injury in pre-clinical models of CKD. The complement system is an integral part of the innate immune system but also augments adaptive immune responses. Complement activation is known to occur in many diverse renal diseases, including glomerulonephritis, thrombotic microangiopathies and transplant rejection. In this review we discuss current evidence that complement activation contributes to progression of CKD, how complement could cause renal inflammation and whether complement inhibition would slow progression of renal disease.
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Zimmer J, Hobkirk J, Mohamed F, Browning MJ, Stover CM. On the Functional Overlap between Complement and Anti-Microbial Peptides. Front Immunol 2015; 5:689. [PMID: 25646095 PMCID: PMC4298222 DOI: 10.3389/fimmu.2014.00689] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/30/2014] [Accepted: 12/22/2014] [Indexed: 12/19/2022] Open
Abstract
Intriguingly, activated complement and anti-microbial peptides share certain functionalities; lytic, phagocytic, and chemo-attractant activities and each may, in addition, exert cell instructive roles. Each has been shown to have distinct LPS detoxifying activity and may play a role in the development of endotoxin tolerance. In search of the origin of complement, a functional homolog of complement C3 involved in opsonization has been identified in horseshoe crabs. Horseshoe crabs possess anti-microbial peptides able to bind to acyl chains or phosphate groups/saccharides of endotoxin, LPS. Complement activity as a whole is detectable in marine invertebrates. These are also a source of anti-microbial peptides with potential pharmaceutical applicability. Investigating the locality for the production of complement pathway proteins and their role in modulating cellular immune responses are emerging fields. The significance of local synthesis of complement components is becoming clearer from in vivo studies of parenchymatous disease involving specifically generated, complement-deficient mouse lines. Complement C3 is a central component of complement activation. Its provision by cells of the myeloid lineage varies. Their effector functions in turn are increased in the presence of anti-microbial peptides. This may point to a potentiating range of activities, which should serve the maintenance of health but may also cause disease. Because of the therapeutic implications, this review will consider closely studies dealing with complement activation and anti-microbial peptide activity in acute inflammation (e.g., dialysis-related peritonitis, appendicitis, and ischemia).
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Affiliation(s)
- Jana Zimmer
- Department of Infectious Diseases - Medical Microbiology and Hygiene, Ruprecht-Karls-University of Heidelberg , Heidelberg , Germany
| | - James Hobkirk
- Department of Academic Endocrinology, Diabetes and Metabolism, Hull York Medical School, University of Hull , Hull , UK
| | - Fatima Mohamed
- Department of Infection, Immunity and Inflammation, University of Leicester , Leicester , UK
| | - Michael J Browning
- Department of Infection, Immunity and Inflammation, University of Leicester , Leicester , UK ; Department of Immunology, Leicester Royal Infirmary , Leicester , UK
| | - Cordula M Stover
- Department of Infection, Immunity and Inflammation, University of Leicester , Leicester , UK
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Abstract
The complement cascade, traditionally considered an effector arm of innate immunity required for host defense against pathogens, is now recognized as a crucial pathogenic mediator of various kidney diseases. Complement components produced by the liver and circulating in the plasma undergo activation through the classical and/or mannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidney transplant rejection and autoantibody-initiated GN, the latter including membranous glomerulopathy, antiglomerular basement membrane disease, and lupus nephritis. Inherited and/or acquired abnormalities of complement regulators, which requisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3 nephropathies and atypical hemolytic uremic syndrome. Increasing evidence links complement produced by endothelial cells and/or tubular cells to the pathogenesis of kidney ischemia-reperfusion injury and progressive kidney fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells and antigen-presenting cells, produce alternative pathway complement components during cognate interactions. The subsequent local complement activation yields production of the anaphylatoxins C3a and C5a, which bind to their respective receptors (C3aR and C5aR) on both partners to augment effector T-cell proliferation and survival, while simultaneously inhibiting regulatory T-cell induction and function. This immune cell-derived complement enhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to the pathogenesis of other T cell-mediated kidney diseases. C5a/C5aR ligations on neutrophils have additionally been shown to contribute to vascular inflammation in models of ANCA-mediated renal vasculitis. New translational immunology efforts along with the development of pharmacologic agents that block human complement components and receptors now permit testing of the intriguing concept that targeting complement in patients with an assortment of kidney diseases has the potential to abrogate disease progression and improve patient health.
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Affiliation(s)
- Douglas R Mathern
- Translational Transplant Research Center, Department of Medicine, Recanati Miller Transplant Institute, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Peter S Heeger
- Translational Transplant Research Center, Department of Medicine, Recanati Miller Transplant Institute, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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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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Abstract
Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the molecular mechanism involved and of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. Here we review the pathophysiological changes that occur in the kidney in response to hyperglycemia, including the cellular responses to high glucose and the responses in vascular, glomerular, podocyte, and tubular function. The molecular basis, characteristics, and consequences of the unique growth phenotypes observed in the diabetic kidney, including glomerular structures and tubular segments, are outlined. We delineate mechanisms of early diabetic glomerular hyperfiltration including primary vascular events as well as the primary role of tubular growth, hyperreabsorption, and tubuloglomerular communication as part of a "tubulocentric" concept of early diabetic kidney function. The latter also explains the "salt paradox" of the early diabetic kidney, that is, a unique and inverse relationship between glomerular filtration rate and dietary salt intake. The mechanisms and consequences of the intrarenal activation of the renin-angiotensin system and of diabetes-induced tubular glycogen accumulation are discussed. Moreover, we aim to link the changes that occur early in the diabetic kidney including the growth phenotype, oxidative stress, hypoxia, and formation of advanced glycation end products to mechanisms involved in progressive kidney disease.
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Affiliation(s)
- Volker Vallon
- Department of Medicine, University of California San Diego & VA San Diego Healthcare System, San Diego, California, USA.
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37
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Abstract
Acute kidney injury is a common and severe clinical problem. Patients who develop acute kidney injury are at increased risk of death despite supportive measures such as hemodialysis. Research in recent years has shown that tissue inflammation is central to the pathogenesis of renal injury, even after nonimmune insults such as ischemia/reperfusion and toxins. Examination of clinical samples and preclinical models has shown that activation of the complement system is a critical cause of acute kidney injury. Furthermore, complement activation within the injured kidney is a proximal trigger of many downstream inflammatory events within the renal parenchyma that exacerbate injury to the kidney. Complement activation also may account for the systemic inflammatory events that contribute to remote organ injury and patient mortality. Complement inhibitory drugs have now entered clinical use and may provide an important new therapeutic approach for patients suffering from, or at high risk of developing, acute kidney injury.
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Affiliation(s)
- James W McCullough
- Department of Medicine, University of Colorado Denver School of Medicine, Aurora, CO
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Fukuoka Y, Hite MR, Dellinger AL, Schwartz LB. Human skin mast cells express complement factors C3 and C5. THE JOURNAL OF IMMUNOLOGY 2013; 191:1827-34. [PMID: 23833239 DOI: 10.4049/jimmunol.1202889] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 01/23/2023]
Abstract
We examine whether complement factor C3 or C5 is synthesized by human skin-derived mast cells and whether their synthesis is regulated by cytokines. C3 and C5 mRNAs were assessed by RT-PCR, and proteins by flow cytometry, confocal microscopy, Western blotting, and ELISA. C3 and C5 mRNAs were each expressed, and baseline protein levels/10(6) cultured mast cells were 0.9 and 0.8 ng, respectively, and located in the cytoplasm outside of secretory granules. C3 accumulated in mast cell culture medium over time and by 3 d reached a concentration of 9.4 ± 8.0 ng/ml, whereas C5 levels were not detectable (<0.15 ng/ml). Three-day incubations of mast cells with IL-1α, IL-1β, IL-17, IFN-γ, IL-6, or anti-FcεRI did not affect C3 protein levels in culture medium, whereas incubations with PMA, TNF-α, IL-13, or IL-4 enhanced levels of C3 1.7- to 3.3-fold. In contrast with C3, levels of C5 remained undetectable. Importantly, treatment with TNF-α together with either IL-4 or IL-13 synergistically enhanced C3 (but not C5) production in culture medium by 9.8- or 7.1-fold, respectively. This synergy was blocked by attenuating the TNF-α pathway with neutralizing anti-TNF-α Ab, soluble TNFR, or an inhibitor of NF-κB, or by attenuating the IL-4/13 pathway with Jak family or Erk antagonists. Inhibitors of PI3K, Jnk, and p38 MAPK did not affect this synergy. Thus, human mast cells can produce and secrete C3, whereas β-tryptase can act on C3 to generate C3a and C3b, raising the likelihood that mast cells engage complement to modulate immunity and inflammation in vivo.
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Affiliation(s)
- Yoshihiro Fukuoka
- Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
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39
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Abstract
Multiorgan failure (MOF) represents the leading cause of death in patients with sepsis and systemic inflammatory response syndrome (SIRS) following severe trauma. The underlying immune response is highly complex and involves activation of the complement system as a crucial entity of innate immunity. Uncontrolled activation of the complement system during sepsis and SIRS with in excessive generation of complement activation products contributes to an ensuing dysfunction of various organ systems. In the present review, mechanisms of the inflammatory response in the development of MOF in sepsis and SIRS with particular focus on the complement system are discussed.
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Farrar CA, Asgari E, Schwaeble WJ, Sacks SH. Which pathways trigger the role of complement in ischaemia/reperfusion injury? Front Immunol 2012; 3:341. [PMID: 23181062 PMCID: PMC3500775 DOI: 10.3389/fimmu.2012.00341] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/20/2012] [Accepted: 10/25/2012] [Indexed: 01/04/2023] Open
Abstract
Investigations into the role of complement in ischemia/reperfusion (I/R) injury have identified common effector mechanisms that depend on the production of C5a and C5b-9 through the cleavage of C3. These studies have also defined an important role for C3 synthesized within ischemic kidney. Less clear however is the mechanism of complement activation that leads to the cleavage of C3 in ischemic tissues and to what extent the potential trigger mechanisms are organ dependent - an important question which informs the development of therapies that are more selective in their ability to limit the injury, yet preserve the other functions of complement where possible. Here we consider recent evidence for each of the three major pathways of complement activation (classical, lectin, and alternative) as mediators of I/R injury, and in particular highlight the role of lectin molecules that increasingly seem to underpin the injury in different organ models and in addition reveal unusual routes of complement activation that contribute to organ damage.
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Affiliation(s)
- Conrad A. Farrar
- MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, King’s College London School of Medicine at Guy’s, King’s College and St Thomas’ HospitalsLondon, UK
| | - Elham Asgari
- MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, King’s College London School of Medicine at Guy’s, King’s College and St Thomas’ HospitalsLondon, UK
| | - Wilhelm J. Schwaeble
- Department of Infection, Immunity, and Inflammation, Leicester UniversityLeicester, UK
| | - Steven H. Sacks
- MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, King’s College London School of Medicine at Guy’s, King’s College and St Thomas’ HospitalsLondon, UK
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Kaczorowski DJ, Scott MJ, Pibris JP, Afrazi A, Nakao A, Edmonds RD, Kim S, Kwak JH, Liu Y, Fan J, Billiar TR. Mammalian DNA is an endogenous danger signal that stimulates local synthesis and release of complement factor B. Mol Med 2012; 18:851-60. [PMID: 22526919 DOI: 10.2119/molmed.2012.00011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/12/2012] [Accepted: 04/19/2012] [Indexed: 11/06/2022] Open
Abstract
Complement factor B plays a critical role in ischemic tissue injury and autoimmunity. Factor B is dynamically synthesized and released by cells outside of the liver, but the molecules that trigger local factor B synthesis and release during endogenous tissue injury have not been identified. We determined that factor B is upregulated early after cold ischemia-reperfusion in mice, using a heterotopic heart transplant model. These data suggested upregulation of factor B by damage-associated molecular patterns (DAMPs), but multiple common DAMPs did not induce factor B in RAW264.7 mouse macrophages. However, exogenous DNA induced factor B mRNA and protein expression in RAW cells in vitro, as well as in peritoneal and alveolar macrophages in vivo. To determine the cellular mechanisms involved in DNA-induced factor B upregulation we then investigated the role of multiple known DNA receptors or binding partners. We stimulated peritoneal macrophages from wild-type (WT), toll-like receptor 9 (TLR9)-deficient, receptor for advanced glycation end products (RAGE)⁻/⁻ and myeloid differentiation factor 88 (MyD88)⁻/⁻ mice, or mouse macrophages deficient in high-mobility group box proteins (HMGBs), DNA-dependent activator of interferon-regulatory factors (DAI) or absent in melanoma 2 (AIM2), with DNA in the presence or absence of lipofection reagent. Reverse transcription-polymerase chain reaction, Western blotting and immunocytochemical analysis were employed for analysis. Synthesis of factor B was independent of TLR9, RAGE, DAI and AIM2, but was dependent on HMGBs, MyD88, p38 and NF-κB. Our data therefore show that mammalian DNA is an endogenous molecule that stimulates factor B synthesis and release from macrophages via HMGBs, MyD88, p38 and NF-κB signaling. This activation of the immune system likely contributes to damage following sterile injury such as hemorrhagic shock and ischemia-reperfusion.
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Affiliation(s)
- David J Kaczorowski
- Division of Cardiovascular Surgery, University of Pennsylvania, Philadelphia, PA, United States of America
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Abstract
The complement system is a key element of the innate immune system, and the production of complement components can be divided into central (hepatic) and peripheral compartments. Essential complement components such as C3 are produced in both of these compartments, but until recently the functional relevance of the peripheral synthesis of complement was unclear. Here, we review recent findings showing that local peripheral synthesis of complement in a transplanted organ is required for the immediate response of the donor organ to tissue stress and for priming alloreactive T cells that can mediate transplant rejection. We also discuss recent insights into the role of complement in antibody-mediated rejection, and we examine how new treatment strategies that take into account the separation of central and peripheral production of complement are expected to make a difference to transplant outcome.
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Bulla R, Bossi F, Tedesco F. The complement system at the embryo implantation site: friend or foe? Front Immunol 2012; 3:55. [PMID: 22566936 PMCID: PMC3341982 DOI: 10.3389/fimmu.2012.00055] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/21/2011] [Accepted: 03/02/2012] [Indexed: 12/19/2022] Open
Abstract
An inflammatory-like process and vascular remodeling represent the main changes that occur in decidua in the early phase of pregnancy. These changes are partly induced by trophoblast cells that colonize the decidua and are also contributed by the complement system, which can easily be activated as a result of tissue remodeling. Local control by several complement regulators including surface-bound and soluble molecules is critical to prevent complement-mediated tissue damage in normal pregnancy. C7 expressed on the endothelial cells (ECs) surface has been recognized as a novel complement regulator involved in the control of the proinflammatory effect of the terminal complement complex. The protective role of placental complement regulators in pregnancy is underscored by the recent finding of an association of preeclampsia with mutations in the genes encoding for some of these proteins. Complement components produced at feto-maternal interface serve an important function in placental development. C1q synthesized by decidual ECs and expressed on the cell surface is particularly important in this regard because it acts as a molecular bridge between endovascular trophoblast and ECs. C1q is also produced by extravillous trophoblast and is used to favor trophoblast migration through the decidua. Defective expression of C1q by trophoblast is associated with impaired trophoblast invasion of decidua and may have important implications in pregnancy disorders such as preeclampsia characterized by reduced vascular remodeling.
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Affiliation(s)
- R Bulla
- Department of Life Sciences, University of Trieste Trieste, Italy
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Quantitative and qualitative urinary cellular patterns correlate with progression of murine glomerulonephritis. PLoS One 2011; 6:e16472. [PMID: 21304992 PMCID: PMC3031591 DOI: 10.1371/journal.pone.0016472] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/21/2010] [Accepted: 12/17/2010] [Indexed: 11/19/2022] Open
Abstract
The kidney is a nonregenerative organ composed of numerous functional nephrons and collecting ducts (CDs). Glomerular and tubulointerstitial damages decrease the number of functional nephrons and cause anatomical and physiological alterations resulting in renal dysfunction. It has recently been reported that nephron constituent cells are dropped into the urine in several pathological conditions associated with renal functional deterioration. We investigated the quantitative and qualitative urinary cellular patterns in a murine glomerulonephritis model and elucidated the correlation between cellular patterns and renal pathology. Urinary cytology and renal histopathology were analyzed in BXSB/MpJ (BXSB; glomerulonephritis model) and C57BL/6 (B6; control) mice. Urinary cytology revealed that the number of urinary cells in BXSB mice changed according to the histometric score of glomerulonephritis and urinary albumin; however, no correlation was detected for the levels of blood urea nitrogen and creatinine. The expression of specific markers for podocytes, distal tubules (DTs), and CDs was detected in BXSB urine. Cells immunopositive for Wilms tumor 1 (podocyte marker) and interleukin-1 family, member 6 (damaged DT and CD marker) in the kidney significantly decreased and increased in BXSB versus B6, respectively. In the PCR array analysis of inflammatory cytokines and chemokines, Il10, Cxcl2, C3, and Il1rn showed relatively higher expression in BXSB kidneys than in B6 kidneys. In particular, the highest expression of C3 mRNA was detected in the urine from BXSB mice. Furthermore, C3 protein and mRNA were localized in the epithelia of damaged nephrons. These findings suggest that epithelial cells of the glomerulus, DT, and CD are dropped into the urine, and that these patterns are associated with renal pathology progression. We conclude that evaluation of urinary cellular patterns plays a key role in the early, noninvasive diagnosis of renal disease.
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45
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Damman J, Nijboer WN, Schuurs TA, Leuvenink HG, Morariu AM, Tullius SG, van Goor H, Ploeg RJ, Seelen MA. Local renal complement C3 induction by donor brain death is associated with reduced renal allograft function after transplantation. Nephrol Dial Transplant 2010; 26:2345-54. [PMID: 21127132 DOI: 10.1093/ndt/gfq717] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Kidneys derived from brain-dead donors have inferior outcomes after transplantation compared to kidneys from living donors. Strikingly, early and profound serum levels of IL-6 in brain-dead donors are observed. IL-6 is the main regulator of the acute phase response (APR). The aim of this translational study was to investigate the expression of renal acute phase proteins (APPs) following brain death (BD) and to assess the association with renal allograft outcome after transplantation. METHODS BD was induced in rats by inflating a subdurally placed balloon catheter. Kidney biopsies were obtained from human living and brain-dead donors at donation, after cold preservation and reperfusion. In vitro, renal proximal tubular epithelial cells (HK-2 cells) were stimulated with IL-6. RESULTS Both in human and rat brain-dead donors, C3 and FBG expression was enhanced at donation compared to living donors and sham-operated animals. In human donors, no additional expression was found after cold ischaemia or reperfusion. C3 expression after reperfusion was independently associated with decreased short-term function after transplantation in grafts from brain-dead donors. In cultured HK-2 cells, C3 production was induced in the presence of IL-6. CONCLUSIONS In conclusion, BD induces renal C3 and FBG expression. Moreover, C3 expression is associated with a worse allograft function early after transplantation. Therefore, targeting renal APPs in brain-dead donors, especially complement C3, may improve transplant outcome.
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Affiliation(s)
- Jeffrey Damman
- Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands.
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47
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Ohsawa I, Inoshita H, Ishii M, Kusaba G, Sato N, Mano S, Onda K, Gohda T, Horikoshi S, Ohi H, Tomino Y. Metabolic impact on serum levels of complement component 3 in Japanese patients. J Clin Lab Anal 2010; 24:113-8. [PMID: 20333766 DOI: 10.1002/jcla.20372] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/07/2022] Open
Abstract
The aim of this study was to explore the association between the serum concentration of complement component 3 (C3) and a variety of metabolic parameters. The study involved 125 patients in our outpatient clinic. Anthropometric and clinical laboratory data were collected and statistical associations between the serum concentration of C3 and other parameters were evaluated in a cross-sectional as well as a prospective manner. A group of male patients with metabolic syndrome (Mets, n=35) were characterized by marked increase in serum concentrations of C3, body mass index (BMI), waist circumference, hemoglobin (Hb) A1c, insulin resistance (HOMA-IR), triglyceride, uric acid, urinary protein, and Hb. In a one-way analysis of variance of all subjects, the serum concentration of C3 was significantly elevated as the number of items of complying with the Mets diagnostic criteria increased. In 60 of 125 patients who did not have diabetes and were given anti-lipogenetic medication, the serum concentration of C3 showed significant positive associations with serum levels of CH50, insulin, HOMA-IR, total cholesterol, hematocrit, LDL-c, C4, Hb, triglyceride, BMI, and albumin. In a prospective follow-up evaluation (n=35), there was a significant positive association between DeltaC3 (the second concentration of serum C3 minus the first concentration of serum C3)and DeltaHOMA-IR (the second concentration of HOMA-IR minus the first concentration of HOMA-IR). In conclusion, in Japanese patients, there is evidence implicating C3 concentration as a marker of Mets coinciding with insulin resistance.
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Affiliation(s)
- Isao Ohsawa
- Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
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Abstract
Diabetic nephropathy is associated with increased mortality in diabetic patients and is a major cause of end-stage renal disease in most countries. Understanding its pathogenesis is important as it may equip us with novel ways in its prevention and in slowing its progression. To date, attempts to unravel the complex pathogenesis and pathophysiology of diabetic nephropathy have mostly focused on the glomerulus. However, recently a lot of data has accumulated that implicates the tubules as playing a key role. This article reviews these data and the light they throw on the role of renal tubules in the pathogenesis of diabetic nephropathy.
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49
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Welch TR, Blystone LW. Immune complex glomerulonephritis following bone marrow transplantation in C3 deficient mice. PLoS One 2008; 3:e3334. [PMID: 18836527 PMCID: PMC2553262 DOI: 10.1371/journal.pone.0003334] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/29/2008] [Accepted: 09/11/2008] [Indexed: 11/21/2022] Open
Abstract
Background The role of circulating complement in host defense and immune disease is well established. Although a number of cells and tissues are capable of synthesizing complement components locally, the importance of such local synthesis in immune disease has been difficult to establish. Methodology/Principal Findings We used bone marrow transplantation (BMT) between C3 knockout (C3KO) and wild type (WT) mice to construct animals that were discordant for systemic (hepatic) and local (monocytic) C3 synthetic capacity. An immune complex glomerulonephritis (GN) was then induced using intraperitoneal injections of horse spleen apoferritin (HSA) with a lipopolysaccharide (LPS) adjuvant. All HSA/LPS animals developed a proliferative GN with glomerular infiltration by monocytes. By sensitive ELISA, monocyte C3 synthesis could be detected in C3KO animals transplanted with WT bone marrow cells. Despite this, there were no significant differences among groups of mice in measures of clinical (proteinuria, renal function) or histologic (glomerular cellularity, crescents) disease severity. Conclusions/Significance In this model of GN, local synthesis of C3 by infiltrating cells does not appear to be of pathologic importance.
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Affiliation(s)
- Thomas R Welch
- Department of Pediatrics, SUNY Upstate Medical University, Syracuse, New York, United States of America.
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50
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Abstract
Mrug et al. propose that innate immunity is a hallmark of progressive polycystic kidney disease (PKD). We propose that innate immunity is a driving force in the progression of many renal diseases. Renal epithelial cells are capable of expressing a large variety of proinflammatory genes resulting in the production of cytokines, chemokines, cell-adhesion molecules, and complement components. We suggest that future therapeutic interventions should be directed toward control of innate immunity in renal disease.
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