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Netzel BC, Charlesworth MC, Johnson KL, French AJ, Dispenzieri A, Maleszewski JJ, McPhail ED, Grogan M, Redfield MM, Weivoda M, Muchtar E, Gertz MA, Kumar SK, Misra P, Vrana J, Theis J, Hayman SR, Ramirez-Alvarado M, Dasari S, Kourelis T. Whole tissue proteomic analyses of cardiac ATTR and AL unveil mechanisms of tissue damage. Amyloid 2025; 32:72-80. [PMID: 39773246 PMCID: PMC11825277 DOI: 10.1080/13506129.2024.2448440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/13/2024] [Revised: 12/10/2024] [Accepted: 12/27/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND Cardiac AL and ATTR are potentially fatal cardiomyopathies. Current therapies do not address mechanisms of tissue dysfunction because these remain unknown. Our prior work focused on the amyloid plaque proteome, which may not capture tissue-wide proteomic alterations. OBJECTIVES To evaluate mechanisms of tissue dysfunction in cardiac AL and ATTR using a full biopsy tissue proteomics approach. METHODS We performed proteomics analysis on 76 ATTR and 27 AL diagnostic endomyocardial biopsies. RESULTS Stage-3 AL patients exhibited increased coagulation, extracellular matrix remodelling (ECM), epithelial-to-mesenchymal transition (EMT), complement activation, hypoxia, and clathrin-mediated endocytosis pathways vs. stages-1/2, with decreased healthy cardiac metabolism. In stages-2 and 3 ATTR, immunoglobulin proteins, complement, and keratinisation pathways were increased compared to stage-1. Unsupervised analyses identified an ATTR group with worse survival characterised by upregulated complement and downregulated metabolic pathways. Compared to ATTR, AL had higher clathrin-mediated endocytosis, mRNA splicing, and ribosomal proteins, while ATTR had higher complement levels. CONCLUSIONS This study identifies known processes dysregulated in heart failure with preserved ejection fraction as well as novel pathways responsible for tissue damage. Our results support an immune-mediated mechanism of tissue toxicity in cardiac amyloidosis, especially among patients with worse outcomes.
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Affiliation(s)
- Brian C. Netzel
- Bioinformatics and Computational Biology Graduate Program, University of Minnesota
| | | | | | | | - Angela Dispenzieri
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Ellen D. McPhail
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Martha Grogan
- Department of Cardiology, Mayo Clinic, Rochester, MN
| | | | - Megan Weivoda
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Eli Muchtar
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Morie A. Gertz
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Shaji K. Kumar
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Pinaki Misra
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN
| | - Julie Vrana
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Jason Theis
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Suzanne R. Hayman
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Surendra Dasari
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN
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2
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Kordowski A, Mulay O, Tan X, Vo T, Baumgartner U, Maybury MK, Hassall T, Harris L, Nguyen Q, Day BW. Spatial analysis of a complete DIPG-infiltrated brainstem reveals novel ligand-receptor mediators of tumour-to-TME crosstalk. Acta Neuropathol Commun 2025; 13:35. [PMID: 39972389 PMCID: PMC11837654 DOI: 10.1186/s40478-025-01952-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/31/2024] [Accepted: 02/09/2025] [Indexed: 02/21/2025] Open
Abstract
Previous studies have highlighted the capacity of brain cancer cells to functionally interact with the tumour microenvironment (TME). This TME-cancer crosstalk crucially contributes to tumour cell invasion and disease progression. In this study, we performed spatial transcriptomic sequencing analysis of a complete annotated tumour-infiltrated brainstem from a single diffuse intrinsic pontine glioma (DIPG) patient. Gene signatures from ten sequential tumour regions were analysed to assess mechanisms of disease progression and oncogenic interactions with the TME. We identified four distinct tumour subpopulations and assessed respective ligand-receptor pairs that actively promote DIPG tumour progression via crosstalk with endothelial, neuronal and immune cell communities. Our analysis found potential targetable mediators of tumour-to-TME communication, including members of the complement component system and the neuropeptide/GPCR ligand-receptor pair ADCYAP1-ADCYAP1R1. These interactions could influence DIPG tumour progression and represent novel therapeutic targets.
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Affiliation(s)
- Anja Kordowski
- Queensland Institute for Medical Research, Brisbane, QLD, 4006, Australia.
| | - Onkar Mulay
- Queensland Institute for Medical Research, Brisbane, QLD, 4006, Australia
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4067, Australia
| | - Xiao Tan
- Queensland Institute for Medical Research, Brisbane, QLD, 4006, Australia
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4067, Australia
| | - Tuan Vo
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4067, Australia
- Hunter Medical Research Institute, Precision Medicine Research Program, Newcastle, NSW, 2305, Australia
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, NSW, 2308, Australia
| | - Ulrich Baumgartner
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4067, Australia
| | - Mellissa K Maybury
- Child Health Research Centre, The University of Queensland, Brisbane, QLD, 4101, Australia
| | - Timothy Hassall
- Children's Brain Cancer Centre, UQ Frazer Institute, Brisbane, QLD, 4102, Australia
- Queensland Children's Hospital, Brisbane, QLD, 4101, Australia
| | - Lachlan Harris
- Queensland Institute for Medical Research, Brisbane, QLD, 4006, Australia
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4067, Australia
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, 4059, Australia
| | - Quan Nguyen
- Queensland Institute for Medical Research, Brisbane, QLD, 4006, Australia
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4067, Australia
| | - Bryan W Day
- Queensland Institute for Medical Research, Brisbane, QLD, 4006, Australia.
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4067, Australia.
- Children's Brain Cancer Centre, UQ Frazer Institute, Brisbane, QLD, 4102, Australia.
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3
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Magnusen AF, Pandey MK. Complement System and Adhesion Molecule Skirmishes in Fabry Disease: Insights into Pathogenesis and Disease Mechanisms. Int J Mol Sci 2024; 25:12252. [PMID: 39596318 PMCID: PMC11594573 DOI: 10.3390/ijms252212252] [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: 09/12/2024] [Revised: 11/05/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024] Open
Abstract
Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene, resulting in the accumulation of globotriaosylceramide (Gb3) and its deacetylated form, globotriaosylsphingosine (Lyso-Gb3) in various tissues and fluids throughout the body. This pathological accumulation triggers a cascade of processes involving immune dysregulation and complement system activation. Elevated levels of complement 3a (C3a), C5a, and their precursor C3 are observed in the plasma, serum, and tissues of patients with Fabry disease, correlating with significant endothelial cell abnormalities and vascular dysfunction. This review elucidates how the complement system, particularly through the activation of C3a and C5a, exacerbates disease pathology. The activation of these pathways leads to the upregulation of adhesion molecules, including vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), platelet and endothelial cell adhesion molecule 1 (PECAM1), and complement receptor 3 (CR3) on leukocytes and endothelial cells. This upregulation promotes the excessive recruitment of leukocytes, which in turn exacerbates disease pathology. Targeting complement components C3a, C5a, or their respective receptors, C3aR (C3a receptor) and C5aR1 (C5a receptor 1), could potentially reduce inflammation, mitigate tissue damage, and improve clinical outcomes for individuals with Fabry disease.
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Affiliation(s)
- Albert Frank Magnusen
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
| | - Manoj Kumar Pandey
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
- Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA
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4
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Liu B, Wang X, Yang Z, Yin Z, Tang C, He Y, Ling Q, Huang Z, Feng S. A genetic study to identify pathogenic mechanisms and drug targets for benign prostatic hyperplasia: a multi-omics Mendelian randomization study. Sci Rep 2024; 14:23120. [PMID: 39367121 PMCID: PMC11452698 DOI: 10.1038/s41598-024-73466-w] [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: 03/20/2024] [Accepted: 09/17/2024] [Indexed: 10/06/2024] Open
Abstract
Benign prostatic hyperplasia (BPH) as a common geriatric disease in urology, the incidence and prevalence are rapidly increasing with the aging society, prompting an urgent need for effective prevention and treatment of BPH. However, limited therapeutic efficacy and higher risk of complications result in the treatment of BPH remaining challenging. The unclear pathogenic mechanism also hampers further exploration of therapeutic approaches for BPH. In this study, we used multi-omics methods to integrate genomics, transcriptomics, immunomics, and metabolomics data and identify biomolecules associated with BPH. We performed transcriptomic imputation, summary data-based Mendelian randomization (SMR), joint/conditional analysis, colocalization analysis, and FOCUS to explore high-confidence genes associated with BPH in blood and prostate tissue. Subsequently, three-step SMR was used to identify the DNA methylation sites regulating high-confidence genes to improve the pathogenic pathways of BPH. We also used cis-instruments of druggable genes to conduct SMR analysis to find potential drug targets for BPH. Finally, we used MR analysis to explore the immune pathways and metabolomics related to BPH. Multiple analytical methods identified BTN3A2 (Blood: TWAS Z score = 5.02912, TWAS P = 4.93 × 10-7; Prostate: TWAS Z score = 4.89, TWAS P = 1.01 × 10-6) and C4A (Blood: TWAS Z score = 4.90754, TWAS P = 9.22 × 10-7; Prostate: TWAS Z score = 5.084, TWAS P = 3.70 × 10-7) as high-confidence genes for BPH and identified the cg14345882-BTN3A2-BPH pathogenic pathway. We also used druggable gene data to identify 30 promising therapeutic target genes, including BTN3A2 and C4A. For MR analysis of immune pathways, we identified immune cell surface molecules as well as the inflammatory factor IL-17 (OR = 1.25, 95% CI = 1.09-1.43, PFDR = 0.12, Maximum likelihood) as risk factors for BPH. In addition, we found that disulfide levels of cysteinylglycine (OR = 1.11, 95% CI = 1.05-1.18, P = 5.18 × 10-4, Weighted median), oxidation levels of cysteinylglycine (OR = 1.09, 95% CI = 1.04-1.14, P = 3.87 × 10-4, Weighted median), and sebacate levels (OR = 1.05, 95% CI = 1.02-1.08, P = 3.0 × 10-4, Maximum likelihood) increase the risk of BPH. This multi-omics study explored biomolecules associated with BPH, improved the pathogenic pathways of BPH, and identified promising therapeutic targets. Our results provide evidence for future studies aimed at developing appropriate therapeutic interventions.
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Affiliation(s)
- Bohan Liu
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology) and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan, People's Republic of China
| | - Xinyi Wang
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology) and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan, People's Republic of China
| | - Zerui Yang
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology) and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan, People's Republic of China
| | - Zhaofa Yin
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology) and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan, People's Republic of China
| | - Cai Tang
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology) and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yushi He
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology) and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan, People's Republic of China
| | - Qi Ling
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology) and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan, People's Republic of China
| | - Zhongli Huang
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology) and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan, People's Republic of China.
| | - Shijian Feng
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology) and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan, People's Republic of China.
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Patel VJ, Joharapurkar AA, Kshirsagar SG, Patel MS, Savsani HH, Dodiya HS, Rakhasiya MH, Patel AK, Sundar R, Jain MR. HIF Stabilizer Desidustat Protects against Complement-Mediated Diseases. Drug Res (Stuttg) 2024; 74:325-334. [PMID: 38991528 DOI: 10.1055/a-2347-9919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 07/13/2024]
Abstract
Complement cascade is a defence mechanism useful for eliminating pathogenic microorganisms and damaged cells. However, activation of alternative complement system can also cause inflammation and promote kidney and retinal disease progression. Inflammation causes tissue hypoxia, which induces hypoxia-inducible factor (HIF) and HIF helps the body to adapt to inflammation. In this study, we investigated the effect of HIF stabilizer desidustat in complement-mediated diseases. Oral administration of desidustat (15 mg/kg) was effective to reduce the kidney injury in mice that was induced by either lipopolysaccharide (LPS), doxorubicin or bovine serum albumin (BSA)-overload. Complement activation-induced membrane attack complex (MAC) formation and factor B activity were also reduced by desidustat treatment. In addition, desidustat was effective against membranous nephropathy caused by cationic BSA and retinal degeneration induced by sodium iodate in mice. C3-deposition, proteinuria, malondialdehyde, and interleukin-1ß were decreased and superoxide dismutase was increased by desidustat treatment in cBSA-induced membranous nephropathy. Desidustat specifically inhibited alternative complement system, without affecting the lectin-, or classical complement pathway. This effect appears to be mediated by inhibition of factor B. These data demonstrate the potential therapeutic value of HIF stabilization by desidustat in treatment of complement-mediated diseases.
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Affiliation(s)
- Vishal J Patel
- Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India
| | - Amit A Joharapurkar
- Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India
| | - Samadhan G Kshirsagar
- Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India
| | - Maulik S Patel
- Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India
| | - Hardikkumar H Savsani
- Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India
| | - Harshad S Dodiya
- Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India
| | - Milan H Rakhasiya
- Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India
| | - Ashvin K Patel
- Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India
| | - Rajesh Sundar
- Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India
| | - Mukul R Jain
- Department of Pharmacology and Toxicology, Zydus Research Centre, Zydus Lifesciences Limited, Moraiya, Ahmedabad, India
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6
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Alkaff FF, Lammerts RGM, Daha MR, Berger SP, van den Born J. Apical tubular complement activation and the loss of kidney function in proteinuric kidney diseases. Clin Kidney J 2024; 17:sfae215. [PMID: 39135935 PMCID: PMC11318052 DOI: 10.1093/ckj/sfae215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/07/2024] [Indexed: 08/15/2024] Open
Abstract
Many kidney diseases are associated with proteinuria. Since proteinuria is independently associated with kidney function loss, anti-proteinuric medication, often in combination with dietary salt restriction, comprises a major cornerstone in the prevention of progressive kidney failure. Nevertheless, complete remission of proteinuria is very difficult to achieve, and most patients with persistent proteinuria slowly progress toward kidney failure. It is well-recognized that proteinuria leads to kidney inflammation and fibrosis via various mechanisms. Among others, complement activation at the apical side of the proximal tubular epithelial cells is suggested to play a crucial role as a cause of progressive loss of kidney function. However, hitherto limited attention is given to the pathophysiological role of tubular complement activation relative to glomerular complement activation. This review aims to summarize the evidence for tubular epithelial complement activation in proteinuric kidney diseases in relation to loss of kidney function.
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Affiliation(s)
- Firas F Alkaff
- Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Division of Pharmacology and Therapy, Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia
| | - Rosa G M Lammerts
- Transplantation Immunology, Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Mohamed R Daha
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Stefan P Berger
- Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jacob van den Born
- Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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7
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Kesarwani V, Bukhari MH, Kahlenberg JM, Wang S. Urinary complement biomarkers in immune-mediated kidney diseases. Front Immunol 2024; 15:1357869. [PMID: 38895123 PMCID: PMC11184941 DOI: 10.3389/fimmu.2024.1357869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/18/2023] [Accepted: 05/09/2024] [Indexed: 06/21/2024] Open
Abstract
The complement system, an important part of the innate system, is known to play a central role in many immune mediated kidney diseases. All parts of the complement system including the classical, alternative, and mannose-binding lectin pathways have been implicated in complement-mediated kidney injury. Although complement components are thought to be mainly synthesized in the liver and activated in the circulation, emerging data suggest that complement is synthesized and activated inside the kidney leading to direct injury. Urinary complement biomarkers are likely a better reflection of inflammation within the kidneys as compared to traditional serum complement biomarkers which may be influenced by systemic inflammation. In addition, urinary complement biomarkers have the advantage of being non-invasive and easily accessible. With the rise of therapies targeting the complement pathways, there is a critical need to better understand the role of complement in kidney diseases and to develop reliable and non-invasive biomarkers to assess disease activity, predict treatment response and guide therapeutic interventions. In this review, we summarized the current knowledge on urinary complement biomarkers of kidney diseases due to immune complex deposition (lupus nephritis, primary membranous nephropathy, IgA nephropathy) and due to activation of the alternative pathway (C3 glomerulopathy, thrombotic microangiography, ANCA-associated vasculitis). We also address the limitations of current research and propose future directions for the discovery of urinary complement biomarkers.
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Affiliation(s)
- Vartika Kesarwani
- Division of Rheumatology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
| | - Muhammad Hamza Bukhari
- Department of Medicine, Johns Hopkins Howard County Medical Center, Columbia, MD, United States
| | - J. Michelle Kahlenberg
- Division of Rheumatology, Department of Medicine, University of Michigan, Columbia, MI, United States
| | - Shudan Wang
- Division of Rheumatology, Department of Medicine, Montefiore Medical Center / Albert Einstein College of Medicine, Bronx, NY, United States
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8
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Isaksson GL, Hinrichs GR, Andersen H, Bach ML, Weyer K, Zachar R, Henriksen JE, Madsen K, Lund IK, Mollet G, Bistrup C, Birn H, Jensen BL, Palarasah Y. Amiloride Reduces Urokinase/Plasminogen-Driven Intratubular Complement Activation in Glomerular Proteinuria. J Am Soc Nephrol 2024; 35:410-425. [PMID: 38254266 PMCID: PMC11000727 DOI: 10.1681/asn.0000000000000312] [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: 07/26/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024] Open
Abstract
SIGNIFICANCE STATEMENT Proteinuria predicts accelerated decline in kidney function in CKD. The pathologic mechanisms are not well known, but aberrantly filtered proteins with enzymatic activity might be involved. The urokinase-type plasminogen activator (uPA)-plasminogen cascade activates complement and generates C3a and C5a in vitro / ex vivo in urine from healthy persons when exogenous, inactive, plasminogen, and complement factors are added. Amiloride inhibits uPA and attenuates complement activation in vitro and in vivo . In conditional podocin knockout (KO) mice with severe proteinuria, blocking of uPA with monoclonal antibodies significantly reduces the urine excretion of C3a and C5a and lowers tissue NLRP3-inflammasome protein without major changes in early fibrosis markers. This mechanism provides a link to proinflammatory signaling in proteinuria with possible long-term consequences for kidney function. BACKGROUND Persistent proteinuria is associated with tubular interstitial inflammation and predicts progressive kidney injury. In proteinuria, plasminogen is aberrantly filtered and activated by urokinase-type plasminogen activator (uPA), which promotes kidney fibrosis. We hypothesized that plasmin activates filtered complement factors C3 and C5 directly in tubular fluid, generating anaphylatoxins, and that this is attenuated by amiloride, an off-target uPA inhibitor. METHODS Purified C3, C5, plasminogen, urokinase, and urine from healthy humans were used for in vitro / ex vivo studies. Complement activation was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, immunoblotting, and ELISA. Urine and plasma from patients with diabetic nephropathy treated with high-dose amiloride and from mice with proteinuria (podocin knockout [KO]) treated with amiloride or inhibitory anti-uPA antibodies were analyzed. RESULTS The combination of uPA and plasminogen generated anaphylatoxins C3a and C5a from intact C3 and C5 and was inhibited by amiloride. Addition of exogenous plasminogen was sufficient for urine from healthy humans to activate complement. Conditional podocin KO in mice led to severe proteinuria and C3a and C5a urine excretion, which was attenuated reversibly by amiloride treatment for 4 days and reduced by >50% by inhibitory anti-uPA antibodies without altering proteinuria. NOD-, LRR- and pyrin domain-containing protein 3-inflammasome protein was reduced with no concomitant effect on fibrosis. In patients with diabetic nephropathy, amiloride reduced urinary excretion of C3dg and sC5b-9 significantly. CONCLUSIONS In conditions with proteinuria, uPA-plasmin generates anaphylatoxins in tubular fluid and promotes downstream complement activation sensitive to amiloride. This mechanism links proteinuria to intratubular proinflammatory signaling. In perspective, amiloride could exert reno-protective effects beyond natriuresis and BP reduction. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Increased Activity of a Renal Salt Transporter (ENaC) in Diabetic Kidney Disease, NCT01918488 and Increased Activity of ENaC in Proteinuric Kidney Transplant Recipients, NCT03036748 .
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Affiliation(s)
- Gustaf L. Isaksson
- Department of Molecular Medicine–Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
- Department of Nephrology, Odense University Hospital, Odense, Denmark
| | - Gitte R. Hinrichs
- Department of Molecular Medicine–Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
- Department of Nephrology, Odense University Hospital, Odense, Denmark
| | - Henrik Andersen
- Department of Molecular Medicine–Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
| | - Marie L. Bach
- Department of Molecular Medicine–Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
| | - Kathrin Weyer
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Rikke Zachar
- Department of Molecular Medicine–Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
| | - Jan Erik Henriksen
- Steno Diabetes Center Odense, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Kirsten Madsen
- Department of Molecular Medicine–Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
- Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Ida K. Lund
- The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark
- Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Géraldine Mollet
- Laboratory of Hereditary Kidney Diseases, Inserm UMR1163, Imagine Institute, Université Paris Cité, Paris, France
| | - Claus Bistrup
- Department of Nephrology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Henrik Birn
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Boye L. Jensen
- Department of Molecular Medicine–Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark
| | - Yaseelan Palarasah
- Department of Molecular Medicine–Cancer and Inflammation, University of Southern Denmark, Odense, Denmark
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9
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Buelli S, Imberti B, Morigi M. The Complement C3a and C5a Signaling in Renal Diseases: A Bridge between Acute and Chronic Inflammation. Nephron Clin Pract 2024; 148:712-723. [PMID: 38452744 DOI: 10.1159/000538241] [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: 09/21/2023] [Accepted: 03/04/2024] [Indexed: 03/09/2024] Open
Abstract
The complement system, a cornerstone of the innate immune defense, typically confers protection against pathogens. However, in various clinical scenarios the complement's defensive actions can harm host cells, exacerbating immune and inflammatory responses. The central components C3 and C5 undergo proteolytic cleavage during complement activation, yielding small active fragments C3a and C5a anaphylatoxins. Traditionally, these fragments were associated with inflammation via the specific receptors C3a receptor (R), C5aR1 and C5aR2. Recent insights, however, spotlight the excessive C3a/C3aR and C5a/C5aR1 signaling as culprits in diverse disorders of inflammatory and autoimmune etiology. This is particularly true for several kidney diseases, where the potential involvement of anaphylatoxins in renal damage is supported by the enhanced renal expression of their receptors and the high levels of C3a and C5a in both plasma and urine. Furthermore, the production of complement proteins in the kidney, with different renal cells synthesizing C3 and C5, significantly contributes to local tissue injury. In the present review, we discuss the different aspects of C3a/C3aR and C5a/C5aR signaling in acute and chronic kidney diseases and explore the therapeutic potential of emerging targeted drugs for future clinical applications.
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Affiliation(s)
- Simona Buelli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Barbara Imberti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Marina Morigi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
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Hata J, Matsuoka K, Akaihata H, Meguro S, Honda-Takinami R, Onagi A, Koguchi T, Sato Y, Kataoka M, Uemura M, Kojima Y. The activated complement pathway in the fibrous process of benign prostatic hyperplasia. Prostate 2024; 84:203-211. [PMID: 37876324 DOI: 10.1002/pros.24639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/06/2023] [Revised: 10/05/2023] [Accepted: 10/16/2023] [Indexed: 10/26/2023]
Abstract
BACKGROUND To elucidate the changes in activated complement pathway in the fibrous process of benign prostatic hyperplasia (BPH), we analyzed the correlation between complement component expression and histological types of fibrosis using human BPH tissue. METHODS Fifty-six histological BPH patients who underwent prostate needle biopsy at our institution (mean age 68.6 ± 6.5 years), divided into two histological groups, fibromuscular and fibrous, were compared. Inflammatory cell infiltration in BPH tissue was evaluated by immunohistochemical staining using CD45, with complement expression analysis performed using C3, factor B, and C5b-9 antibody, and the occupancy ratio of the stained region was calculated. Further, correlation between the histological types of fibrous components in BPH tissue and lower urinary tract symptoms questionnaires was analyzed. RESULTS Twenty-seven (48.2%) and 29 (51.8%) cases were classified in the fibromuscular and fibrous groups, respectively. The proportion of CD45-positive cells in BPH tissue was significantly higher in the fibromuscular group. In complement component analysis, factor B did not significantly differ between groups, while C3 (fibromuscular group; 10.7 ± 8.2%, fibrous group; 16.4 ± 12.7%) and C5b-9 (fibromuscular group; 15.9 ± 6.2%, fibrous group; 17.6 ± 9.2%) were significantly higher in the fibrous group (p = 0.04, p = 0.04, respectively). International Prostate Symptom Score Q5 subscore, indicating slow stream, was significantly higher in the fibrous group (p = 0.04). CONCLUSIONS In fibrous BPH with abundant fibrosis, the late complement pathway in addition to alternative pathway was activated compared to fibromuscular BPH. These results suggested that the alternative and late complement pathways were involved in the histological fibrous process of BPH.
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Affiliation(s)
- Junya Hata
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kanako Matsuoka
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hidenori Akaihata
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Satoru Meguro
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Ruriko Honda-Takinami
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Akifumi Onagi
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Tomoyuki Koguchi
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Yuichi Sato
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Masao Kataoka
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Motohide Uemura
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Yoshiyuki Kojima
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
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11
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Faria B, Gaya da Costa M, Meter-Arkema AH, Berger SP, Lima C, Pêgo C, van den Born J, Franssen CF, Daha MR, Pestana M, Seelen MA, Poppelaars F. Systemic and local complement activation in peritoneal dialysis patients via conceivably distinct pathways. Perit Dial Int 2024; 44:37-47. [PMID: 37794761 DOI: 10.1177/08968608231198984] [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] [Indexed: 10/06/2023] Open
Abstract
BACKGROUND Despite several advantages compared to haemodialysis (HD), peritoneal dialysis (PD) remains an underused dialysis technique due to its high technique failure rate related to membrane fibrosis and peritonitis events. Previous work has suggested a harmful role for the complement system in these processes, highlighting the need for a more comprehensive examination in PD. METHODS Plasma levels of C1q, mannose-binding lectin (MBL), Properdin, Factor D, C3d/C3-ratio and soluble membrane attack complex (sC5b-9) were determined in PD patients (n = 55), HD patients (n = 41), non-dialysis chronic kidney disease (CKD) patients (n = 15) and healthy controls (n = 14). Additionally, C1q, MBL, Properdin, Factor D and sC5b-9 levels were assessed in the peritoneal dialysis fluid (PDF). In a subgroup, interleukin-6, matrix metalloproteinase-2 (MMP-2), myeloperoxidase (MPO) and elastase were measured in the PDF. RESULTS PD patients had significantly higher systemic levels of sC5b-9 compared to healthy controls, CKD and HD patients (p < 0.001). Plasma levels of C1q and C3d/C3-ratios were significantly associated with systemic sC5b-9 levels (p < 0.001). Locally, sC5b-9 was detected in the PDF of all PD patients, and levels were approximately 33% of those in matched plasma, but they did not correlate. In the PDF, only Properdin levels remained significantly associated with PDF sC5b-9 levels in multivariate analysis (p < 0.001). Additionally, PDF levels of sC5b-9 positively correlated with elastase, MPO and MMP-2 levels in the PDF (p < 0.01). CONCLUSIONS Our data reveal both systemic and local complement activation in PD patients. Furthermore, these two processes seem independent considering the involvement of different pathways and the lack of correlation.
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Affiliation(s)
- Bernardo Faria
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands
- Nephrology and Infectious Disease R&D Group, INEB, Institute of Investigation and Innovation in Health (i3S), University of Porto, Portugal
- Department of Medicine, Faculty of Medicine, University of Porto, Portugal
| | - Mariana Gaya da Costa
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands
- Department of Anesthesiology, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Anita H Meter-Arkema
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Stefan P Berger
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Carla Lima
- Division of Nephrology, Hospital São Teotônio, Viseu, Portugal
| | - Catia Pêgo
- Division of Nephrology, Hospital São Teotônio, Viseu, Portugal
| | - Jacob van den Born
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Casper Fm Franssen
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Mohamed R Daha
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands
- Department of Nephrology, Leiden University Medical Center, University of Leiden, The Netherlands
| | - Manuel Pestana
- Nephrology and Infectious Disease R&D Group, INEB, Institute of Investigation and Innovation in Health (i3S), University of Porto, Portugal
- Department of Medicine, Faculty of Medicine, University of Porto, Portugal
| | - Marc A Seelen
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Felix Poppelaars
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, The Netherlands
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12
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You D, Nie K, Wu X, Weng M, Yang L, Chen Y, Cui J, Wan J. C3a/C3aR synergies with TGF-β to promote epithelial-mesenchymal transition of renal tubular epithelial cells via the activation of the NLRP3 inflammasome. J Transl Med 2023; 21:904. [PMID: 38082306 PMCID: PMC10714586 DOI: 10.1186/s12967-023-04764-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/23/2023] [Accepted: 11/25/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND Complement component 3a and its receptor (C3a/C3aR) and the nucleotide-binding oligomerization domain-like receptor protein-3 (NLRP3) inflammasome contribute to epithelial-mesenchymal transition (EMT). However, the relationship between C3a/C3aR and the NLRP3 inflammasome in EMT remains unclear. This study aimed to elucidate the roles of C3a/C3aR and the NLRP3 inflammasome involved in TGF-β-induced EMT. METHOD Mouse renal tubular epithelial cells (TCMK-1) were exposed to C3a and TGF-β for 48 h. C3aR antagonist, MCC950, an inhibitor of the NLRP3 inflammasome and PD98059, an inhibitor of ERK signaling, were respectively applied to pretreat the cells at 30 min before C3a and TGF-β administration.The cells were collected for western blot, immunofluorescence staining and ELISA. Unilateral ureteral obstruction (UUO) models were established using male C57BL/6 wild-type (WT) mice and age-matched C3aR-deficient mice. MCC950 was intraperitoneally injected in UUO mice. Kidney samples were collected for immunohistochemistry staining. RESULTS In vitro, C3a synergized with TGF-β to promote EMT and the activation of the NLRP3 inflammasome. Inhibition of C3aR attenuated EMT and the activation of the NLRP3 inflammasome. Inhibition of the NLRP3 inflammasome alleviated EMT but didn't affect the expression of C3aR. Inhibition of ERK signaling inhibited the activation of the NLRP3 inflammasome. In vivo, the expression of IL-1β was significantly higher in UUO mice compared to the sham-operated mice. C3aR deficiency and inhibition of the NLRP3 Inflammasome contributed to decreased IL-1β in UUO mice. CONCLUSION Our data revealed that C3a/C3aR synergies with TGF-β to activate the NLRP3 inflammasome to promote epithelial-mesenchymal transition of renal tubular epithelial cells through ERK signaling, and the way in which C3aR activates the inflammasome is to promote the assembly of the NLRP3 inflammasome.
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Affiliation(s)
- Danyu You
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Kun Nie
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Xiaoting Wu
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Mengjie Weng
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Liyan Yang
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Yi Chen
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Jiong Cui
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Jianxin Wan
- Department of Nephrology, Blood Purification Research Center, The First Affiliated Hospital of Fujian Medical University, Chazhong Road 20, Fuzhou, 350005, China.
- Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
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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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14
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Gibson B, Connelly C, Moldakhmetova S, Sheerin NS. Complement activation and kidney transplantation; a complex relationship. Immunobiology 2023; 228:152396. [PMID: 37276614 DOI: 10.1016/j.imbio.2023.152396] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/24/2023] [Revised: 05/14/2023] [Accepted: 05/15/2023] [Indexed: 06/07/2023]
Abstract
Although kidney transplantation is the best treatment for end stage kidney disease, the benefits are limited by factors such as the short fall in donor numbers, the burden of immunosuppression and graft failure. Although there have been improvements in one-year outcomes, the annual rate of graft loss beyond the first year has not significantly improved, despite better therapies to control the alloimmune response. There is therefore a need to develop alternative strategies to limit kidney injury at all stages along the transplant pathway and so improve graft survival. Complement is primarily part of the innate immune system, but is also known to enhance the adaptive immune response. There is increasing evidence that complement activation occurs at many stages during transplantation and can have deleterious effects on graft outcome. Complement activation begins in the donor and occurs again on reperfusion following a period of ischemia. Complement can contribute to the development of the alloimmune response and may directly contribute to graft injury during acute and chronic allograft rejection. The complexity of the relationship between complement activation and allograft outcome is further increased by the capacity of the allograft to synthesise complement proteins, the contribution complement makes to interstitial fibrosis and complement's role in the development of recurrent disease. The better we understand the role played by complement in kidney transplant pathology the better placed we will be to intervene. This is particularly relevant with the rapid development of complement therapeutics which can now target different the different pathways of the complement system. Combining our basic understanding of complement biology with preclinical and observational data will allow the development and delivery of clinical trials which have best chance to identify any benefit of complement inhibition.
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Affiliation(s)
- B Gibson
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK
| | - C Connelly
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK
| | - S Moldakhmetova
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK
| | - N S Sheerin
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK.
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15
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Labib HS, Salman MI, Halim MI, Fawaz SI. Apoptosis in lupus nephritis patients: a study of Bcl-2 to assess glomerular and tubular damage. EGYPTIAN RHEUMATOLOGY AND REHABILITATION 2023. [DOI: 10.1186/s43166-023-00186-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 03/28/2023] Open
Abstract
Abstract
Background
Systemic lupus erythematosus (SLE) is an immune-mediated disease, due to exposure of self-antigens, through impairment of apoptosis and failure of lymphocytic tolerance. Impaired regulation of the pro- and anti-apoptotic gene products which coordinate programmed cell death may result in autoreactive B and T cells and autoimmunity. Genetically engineered mice that over-express the anti-apoptotic molecule Bcl-2, B cell lymphoma 2 (Bcl2) in B-lymphocytes advance a lupus-like illness. Lupus nephritis (LN) is one of the most serious manifestations of this autoimmune disorder. Glomerulonephritis (GN) is caused by either impaired regulation of apoptosis and/or clearance of apoptotic cells leading to a T cell-mediated autoimmune reaction with initiation of pathological immune complex deposits.
Objective
To evaluate the correlation between Bcl2 glomerular and tubular expression and pathological findings and laboratory data in different types of SLE GN.
Results
Compared to the control group, patients with lupus nephritis have significantly higher glomerular, interstitial and tubular expression level (P value < 0.001). BCL2 expression was positively correlated with serum anti-ds-DNA, urine 24-h protein and with the chronicity index. All LN patients had significant glomerular, interstitial and tubular deposits of BCL2, P value < 0.001, P value 0.004, and P value 0.03, respectively.
Conclusion
The intrinsic pathway of apoptosis interferes not only with the pathogenesis of lupus glomerulonephritis but also interferes with the pathogenesis of tubulointerstitial lupus nephritis. tubulointerstitial lesions may not only be a result of glomerular injury but also a significant factor in lupus nephritis.
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You D, Weng M, Wu X, Nie K, Cui J, Chen Y, Yang L, Wan J. C3aR contributes to unilateral ureteral obstruction-induced renal interstitial fibrosis via the activation of the NLRP3 inflammasome. Life Sci 2022; 308:120905. [PMID: 36041502 DOI: 10.1016/j.lfs.2022.120905] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/06/2022] [Revised: 08/14/2022] [Accepted: 08/18/2022] [Indexed: 11/17/2022]
Abstract
AIMS Complement component 3a and its receptor (C3a/C3aR) and nucleotide-binding oligomerization domain-like receptor protein-3 (NLRP3) inflammasome are involved in the pathogenesis of renal interstitial fibrosis (RIF). However, the mechanisms have not been clearly illuminated. This study aimed to elucidate the roles of C3aR and the NLRP3 inflammasome involved in unilateral ureteral obstruction (UUO)-induced renal interstitial fibrosis. MAIN METHODS UUO models were established using male C57BL/6 wild-type (WT) mice and age-matched C3aR-deficient mice. MCC950, an inhibitor of the NLRP3 inflammasome, was intraperitoneally injected in UUO mice. Blood samples were collected to quantify serum creatinine and urea. Kidney samples were collected for hematoxylin-eosin (HE), Masson, and immunohistochemistry staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, and Western blotting. KEY FINDINGS Renal function, renal fibrosis, and renal inflammation in WT mice were aggravated with longer periods of UUO. C3aR deficiency improved renal function and attenuated renal fibrosis and the activation of the NLRP3 inflammasome in UUO mice. Renal function and renal fibrosis in UUO mice were attenuated after NLRP3 inflammasome inhibition; however, the expression of C3aR did not change. SIGNIFICANCE Our data revealed that C3aR may aggravate RIF by regulating the activation of the NLRP3 inflammasome (particularly regulating inflammasome assembly) in renal tubular epithelial cells in the UUO model.
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Affiliation(s)
- Danyu You
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Mengjie Weng
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Xiaoting Wu
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Kun Nie
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Jiong Cui
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Yi Chen
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Liyan Yang
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Jianxin Wan
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Clinical Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
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Llorián-Salvador M, Byrne EM, Szczepan M, Little K, Chen M, Xu H. Complement activation contributes to subretinal fibrosis through the induction of epithelial-to-mesenchymal transition (EMT) in retinal pigment epithelial cells. J Neuroinflammation 2022; 19:182. [PMID: 35831910 PMCID: PMC9447479 DOI: 10.1186/s12974-022-02546-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/09/2021] [Accepted: 06/22/2022] [Indexed: 11/16/2022] Open
Abstract
Background We previously reported higher plasma levels of complement fragments C3a and C5a in neovascular Age-related Macular Degeneration (nAMD) patients with macular fibrosis. This study aimed to understand whether complement activation contributes to the development of macular fibrosis and the underlying mechanisms involved. Methods Complement activation was blocked using a C5 neutralizing antibody (BB5.1) in C57BL/6J mice after induction of subretinal fibrosis using the two-stage laser protocol. Fibrotic lesions were examined 10 days after the 2nd laser through fundus examination and immunohistochemistry. The expression of C5aR in fibrotic lesions and retinal pigment epithelial (RPE) cultures were examined by confocal microscopy. Primary murine RPE cells were treated with C3a or C5a (10–100 ng/mL) or TGF-β2 (10 ng/mL). Epithelial-to-mesenchymal transition (EMT) was assessed through various readouts. The expression of E-cadherin, vimentin, fibronectin, α-SMA, Slug, ERK/AKT and pSMAD2/3 were determined by Western blot and immunocytochemistry. Collagen contraction and wound-healing assays were used as functional readouts of EMT. The production of IL-6, TGF-β1, TGF-β2 and VEGF by RPE cells were determined by ELISA. PMX53 was used to block C5aR in RPE cultures and in vivo in mice with subretinal fibrosis. Results Extensive C5b-9 deposition was detected at the site of subretinal fibrosis. BB5.1 treatment completely abrogated complement activation and significantly reduced subretinal fibrosis. C5aR was detected in RPE and infiltrating MHC-II+ cells in subretinal fibrosis. In vitro, RPE cells constitutively express C5/C5a and C5aR, and their expression was increased by TGF-β2 treatment. C5a but not C3a increased fibronectin, α-SMA, vimentin and Slug expression, and decreased E-cadherin expression in RPE cells. C5a treatment also increased the contractility and migration of RPE cells and enhanced the production of VEGF and TGF-β1/2. C5a treatment induced pSmad2/3 and pERK1/2 expression in RPE cells and this was blocked by PMX53. PMX53 treatment significantly reduced sodium fluorescein leakage in the subretinal fibrosis model, while collagen-I+ lesions only mildly reduced. Conclusions Complement activation is critically involved in the development of subretinal fibrosis, partially through C5a–C5aR-mediated EMT in RPE cells. Targeting complement activation rather than C5a may be a novel approach for the management of macular fibrosis. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02546-3.
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Affiliation(s)
- María Llorián-Salvador
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK.,Vall d´Hebron Research Institute (VHIR), Universitat Autonòma de Barcelona, 08035, Barcelona, Spain
| | - Eimear M Byrne
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK.,Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003, Barcelona, Spain
| | - Manon Szczepan
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK
| | - Karis Little
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK
| | - Mei Chen
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK
| | - Heping Xu
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK.
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18
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Yuan R, Zhong Y, Zeng Y, Zhang J. Correlation between Tubulointerstitial Lesion and Blood Pressure in Lupus Nephritis Patients: A Pathological, Retrospective Study. Kidney Blood Press Res 2022; 47:391-398. [PMID: 35259751 DOI: 10.1159/000523793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/15/2021] [Accepted: 02/23/2022] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE The objective was to study the influence of pathological factors of glomerular lesion (GL), tubulointerstitial lesion (TIL), and arteriosclerotic lesion on the blood pressure (BP) of lupus nephritis (LN). METHODS The pathological data and clinical characteristics of 69 LN patients who underwent their first renal biopsy in Chengdu Second People's Hospital from 2012 to 2018 were retrospectively analyzed. The revised 2018 ISN/RPS classification criteria of LN were used to assess the GL and TIL. The lesion index of interlobar/arcuate artery and arteriolar was calculated. Multiple linear regressions were used to analyze the effects of GL, TIL, and vascular lesion (VL) on estimated glomerular filtration rate, systolic BP (SBP), and proteinuria. RESULTS TIL and VL scores were different between the various grades of BP (p = 0.009, 0.019). After adjusting for gender and age, multiple linear regression showed that only TIL was linearly correlated with SBP (p = 0.022). CONCLUSION After adjusting for gender and age, TIL is related to SBP and has a linear relationship with them.
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Affiliation(s)
- Ruili Yuan
- Department of Hematology and Rheumatology Chengdu Second People's Hospital, Chengdu, China
| | - Yu Zhong
- Department of the Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan Zeng
- Department of Hematology and Rheumatology Chengdu Second People's Hospital, Chengdu, China
| | - Jing Zhang
- Department of Hematology and Rheumatology Chengdu Second People's Hospital, Chengdu, China
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19
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Wang C, Wang Z, Zhang W. The potential role of complement alternative pathway activation in hypertensive renal damage. Exp Biol Med (Maywood) 2022; 247:797-804. [PMID: 35473318 DOI: 10.1177/15353702221091986] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/17/2022] Open
Abstract
Hypertensive renal damage is a common secondary kidney disease caused by poor control of blood pressure. Recent evidence has revealed abnormal activation of the complement alternative pathway (AP) in hypertensive patients and animal models and that this phenomenon is related to hypertensive renal damage. Conditions in the setting of hypertension, including high renin concentration, reduced binding of factor H to the glomerular basement membrane, and abnormal local synthesis of complement proteins, potentially promote the AP activation in the kidney. The products of the AP activation promote the phenotypic transition of mesangial cells and tubular cells, attack endothelial cells and recruit immunocytes to worsen hypertensive renal damage. The effects of complement inhibition on hypertensive renal damage are contradictory. Although clinical data support the use of C5 monoclonal antibody in malignant hypertension, pharmacological inhibition in hypertensive animals provides little benefit to kidney function. Therefore, the role of the complement AP in the pathogenesis of hypertensive renal damage and the value of complement inhibition in hypertensive renal damage treatment must be further explored.
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Affiliation(s)
- Chongjian Wang
- Division of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhiyu Wang
- Division of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wen Zhang
- Division of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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20
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Core fucosylation involvement in the paracrine regulation of proteinuria-induced renal interstitial fibrosis evaluated with the use of a microfluidic chip. Acta Biomater 2022; 142:99-112. [PMID: 35189379 DOI: 10.1016/j.actbio.2022.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/15/2021] [Revised: 02/11/2022] [Accepted: 02/15/2022] [Indexed: 11/23/2022]
Abstract
Proteinuria is a clinical manifestation of chronic kidney disease that aggravates renal interstitial fibrosis (RIF), in which injury of peritubular microvessels is an important event. However, the changes in peritubular microvessels induced by proteinuria and their molecular mechanisms remain unclear. Thus, we aimed to develop a co-culture microfluidic device that contains renal tubules and peritubular microvessels to create a proteinuria model. We found that protein overload in the renal tubule induced trans-differentiation and apoptosis of endothelial cells (ECs) and pericytes. Moreover, profiling of secreted proteins in this model revealed that a paracrine network between tubules and microvessels was activated in proteinuria-induced microvascular injury. Multiple cytokine receptors in this paracrine network were core-fucosylated. Inhibition of core fucosylation significantly reduced ligand-receptor binding ability and blocked downstream pathways, alleviating trans-differentiation and apoptosis of ECs and pericytes. Furthermore, the protective effect of genetic FUT8 deficiency on proteinuria overload-induced RIF and pericyte-myofibroblast trans-differentiation was validated in FUT8 knockout heterozygous mice. In conclusion, we constructed and used a multiple-unit integrated microfluidic device to uncover the mechanism of proteinuria-induced RIF. Furthermore, FUT8 may serve as a hub-like therapeutic target to alleviate peritubular microvascular injury in RIF. STATEMENT OF SIGNIFICANCE: In this study, we constructed a multiple-unit integrated renal tubule-vascular chip. We reproduced human proteinuria on the chip and found that multiple receptors were modified by FUT8-catalyzed core fucosylation (CF) involved in the cross-talk between renal tubules and peritubular microvessels in proteinuria-induced RIF, and inhibiting the FUT8 of receptors could block the tubule-microvessel paracrine network and reverse the damage of peritubular microvessels and renal interstitial fibrosis. This tubule-vascular chip may provide a prospective platform to facilitate future investigations into the mechanisms of kidney diseases, and target-FUT8 inhibition may be an innovative and potential therapeutic strategy for RIF induced by proteinuria.
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21
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Complement C3-targeted therapy in C3 glomerulopathy, a prototype of complement-mediated kidney diseases. Semin Immunol 2022; 60:101634. [PMID: 35817659 DOI: 10.1016/j.smim.2022.101634] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 04/07/2022] [Revised: 06/28/2022] [Accepted: 07/01/2022] [Indexed: 01/15/2023]
Abstract
C3 glomerulopathy (C3G) is a rare and complex kidney disease that primarily affects young adults. Renal outcomes remain poor in the absence of specific treatment. C3G is driven by uncontrolled overactivation of the alternative complement pathway, which is mainly of acquired origin. Functional characterization of complement abnormalities (i.e., autoantibodies targeting complement components and variants in complement genes) identified in patients and experimental models of the disease improved the understanding of the disease, making C3G a prototype of complement-mediated diseases. The contribution of C3 convertase, as well as C5 convertase, in disease occurrence, phenotype, and severity is now well established, offering various potential therapeutic interventions. However, the lack of sufficient efficiency in anti-C5 therapy highlights the extreme complexity of the disease and the need for new therapeutic approaches based on C3 and C3 convertase axis inhibition. Here, we provide an overview of the complement activation mechanism involved in C3G and discuss therapeutic options based on complement inhibitors, with a specific focus on C3 inhibition.
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22
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Qi R, Qin W. Role of Complement System in Kidney Transplantation: Stepping From Animal Models to Clinical Application. Front Immunol 2022; 13:811696. [PMID: 35281019 PMCID: PMC8913494 DOI: 10.3389/fimmu.2022.811696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/09/2021] [Accepted: 01/31/2022] [Indexed: 12/23/2022] Open
Abstract
Kidney transplantation is a life-saving strategy for patients with end-stage renal diseases. Despite the advances in surgical techniques and immunosuppressive agents, the long-term graft survival remains a challenge. Growing evidence has shown that the complement system, part of the innate immune response, is involved in kidney transplantation. Novel insights highlighted the role of the locally produced and intracellular complement components in the development of inflammation and the alloreactive response in the kidney allograft. In the current review, we provide the updated understanding of the complement system in kidney transplantation. We will discuss the involvement of the different complement components in kidney ischemia-reperfusion injury, delayed graft function, allograft rejection, and chronic allograft injury. We will also introduce the existing and upcoming attempts to improve allograft outcomes in animal models and in the clinical setting by targeting the complement system.
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Affiliation(s)
| | - Weijun Qin
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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23
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Wang W, Sheng L, Chen Y, Li Z, Wu H, Ma J, Zhang D, Chen X, Zhang S. Total coumarin derivates from Hydrangea paniculata attenuate renal injuries in cationized-BSA induced membranous nephropathy by inhibiting complement activation and interleukin 10-mediated interstitial fibrosis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 96:153886. [PMID: 35026512 DOI: 10.1016/j.phymed.2021.153886] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 07/02/2021] [Revised: 11/21/2021] [Accepted: 12/05/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND Total coumarins extracted from Hydrangea. Paniculata, Sieb (HP) have showed renal protective effect in several experimental acute and chronic kidney diseases. PURPOSE The aim of current study is to evaluate renal protective effect of HP against cationized-BSA (c-BSA) induced experimental membranous nephritis (MN), and further investigate its underlying mechanisms. METHODS Rat MN model was established by intravenous injection of 5 mg c-BSA for consecutive 14 days, and after albuminuria confirmed, HP was orally administrated with 7.5, 15, 30 mg/kg for nine weeks. The renal function was measured and histopathological injuries were observed. RNA sequencing was used to analyze the altered signaling pathways in kidneys. Pharmacokinetics was performed to investigate the pharmacodynamics of major ingredients in HP and possible metabolites. Discover X platform helped to clarify the possible molecular mechanisms of major compound in HP. RESULTS HP administration could significantly improve the renal function, and ameliorate the dyslipidemia and histopathological injuries. mRNA sequencing demonstrated that HP had anti-inflammation and anti-fibrosis effects possible through down-regulating the complement activation and PI3K-AKT pathways. Pharmacokinetics demonstrated that skimmin and 7-hydoxycoumarin (7-HC) were major compound or metabolite in plasma after oral administration. Based on Discover X platform, we confirmed that skimmin and 7-HC inhibited the IL10 production by inflammatory macrophages through blocking PI3K-AKT and NFκB signaling pathways. Finally, we demonstrated that HP protected tubulointerstitium from complement attack by reducing the C3 self-production and auto-cleavage in tubular cells. CONCLUSIONS HP has a renal protective effect, and its drug development may provide one alternative strategy to treat immune-mediated nephropathy.
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Affiliation(s)
- Weida Wang
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China
| | - Li Sheng
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China
| | - Yuanyuan Chen
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China
| | - Zhaojun Li
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China
| | - Haijie Wu
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China
| | - Jie Ma
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China
| | - Dongming Zhang
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China
| | - Xiaoguang Chen
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China.
| | - Sen Zhang
- State key laboratory of bioactive substances and functions of natural medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, 100050, P.R. China.
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24
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Zhao L, Zhang Y, Liu F, Yang H, Zhong Y, Wang Y, Li S, Su Q, Tang L, Bai L, Ren H, Zou Y, Wang S, Zheng S, Xu H, Li L, Zhang J, Chai Z, Cooper ME, Tong N. Urinary complement proteins and risk of end-stage renal disease: quantitative urinary proteomics in patients with type 2 diabetes and biopsy-proven diabetic nephropathy. J Endocrinol Invest 2021; 44:2709-2723. [PMID: 34043214 PMCID: PMC8572220 DOI: 10.1007/s40618-021-01596-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 01/27/2021] [Accepted: 05/18/2021] [Indexed: 02/05/2023]
Abstract
PURPOSE To investigate the association between urinary complement proteins and renal outcome in biopsy-proven diabetic nephropathy (DN). METHODS Untargeted proteomic and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses and targeted proteomic analysis using parallel reaction-monitoring (PRM)-mass spectrometry was performed to determine the abundance of urinary complement proteins in healthy controls, type 2 diabetes mellitus (T2DM) patients, and patients with T2DM and biopsy-proven DN. The abundance of each urinary complement protein was individually included in Cox proportional hazards models for predicting progression to end-stage renal disease (ESRD). RESULTS Untargeted proteomic and functional analysis using the KEGG showed that differentially expressed urinary proteins were primarily associated with the complement and coagulation cascades. Subsequent urinary complement proteins quantification using PRM showed that urinary abundances of C3, C9, and complement factor H (CFAH) correlated negatively with annual estimated glomerular filtration rate (eGFR) decline, while urinary abundances of C5, decay-accelerating factor (DAF), and CD59 correlated positively with annual rate of eGFR decline. Furthermore, higher urinary abundance of CFAH and lower urinary abundance of DAF were independently associated with greater risk of progression to ESRD. Urinary abundance of CFAH and DAF had a larger area under the curve (AUC) than that of eGFR, proteinuria, or any pathological parameter. Moreover, the model that included CFAH or DAF had a larger AUC than that with only clinical or pathological parameters. CONCLUSION Urinary abundance of complement proteins was significantly associated with ESRD in patients with T2DM and biopsy-proven DN, indicating that therapeutically targeting the complement pathway may alleviate progression of DN.
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Affiliation(s)
- L Zhao
- Division of Nephrology, Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
- Division of General Practice, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Y Zhang
- Key Laboratory of Transplant Engineering and Immunology, MOH, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
- West China-Washington Mitochondria and Metabolism Research Center, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
| | - F Liu
- Division of Nephrology, Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China.
- Division of General Practice, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
- Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
| | - H Yang
- Key Laboratory of Transplant Engineering and Immunology, MOH, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China.
- West China-Washington Mitochondria and Metabolism Research Center, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China.
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China.
| | - Y Zhong
- Key Laboratory of Transplant Engineering and Immunology, MOH, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
- West China-Washington Mitochondria and Metabolism Research Center, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
| | - Y Wang
- Division of Nephrology, Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
- Division of General Practice, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - S Li
- Division of General Practice, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Q Su
- Division of General Practice, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - L Tang
- Histology and Imaging Platform, Core Facility of West China Hospital, Chengdu, Sichuan, China
| | - L Bai
- Histology and Imaging Platform, Core Facility of West China Hospital, Chengdu, Sichuan, China
| | - H Ren
- Division of Nephrology, Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
- Division of General Practice, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Y Zou
- Division of Nephrology, Laboratory of Diabetic Kidney Disease, Centre of Diabetes and Metabolism Research, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
- Division of General Practice, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - S Wang
- Key Laboratory of Transplant Engineering and Immunology, MOH, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
- West China-Washington Mitochondria and Metabolism Research Center, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
| | - S Zheng
- Key Laboratory of Transplant Engineering and Immunology, MOH, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
- West China-Washington Mitochondria and Metabolism Research Center, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
- Frontiers Science Center for Disease-Related Molecular Network, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
| | - H Xu
- Division of Pathology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - L Li
- Division of Pathology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - J Zhang
- Histology and Imaging Platform, Core Facility of West China Hospital, Chengdu, Sichuan, China
| | - Z Chai
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
| | - M E Cooper
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
| | - N Tong
- Division of Endocrinology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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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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26
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Howard MC, Nauser CL, Farrar CA, Sacks SH. Complement in ischaemia-reperfusion injury and transplantation. Semin Immunopathol 2021; 43:789-797. [PMID: 34757496 PMCID: PMC8579729 DOI: 10.1007/s00281-021-00896-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/04/2021] [Accepted: 09/22/2021] [Indexed: 01/08/2023]
Abstract
Until recently, the only known condition in which complement could mediate transplant injury was the rare occurrence of antibody-mediated rejection, in which the original concept of antibody immunity against the transplant was supported by complementary proteins present in the serum. This has changed within the last two decades because of evidence that the processes of ischaemia–reperfusion injury followed by T cell–mediated rejection are also critically dependent on components generated by the complement system. We now have a clearer understanding of the complement triggers and effectors that mediate injury, and a detailed map of their local sites of production and activation in the kidney. This is providing helpful guidelines as to how these harmful processes that restrict transplant outcomes can be targeted for therapeutic benefit. Here we review some of the recent advances highlighting relevant therapeutic targets.
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Affiliation(s)
- Mark C Howard
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
| | - Christopher L Nauser
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK
| | - Conrad A Farrar
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK
| | - Steven H Sacks
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK
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Chinchilla B, Fernandez-Godino R. AMD-Like Substrate Causes Epithelial Mesenchymal Transition in iPSC-Derived Retinal Pigment Epithelial Cells Wild Type but Not C3-Knockout. Int J Mol Sci 2021; 22:ijms22158183. [PMID: 34360950 PMCID: PMC8348968 DOI: 10.3390/ijms22158183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/02/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 11/16/2022] Open
Abstract
The Bruch's membrane (BrM) is a five-layered extracellular matrix (ECM) that supports the retinal pigment epithelium (RPE). Normal age-related changes in the BrM may lead to RPE cell damage and ultimately to the onset and progression of age-related macular degeneration (AMD), which is the most common cause of visual loss among the elderly. A role for the complement system in AMD pathology has been established, but the disease mechanisms are poorly understood, which hampers the design of efficient therapies to treat millions of patients. In an effort to identify the mechanisms that lead from normal aging to pathology, we have developed a cell-based model using complement deficient human induced pluripotent stem cell (iPSC)-derived RPE cells cultured on an AMD-like ECM that mimics BrM. The data present evidence that changes in the ECM result in loss of differentiation and promote epithelial mesenchymal transition (EMT) of healthy RPE cells. This pathological process is mediated by complement activation and involves the formation of a randomly oriented collagen meshwork that drives the dedifferentiation of the RPE monolayer. Genetic ablation of complement component 3 has a protective effect against EMT but does not prevent the abnormal deposition of collagens. These findings offer new insights into the sequence of events that initiate AMD and may guide the design of efficient therapies to treat this disease with unmet medical needs.
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Portilla D, Xavier S. Role of intracellular complement activation in kidney fibrosis. Br J Pharmacol 2021; 178:2880-2891. [PMID: 33555070 DOI: 10.1111/bph.15408] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/11/2020] [Revised: 01/22/2021] [Accepted: 02/02/2021] [Indexed: 02/06/2023] Open
Abstract
Increased expression of complement C1r, C1s and C3 in kidney cells plays an important role in the pathogenesis of kidney fibrosis. Our studies suggest that activation of complement in kidney cells with increased generation of C3 and its fragments occurs by activation of classical and alternative pathways. Single nuclei RNA sequencing studies in kidney tissue from unilateral ureteral obstruction mice show that increased synthesis of complement C3 and C5 occurs primarily in renal tubular epithelial cells (proximal and distal), while increased expression of complement receptors C3ar1 and C5ar1 occurs in interstitial cells including immune cells like monocytes/macrophages suggesting compartmentalization of complement components during kidney injury. Although global deletion of C3 and macrophage ablation prevent inflammation and reduced kidney tissue scarring, the development of mice with cell-specific deletion of complement components and their regulators could bring further insights into the mechanisms by which intracellular complement activation leads to fibrosis and progressive kidney disease. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.
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Affiliation(s)
- Didier Portilla
- Department of Medicine and Center for Immunity and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Sandhya Xavier
- Department of Medicine and Center for Immunity and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, USA
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Little K, Llorián-Salvador M, Tang M, Du X, Marry S, Chen M, Xu H. Macrophage to myofibroblast transition contributes to subretinal fibrosis secondary to neovascular age-related macular degeneration. J Neuroinflammation 2020; 17:355. [PMID: 33239022 PMCID: PMC7690191 DOI: 10.1186/s12974-020-02033-7] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/14/2020] [Accepted: 11/11/2020] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Macular fibrosis causes irreparable vision loss in neovascular age-related macular degeneration (nAMD) even with anti-vascular endothelial growth factor (VEGF) therapy. Inflammation is known to play an important role in macular fibrosis although the underlying mechanism remains poorly defined. The aim of this study was to understand how infiltrating macrophages and complement proteins may contribute to macular fibrosis. METHODS Subretinal fibrosis was induced in C57BL/6J mice using the two-stage laser protocol developed by our group. The eyes were collected at 10, 20, 30 and 40 days after the second laser and processed for immunohistochemistry for infiltrating macrophages (F4/80 and Iba-1), complement components (C3a and C3aR) and fibrovascular lesions (collagen-1, Isolectin B4 and α-SMA). Human retinal sections with macular fibrosis were also used in the study. Bone marrow-derived macrophages (BMDMs) from C57BL/6J mice were treated with recombinant C3a, C5a or TGF-β for 48 and 96 h. qPCR, Western blot and immunohistochemistry were used to examine the expression of myofibroblast markers. The involvement of C3a-C3aR pathway in macrophage to myofibroblast transition (MMT) and subretinal fibrosis was further investigated using a C3aR antagonist (C3aRA) and a C3a blocking antibody in vitro and in vivo. RESULTS Approximately 20~30% of F4/80+ (or Iba-1+) infiltrating macrophages co-expressed α-SMA in subretinal fibrotic lesions both in human nAMD eyes and in the mouse model. TGF-β and C3a, but not C5a treatment, significantly upregulated expression of α-SMA, fibronectin and collagen-1 in BMDMs. C3a-induced upregulation of α-SMA, fibronectin and collagen-1 in BMDMs was prevented by C3aRA treatment. In the two-stage laser model of induced subretinal fibrosis, treatment with C3a blocking antibody but not C3aRA significantly reduced vascular leakage and Isolectin B4+ lesions. The treatment did not significantly alter collagen-1+ fibrotic lesions. CONCLUSIONS MMT plays a role in macular fibrosis secondary to nAMD. MMT can be induced by TGF-β and C3a but not C5a. Further research is required to fully understand the role of MMT in macular fibrosis. Macrophage to myofibroblast transition (MMT) contributes to subretinal fibrosis. Subretinal fibrosis lesions contain various cell types, including macrophages and myofibroblasts, and are fibrovascular. Myofibroblasts are key cells driving pathogenic fibrosis, and they do so by producing excessive amount of extracellular matrix proteins. We have found that infiltrating macrophages can transdifferentiate into myofibroblasts, a phenomenon termed macrophage to myofibroblast transition (MMT) in macular fibrosis. In addition to TGF-β1, C3a generated during complement activation in CNV can also induce MMT contributing to macular fibrosis. RPE = retinal pigment epithelium. BM = Bruch's membrane. MMT = macrophage to myofibroblast transition. TGFB = transforming growth factor β. a-SMA = alpha smooth muscle actin. C3a = complement C3a.
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Affiliation(s)
- Karis Little
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Maria Llorián-Salvador
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Miao Tang
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Xuan Du
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Stephen Marry
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Mei Chen
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Heping Xu
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK.
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Gao S, Cui Z, Zhao MH. The Complement C3a and C3a Receptor Pathway in Kidney Diseases. Front Immunol 2020; 11:1875. [PMID: 32973774 PMCID: PMC7461857 DOI: 10.3389/fimmu.2020.01875] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/26/2020] [Accepted: 07/13/2020] [Indexed: 12/23/2022] Open
Abstract
The pathogenesis of some kidney diseases is closely associated with complement activation, where the C3a/C3a receptor (C3aR) might play a crucial role. C3a/C3aR has dual roles and may exert anti-inflammatory or pro-inflammatory effects depending on different cell types and diseases. In the kidneys, C3aR is primarily expressed on the tubular epithelium and less in glomerular podocytes. C3aR expression is enhanced and the levels of C3a in the plasma and urine are increased in kidney diseases of several types, and are associated with disease progression and severity. The C3a/C3aR pathway facilitates the progression of glomerular and tubulointerstitial diseases, while it has opposite effects on urinary tract infections. Clinical trials targeting C3a/C3aR in kidney diseases are lacking. Here, we reviewed the studies on the C3a/C3aR pathway in kidney disease, with the aim of understanding in-depth its controversial roles and its potential therapeutic value.
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Affiliation(s)
- Shuang Gao
- Renal Division, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China
| | - Zhao Cui
- Renal Division, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China
| | - Ming-Hui Zhao
- Renal Division, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
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31
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Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction. Int J Mol Sci 2020; 21:ijms21155404. [PMID: 32751357 PMCID: PMC7432796 DOI: 10.3390/ijms21155404] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/02/2020] [Revised: 07/22/2020] [Accepted: 07/27/2020] [Indexed: 02/06/2023] Open
Abstract
New biomarkers of early and late graft dysfunction are needed in renal transplant to improve management of complications and prolong graft survival. A wide range of potential diagnostic and prognostic biomarkers, measured in different biological fluids (serum, plasma, urine) and in renal tissues, have been proposed for post-transplant delayed graft function (DGF), acute rejection (AR), and chronic allograft dysfunction (CAD). This review investigates old and new potential biomarkers for each of these clinical domains, seeking to underline their limits and strengths. OMICs technology has allowed identifying many candidate biomarkers, providing diagnostic and prognostic information at very early stages of pathological processes, such as AR. Donor-derived cell-free DNA (ddcfDNA) and extracellular vesicles (EVs) are further promising tools. Although most of these biomarkers still need to be validated in multiple independent cohorts and standardized, they are paving the way for substantial advances, such as the possibility of accurately predicting risk of DGF before graft is implanted, of making a “molecular” diagnosis of subclinical rejection even before histological lesions develop, or of dissecting etiology of CAD. Identification of “immunoquiescent” or even tolerant patients to guide minimization of immunosuppressive therapy is another area of active research. The parallel progress in imaging techniques, bioinformatics, and artificial intelligence (AI) is helping to fully exploit the wealth of information provided by biomarkers, leading to improved disease nosology of old entities such as transplant glomerulopathy. Prospective studies are needed to assess whether introduction of these new sets of biomarkers into clinical practice could actually reduce the need for renal biopsy, integrate traditional tools, and ultimately improve graft survival compared to current management.
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32
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Cedzyński M, Świerzko AS. Components of the Lectin Pathway of Complement in Haematologic Malignancies. Cancers (Basel) 2020; 12:E1792. [PMID: 32635486 PMCID: PMC7408476 DOI: 10.3390/cancers12071792] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/09/2020] [Revised: 07/01/2020] [Accepted: 07/02/2020] [Indexed: 12/12/2022] Open
Abstract
The complement system is activated cascadically via three distinct major routes: classical pathway (CP), alternative pathway (AP) or lectin pathway (LP). The unique factors associated with the latter are collectins (mannose-binding lectin, collectin-10, collectin-11), ficolins (ficolin-1, ficolin-2, ficolin-3) and proteins of the mannose-binding lectin-associated serine protease (MASP) family (MASP-1, MASP-2, MASP-3, MAp19, MAp44). Collectins and ficolins are both pattern-recognising molecules (PRM), reactive against pathogen-associated molecular patterns (PAMP) or danger-associated molecular patterns (DAMP). The MASP family proteins were first discovered as complexes with mannose-binding lectin (MBL) and therefore named MBL-associated serine proteases, but later, they were found to interact with ficolins, and later still, collectin-10 and collectin-11. As well as proteolytic enzymes (MASP-1, MASP-2, MASP-3), the group includes non-enzymatic factors (MAp19, MAp44). In this review, the association-specific factors of the lectin pathway with haematologic malignancies and related infections are discussed.
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Affiliation(s)
- Maciej Cedzyński
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 92-232 Łódź, Poland;
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Rayego-Mateos S, Valdivielso JM. New therapeutic targets in chronic kidney disease progression and renal fibrosis. Expert Opin Ther Targets 2020; 24:655-670. [PMID: 32338087 DOI: 10.1080/14728222.2020.1762173] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The current therapeutic armamentarium to prevent chronic kidney disease (CKD) progression is limited to the control of blood pressure and in diabetic patients, the strict control of glucose levels. Current research is primarily focused on the reduction of inflammation and fibrosis at different levels. AREAS COVERED This article examines the latest progress in this field and places an emphasis on inflammation, oxidative stress, and fibrosis. New therapeutic targets are described and evidence from experimental and clinical studies is summarized. We performed a search in Medline for articles published over the last 10 years. EXPERT OPINION The search for therapeutic targets of renal inflammation is hindered by an incomplete understanding of the pathophysiology. The determination of the specific inducers of inflammation in the kidney is an area of heightened potential. Prevention of the progression of renal fibrosis by blocking TGF-β signaling has been unsuccessful, but the investigation of signaling pathways involved in late stages of fibrosis progression could yield improved results. Preventive strategies such as the modification of microbiota-inducers of uremic toxins involved in CKD progression is a promising field because of the interaction between the gut microbiota and the renal system.
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Affiliation(s)
- Sandra Rayego-Mateos
- Red De Investigación Renal (Redinren) , Spain.,Vascular and Renal Translational Research Group, Institut De Recerca Biomèdica De Lleida IRBLleida , Lleida, Spain
| | - Jose M Valdivielso
- Red De Investigación Renal (Redinren) , Spain.,Vascular and Renal Translational Research Group, Institut De Recerca Biomèdica De Lleida IRBLleida , Lleida, Spain
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34
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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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35
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Gill RG, Lin CM. Linking innate immunity and chronic antibody-mediated allograft rejection. Curr Opin Organ Transplant 2020; 24:694-698. [PMID: 31599762 DOI: 10.1097/mot.0000000000000708] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW To summarize recent findings linking donor-specific antibodies with innate immunity resulting in chronic allograft rejection. RECENT FINDINGS Studies in recent years highlight the significance of donor-specific antibodies (DSA) in both acute and chronic allograft rejection. Since chronic rejection is the leading cause of graft failure, this review centers on the contribution of three areas of innate immunity of particular recent focus: complement, NK cells, and macrophages. Recent advances indicate the diverse roles that complement components play both in directly initiating allograft injury and indirectly by contributing to enhanced alloreactivity. NK cells also have emerged as an additional innate response that directly links DSA with chronic graft injury. Finally, recent studies identify alternatively activated macrophages as an additional arm of innate immunity contributing to chronic allograft rejection. SUMMARY Chronic allograft rejection involves a significant contribution of DSA and differing pathways of the innate immune system. However, key issues remain unresolved. First, it is not always clear which of these varied sources of innate immunity contributing to chronic rejection may be antibody dependent. Moreover, it is not yet clear if these innate pathways represent independent routes that contribute to chronic rejection or rather act in concert to mediate allograft injury.
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Affiliation(s)
- Ronald G Gill
- Department of Surgery, Division of Transplant, University of Colorado Aurora, Denver, Colorado
| | - Christine M Lin
- Department of Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, University of Florida, Gainesville, Florida, USA
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Świerzko AS, Michalski M, Sokołowska A, Nowicki M, Szala-Poździej A, Eppa Ł, Mitrus I, Szmigielska-Kapłon A, Sobczyk-Kruszelnicka M, Michalak K, Gołos A, Wierzbowska A, Giebel S, Jamroziak K, Kowalski ML, Brzezińska O, Thiel S, Matsushita M, Jensenius JC, Gajek G, Cedzyński M. Associations of Ficolins With Hematological Malignancies in Patients Receiving High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantations. Front Immunol 2020; 10:3097. [PMID: 32047495 PMCID: PMC6997528 DOI: 10.3389/fimmu.2019.03097] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/10/2019] [Accepted: 12/18/2019] [Indexed: 01/08/2023] Open
Abstract
A prospective study of 312 patients [194 with multiple myeloma (MM) and 118 with lymphomas (LYMPH)] receiving high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT) was conducted. Ficolins are innate immune defense factors, able to distinguish between "self" "abnormal self," and "non-self" and contribute to the elimination of the last two by direct opsonization and/or initiation of complement activation via the lectin pathway. Concentrations of ficolin-1, ficolin-2, and ficolin-3 in serially taken serum samples were determined as were the polymorphisms of the corresponding (FCN1, FCN2, and FCN3) genes. Serum samples were collected before conditioning chemotherapy, before HSCT, and once weekly post-HSCT (four to five samples in total); some patients were also sampled at 1 and/or 3 months post-transplantation. The control group (C) consisted of 267 healthy unrelated individuals. Median ficolin-1 and ficolin-2 (but not ficolin-3) levels in MM patients' sera taken before chemotherapy were lower (and correspondingly frequencies of the lowest concentrations were higher) compared with controls. That appeared to be associated with the malignant disease itself rather than with post-HSCT complications (febrile neutropenia, infections accompanied, or not with bacteremia). Higher frequencies of the FCN1 genotype G/A-C/C-G/G (corresponding to polymorphisms at positions -542, -144, and +6658, respectively) and FCN2 gene heterozygosity for the -857 C>A polymorphism were found among patients diagnosed with MM compared with the C group. Furthermore, FCN2 G/G homozygosity (-557 A>G) was found more frequently and heterozygosity G/T at +6424 less frequently among LYMPH patients than among the healthy subjects. Heterozygosity for +1637delC mutation of the FCN3 gene was more common among patients diagnosed with lymphomas who experienced hospital infections. Although no evidence for an association of low ficolin-1 or ficolin-2 with infections during neutropenia following chemotherapy before HSCT was found, we observed a possible protective effect of ficolins during follow-up.
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Affiliation(s)
- Anna S. Świerzko
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Łódz, Poland
| | - Mateusz Michalski
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Łódz, Poland
| | - Anna Sokołowska
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Łódz, Poland
| | - Mateusz Nowicki
- Department of Hematology, Comprehensive Cancer Center and Traumatology, Copernicus Memorial Hospital, Łódz, Poland
| | - Agnieszka Szala-Poździej
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Łódz, Poland
| | - Łukasz Eppa
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Łódz, Poland
| | - Iwona Mitrus
- Department of Bone Marrow Transplantation and Oncohematology, Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | | | - Małgorzata Sobczyk-Kruszelnicka
- Department of Bone Marrow Transplantation and Oncohematology, Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Katarzyna Michalak
- Department of Bone Marrow Transplantation and Oncohematology, Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Aleksandra Gołos
- Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | | | - Sebastian Giebel
- Department of Bone Marrow Transplantation and Oncohematology, Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Krzysztof Jamroziak
- Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Marek L. Kowalski
- Department of Immunology and Allergy, Medical University of Łódz, Łódz, Poland
| | - Olga Brzezińska
- Department of Immunology and Allergy, Medical University of Łódz, Łódz, Poland
- Department of Rheumatology, Medical University of Łódz, Łódz, Poland
| | - Steffen Thiel
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Misao Matsushita
- Department of Applied Biochemistry, Tokai University, Hiratsuka, Japan
| | | | - Gabriela Gajek
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Łódz, Poland
| | - Maciej Cedzyński
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Łódz, Poland
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Borceux P, Morelle J, Goffin E. Complement system activation and peritoneal membrane alterations: Culprit or innocent bystander? Perit Dial Int 2020; 40:115-123. [PMID: 32063185 DOI: 10.1177/0896860819896242] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/31/2022] Open
Abstract
Peritoneal dialysis (PD) accounts for approximately 10% of the dialysis population worldwide. Major concern limiting long-term PD success is the loss of the peritoneal membrane function after prolonged exposure to dialysis solutions. The complement system is a major component of the innate immune system, which provides a first-line defense against pathogens. Uncontrolled activation of the complement system directly contributes to the pathophysiology of rare and common kidney diseases and to a growing number of nonrenal diseases. Here, we review currently available evidence of complement activation in patients treated with PD and its association with structural and functional alterations of the peritoneal membrane. Mainly, evidence point toward a local, intraperitoneal, production of complement molecules in response to PD exposure. Dialysis fluids, particularly glucose, play a role in complement activation and dysregulation leading to untoward PD-related pathophysiological processes such as peritoneal fibrosis, angiogenesis, and vasculopathy and, perhaps, encapsulating peritoneal fibrosis development. These findings could lead to further development and use of anticomplement therapeutics in PD patients to prevent membrane damage.
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Affiliation(s)
- Pauline Borceux
- Division of Nephrology, Cliniques universitaires St Luc, Brussels, Belgium.,Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
| | - Johann Morelle
- Division of Nephrology, Cliniques universitaires St Luc, Brussels, Belgium.,Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
| | - Eric Goffin
- Division of Nephrology, Cliniques universitaires St Luc, Brussels, Belgium.,Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
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Duineveld C, Steenbergen EJ, Bomback AS, van de Kar NCAJ, Wetzels JFM. Treatment-resistant nephrotic syndrome in dense deposit disease: complement-mediated glomerular capillary wall injury? Pediatr Nephrol 2020; 35:1791-1795. [PMID: 32447506 PMCID: PMC7384995 DOI: 10.1007/s00467-020-04600-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/05/2020] [Revised: 04/30/2020] [Accepted: 05/04/2020] [Indexed: 01/04/2023]
Abstract
BACKGROUND The C3 glomerulopathies (C3G) are recently defined glomerular diseases, attributed to abnormal complement regulation. Dense deposit disease (DDD) is part of the spectrum of C3G, characterized by electron-dense deposits in the lamina densa of the glomerular basement membrane. Patients with DDD present with hematuria, variable degrees of proteinuria, and kidney dysfunction. Kidney biopsies typically disclose proliferative and inflammatory patterns of injury. Treatment with glucocorticoids and mycophenolate mofetil has been shown to achieve remission of proteinuria in a significant proportion of C3G patients. CASE-DIAGNOSIS/TREATMENT We report two patients with persistent nephrotic syndrome while on immunosuppressive therapy. Repeat kidney biopsies disclosed massive C3 deposits with foot process effacement in the absence of proliferative or inflammatory lesions on light microscopy. CONCLUSION These cases, coupled with data from animal models of disease and the variable response to eculizumab in C3G patients, illustrate that two different pathways might be involved in the development of kidney injury in C3G: a C5-independent pathway leading to glomerular capillary wall injury and the development of proteinuria versus a C5-dependent pathway that causes proliferative glomerulonephritis and kidney dysfunction.
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Affiliation(s)
- Caroline Duineveld
- Department of Nephrology, Radboud University Medical Center, PO BOX 9101, 6500 HB, Nijmegen, Netherlands.
| | - Eric J. Steenbergen
- Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Andrew S. Bomback
- Department of Medicine, Division of Nephrology, Columbia University Medical Center, New York, NY USA
| | - Nicole C. A. J. van de Kar
- Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands
| | - Jack F. M. Wetzels
- Department of Nephrology, Radboud University Medical Center, PO BOX 9101, 6500 HB Nijmegen, Netherlands
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Hata J, Machida T, Matsuoka K, Hoshi S, Akaihata H, Hiraki H, Suzuki T, Ogawa S, Kataoka M, Haga N, Ishibashi K, Homma Y, Sekine H, Kojima Y. Complement activation by autoantigen recognition in the growth process of benign prostatic hyperplasia. Sci Rep 2019; 9:20357. [PMID: 31889151 PMCID: PMC6937285 DOI: 10.1038/s41598-019-57001-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/15/2019] [Accepted: 12/19/2019] [Indexed: 02/02/2023] Open
Abstract
The pathophysiology of benign prostatic hyperplasia (BPH) remained unclear. Here, we concentrated on the complement activation in the growth of BPH using a rat model. BPH tissues were harvested from rats after rat urogenital sinus implantation. The local expression and deposition levels of C1q, C3, mannose-binding lectin (MBL), factor B (FB), and C5b-9 in the rat and human BPH tissues were analyzed by real-time RT-PCR, western blotting and immunohistochemistry (IHC). Serum IgG levels in the rat BPH model were analyzed by ELISA, and IHC was used to assess tissue localization. Proteins binding serum IgG autoantibody in the BPH rats were isolated by immunoprecipitation. C1q, C3, MBL, FB and C5b-9 were highly localized in rat BPH tissues compared to normal tissues. In contrast, C3, FB and C5b-9, but not C1q and MBL, were abundantly detected in human BPH tissues compared to normal tissues. Diffuse localization of IgG in rat BPH tissues was found. Heat shock protein 90, annexin, α-smooth muscle actin, and β-actin were identified as targets for IgG autoantibodies in the BPH model. Our results strongly suggested the role for complement activation in the growth process of BPH, likely triggered by classical pathway activation with autoantibodies.
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Affiliation(s)
- Junya Hata
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.
| | - Takeshi Machida
- Department of Immunology, Fukushima Medical University School of qwMedicine, Fukushima, 960-1295, Japan
| | - Kanako Matsuoka
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan
| | - Seiji Hoshi
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan
| | - Hidenori Akaihata
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan
| | - Hiroyuki Hiraki
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan
| | - Toshiyuki Suzuki
- Department of Biomolecular Science Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan
| | - Soichiro Ogawa
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan
| | - Masao Kataoka
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan
| | - Nobuhiro Haga
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan
| | - Kei Ishibashi
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan
| | - Yoshimi Homma
- Department of Biomolecular Science Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan
| | - Hideharu Sekine
- Department of Immunology, Fukushima Medical University School of qwMedicine, Fukushima, 960-1295, Japan
| | - Yoshiyuki Kojima
- Department of Urology, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan
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40
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Role of complement 3 in the pathogenesis of hypertension. Hypertens Res 2019; 43:255-262. [DOI: 10.1038/s41440-019-0371-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/22/2019] [Revised: 11/08/2019] [Accepted: 11/10/2019] [Indexed: 02/06/2023]
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41
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McCloskey CW, Cook DP, Kelly BS, Azzi F, Allen CH, Forsyth A, Upham J, Rayner KJ, Gray DA, Boyd RW, Murugkar S, Lo B, Trudel D, Senterman MK, Vanderhyden BC. Metformin Abrogates Age-Associated Ovarian Fibrosis. Clin Cancer Res 2019; 26:632-642. [PMID: 31597663 DOI: 10.1158/1078-0432.ccr-19-0603] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/18/2019] [Revised: 06/02/2019] [Accepted: 10/04/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE The ovarian cancer risk factors of age and ovulation are curious because ovarian cancer incidence increases in postmenopausal women, long after ovulations have ceased. To determine how age and ovulation underlie ovarian cancer risk, we assessed the effects of these risk factors on the ovarian microenvironment. EXPERIMENTAL DESIGN Aged C57/lcrfa mice (0-33 months old) were generated to assess the aged ovarian microenvironment. To expand our findings into human aging, we assembled a cohort of normal human ovaries (n = 18, 21-71 years old). To validate our findings, an independent cohort of normal human ovaries was assembled (n = 9, 41-82 years old). RESULTS We first validated the presence of age-associated murine ovarian fibrosis. Using interdisciplinary methodologies, we provide novel evidence that ovarian fibrosis also develops in human postmenopausal ovaries across two independent cohorts (n = 27). Fibrotic ovaries have an increased CD206+:CD68+ cell ratio, CD8+ T-cell infiltration, and profibrotic DPP4+αSMA+ fibroblasts. Metformin use was associated with attenuated CD8+ T-cell infiltration and reduced CD206+:CD68+ cell ratio. CONCLUSIONS These data support a novel hypothesis that unifies the primary nonhereditary ovarian cancer risk factors through the development of ovarian fibrosis and the formation of a premetastatic niche, and suggests a potential use for metformin in ovarian cancer prophylaxis.See related commentary by Madariaga et al., p. 523.
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Affiliation(s)
- Curtis W McCloskey
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - David P Cook
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Brendan S Kelly
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Feryel Azzi
- Institut du Cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, Quebec, Canada.,Department of Pathology and Cellular Biology, Université de Montréal, Montréal, Quebec, Canada
| | | | - Amanda Forsyth
- Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario, Canada
| | - Jeremy Upham
- Department of Physics and School of Electrical Engineering and Computer Science, University of Ottawa, Ottawa, Canada
| | - Katey J Rayner
- University of Ottawa Heart Institute, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, Ottawa, Ontario, Canada
| | - Douglas A Gray
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada
| | - Robert W Boyd
- Department of Physics and School of Electrical Engineering and Computer Science, University of Ottawa, Ottawa, Canada
| | | | - Bryan Lo
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada.,Molecular Oncology Diagnostics Laboratory, Division of Anatomical Pathology, The Ottawa Hospital, Ottawa, Ontario, Canada.,Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Dominique Trudel
- Institut du Cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, Quebec, Canada.,Department of Pathology and Cellular Biology, Université de Montréal, Montréal, Quebec, Canada
| | - Mary K Senterman
- Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario, Canada.,Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Barbara C Vanderhyden
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada. .,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
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Abstract
The current immunosuppressive protocols used in transplant recipients have improved short-term outcomes, but long-term allograft failure remains an important clinical problem. Greater understanding of the immunologic mechanisms that cause allograft failure are needed, as well as new treatment strategies for protecting transplanted organs. The complement cascade is an important part of the innate immune system. Studies have shown that complement activation contributes to allograft injury in several clinical settings, including ischemia/reperfusion injury and antibody mediated rejection. Furthermore, the complement system plays critical roles in modulating the responses of T cells and B cells to antigens. Therapeutic complement inhibitors, therefore, may be effective for protecting transplanted organs from several causes of inflammatory injury. Although several anti-complement drugs have shown promise in selected patients, the role of these drugs in transplantation medicine requires further study.
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Affiliation(s)
- Monica Grafals
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
| | - Joshua M Thurman
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
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Alghadban S, Kenawy HI, Dudler T, Schwaeble WJ, Brunskill NJ. Absence of the Lectin Activation Pathway of Complement Ameliorates Proteinuria-Induced Renal Injury. Front Immunol 2019; 10:2238. [PMID: 31608060 PMCID: PMC6768126 DOI: 10.3389/fimmu.2019.02238] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/12/2019] [Accepted: 09/04/2019] [Indexed: 12/15/2022] Open
Abstract
Proteinuria is an adverse prognostic feature in renal diseases. In proteinuric nephropathies, filtered proteins exert an injurious effect on the renal tubulointerstitium, resulting in inflammation and fibrosis. In the present study, we assessed to what extent complement activation via the lectin pathway may contribute to renal injury in response to proteinuria-related stress in proximal tubular cells. We used the well-established mouse model of protein overload proteinuria (POP) to assess the effect of lectin pathway inhibition on renal injury and fibrotic changes characteristic of proteinuric nephropathy. To this end, we compared experimental outcomes in wild type mice with MASP-2-deficient mice or wild type mice treated with MASP-2 inhibitor to block lectin pathway functional activity. Multiple markers of renal injury were assessed including renal function, proteinuria, macrophage infiltration, and cytokine release profiles. Both MASP-2-deficient and MASP-2 inhibitor-treated wild type mice exhibited renoprotection from proteinuria with significantly less tubulointerstitial injury when compared to isotype control antibody treated mice. This indicates that therapeutic targeting of MASP-2 in proteinuric nephropathies may offer a useful strategy in the clinical management of proteinuria associated pathologies in a variety of different underlying renal diseases.
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Affiliation(s)
- Samy Alghadban
- Department of Infection, Immunity and Inflammation, College of Life Sciences, University of Leicester, Leicester, United Kingdom.,Zoology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt
| | - Hany I Kenawy
- Department of Infection, Immunity and Inflammation, College of Life Sciences, University of Leicester, Leicester, United Kingdom.,Microbiology and Immunology Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | | | - Wilhelm J Schwaeble
- Department of Infection, Immunity and Inflammation, College of Life Sciences, University of Leicester, Leicester, United Kingdom.,Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Nigel J Brunskill
- Department of Infection, Immunity and Inflammation, College of Life Sciences, University of Leicester, Leicester, United Kingdom.,Department of Nephrology, Leicester General Hospital, Leicester, United Kingdom
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Complement Activation in Progression of Chronic Kidney Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1165:423-441. [PMID: 31399977 DOI: 10.1007/978-981-13-8871-2_20] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 12/15/2022]
Abstract
Chronic kidney disease (CKD) is a public health problem worldwide, with increasing incidence and prevalence. The mechanisms underlying the progression to end-stage renal disease (ESRD) is not fully understood. The complement system was traditionally regarded as an important part of innate immunity required for host protection against infection and for maintaining host hemostasis. However, compelling evidence from both clinical and experimental studies has strongly incriminated complement activation as a pivotal pathogenic mediator of the development of multiple renal diseases and progressive replacement of functioning nephrons by fibrosis. Both anaphylatoxins, i.e., C3a and C5a, and membrane attack complex (MAC) contribute to the damage that occurs during chronic renal progression through various mechanisms including direct proinflammatory and fibrogenic activity, chemotactic effect, activation of the renal renin-angiotensin system, and enhancement of T-cell immunity. Evolving understanding of the mechanisms of complement-mediated renal injury has led to the emergence of complement-targeting therapeutics. A variety of specific antibodies and inhibitors targeting complement components have shown efficacy in reducing disease in animal models. Moreover, building on these advances, targeting complement has gained encouraging success in treating patients with renal diseases such as atypical hemolytic uremic syndrome (aHUS). Nevertheless, it still requires a great deal of effort to develop inhibitors that can be applied to treat more patients effectively in routine clinical practice.
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45
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Zheng J, Jiang Z, Chen D, Wang S, Zhao W, Li L. Pathological significance of urinary complement activation in diabetic nephropathy: A full view from the development of the disease. J Diabetes Investig 2019; 10:738-744. [PMID: 30239170 PMCID: PMC6497774 DOI: 10.1111/jdi.12934] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 05/09/2018] [Revised: 08/30/2018] [Accepted: 09/17/2018] [Indexed: 12/13/2022] Open
Abstract
AIMS/INTRODUCTION The aim of the present study was to obtain a full view of the changes of urinary complement activation products in the development of diabetic nephropathy and explore their possible significance in the disease process. MATERIALS AND METHODS A total of 62 patients at different stages of diabetic nephropathy, 20 diabetes patients without nephropathy and 20 healthy persons were enrolled. Urinary complement activation products, including C3a, C5a and C5b-9, were measured, and their associations with the progression of the disease were analyzed. RESULTS The urinary complement activation products increased markedly since the proteinuria stage, and were parallel with the progression of diabetic nephropathy. More severe renal tubular damage was observed in patients with higher levels of urinary complement activation products. The urinary complement activation products levels correlated closely with renal tubulointerstitial injury score and relative tubular interstitial volume. Multivariate regression analysis showed that elevated urinary complement activation products were independent risk factors for tubular injury in diabetic nephropathy patients. CONCLUSIONS Urinary complement activation might have a role in renal tubular interstitial injury in patients with diabetic nephropathy, especially in patients at a later stage of the disease.
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Affiliation(s)
- Jing‐Min Zheng
- Department of Nephrology Taizhou HospitalWenzhou Medical UniversityLihaiZhejiang ProvinceChina
- National Clinical Research Center of Kidney DiseasesJingling HospitalNanjing University School of MedicineNanjingChina
| | - Zuan‐Hong Jiang
- Department of Nephrology Taizhou HospitalWenzhou Medical UniversityLihaiZhejiang ProvinceChina
| | - De‐Jun Chen
- Department of Nephrology Taizhou HospitalWenzhou Medical UniversityLihaiZhejiang ProvinceChina
| | - Sa‐Sa Wang
- Department of Nephrology Taizhou HospitalWenzhou Medical UniversityLihaiZhejiang ProvinceChina
| | - Wen‐Jin Zhao
- National Clinical Research Center of Kidney DiseasesJingling HospitalNanjing University School of MedicineNanjingChina
| | - Li‐Juan Li
- National Clinical Research Center of Kidney DiseasesJingling HospitalNanjing University School of MedicineNanjingChina
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Aristolochic acid I aggravates renal injury by activating the C3a/C3aR complement system. Toxicol Lett 2019; 312:118-124. [PMID: 31048001 DOI: 10.1016/j.toxlet.2019.04.027] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/18/2018] [Revised: 04/15/2019] [Accepted: 04/24/2019] [Indexed: 01/08/2023]
Abstract
Previous studies have reported that the complement system is unconventionally activated in many kinds of glomerulonephritis. Multiple complement components participate in the pathogenic process by triggering immune response or other intracellular signaling pathways. Here, we have investigated the role of C3a and its receptor C3aR in aristolochic acid nephropathy (AAN), which, is featured with progressive interstitial fibrosis. Over release of C3a and increased expression of C3aR parallels to the up-regulation of α-SMA and TGF-β1 in AAN, which appeared to promote epithelial-mesenchymal-transition (EMT). To identify the role of complement activation in AAN, we used an inhibitor of C3aR (C3aRA) to block the coupling of C3a to its receptor. Our results confirmed from decreased EMT, the protective effect of C3aRA in cell apoptosis and inflammatory response induced by aristolochic acid I. These results showed that C3a and its receptor C3aR played pathogenic roles in AAN, and renal tubular epithelial cells were potentially pivotal targets of complement activation that could cause pro-fibrotic effects.
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Han R, Hu S, Qin W, Shi J, Hou Q, Wang X, Xu X, Zhang M, Zeng C, Liu Z, Bao H. C3a and suPAR drive versican V1 expression in tubular cells of focal segmental glomerulosclerosis. JCI Insight 2019; 4:122912. [PMID: 30944246 DOI: 10.1172/jci.insight.122912] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/14/2018] [Accepted: 02/14/2019] [Indexed: 12/13/2022] Open
Abstract
Chronic tubulointerstitial injury impacts the prognosis of focal segmental glomerulosclerosis (FSGS). We found that the level of versican V1 was increased in tubular cells of FSGS patients. Tubular cell-derived versican V1 induced proliferation and collagen synthesis by activating the CD44/Smad3 pathway in fibroblasts. Both urine C3a and suPAR were increased and bound to the tubular cells in FSGS patients. C3a promoted the transcription of versican by activating the AKT/β-catenin pathway. C3aR knockout decreased the expression of versican in Adriamycin-treated (ADR-treated) mice. On the other hand, suPAR bound to integrin β6 and activated Rac1, which bound to SRp40 at the 5' end of exon 7 in versican pre-mRNA. This binding inhibited the 3'-end splicing of intron 6 and the base-pair interactions between intron 6 and intron 8, leading to the formation of versican V1. Cotreatment with ADR and suPAR specifically increased the level of versican V1 in tubulointerstitial tissues and caused more obvious interstitial fibrosis in mice than treatment with only ADR. Altogether, our results show that C3a and suPAR drive versican V1 expression in tubular cells by promoting transcription and splicing, respectively, and the increases in tubular cell-derived versican V1 induce interstitial fibrosis by activating fibroblasts in FSGS.
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Affiliation(s)
- Runhong Han
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.,National Clinical Research Center of Kidney Diseases, Jinling Hospital, Southeast University School of Medicine, Nanjing, China
| | - Shuai Hu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Weisong Qin
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Jinsong Shi
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Qin Hou
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Xia Wang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Xiaodong Xu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Minchao Zhang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Caihong Zeng
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.,National Clinical Research Center of Kidney Diseases, Jinling Hospital, Southeast University School of Medicine, Nanjing, China
| | - Hao Bao
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
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48
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Han R, Hu S, Qin W, Shi J, Zeng C, Bao H, Liu Z. Upregulated long noncoding RNA LOC105375913 induces tubulointerstitial fibrosis in focal segmental glomerulosclerosis. Sci Rep 2019; 9:716. [PMID: 30679767 PMCID: PMC6345783 DOI: 10.1038/s41598-018-36902-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/29/2018] [Accepted: 10/24/2018] [Indexed: 01/17/2023] Open
Abstract
Tubulointerstitial fibrosis impacts renal prognosis of focal segmental glomerulosclerosis (FSGS). Based on transcriptomic analysis, we found that the level of LOC105375913 was increased in tubular cells of FSGS patients. C3a induced the expression of LOC105375913, which promoted the expression of fibronectin and collagen I in tubular cells. Silence of snail reversed the level of fibronectin and collagen I in cells overexpressing LOC105375913. MiR-27b was predicted and confirmed to regulate the expression of snail in tubular cells, and LOC105375913 contained the response element of miR-27b. The competitive binding between LOC105375913 and miR-27b increased the level of snail and promoted fibrogenesis in tubular cells. Upstream, p38 and XBP-1s regulated the expression of LOC105375913. Inhibition of p38 or silence of XBP-1s decreased the level of LOC105375913, and suppressed the expression of snail, fibronectin and collagen I in tubular cells treated with C3a. Overexpression of LOC105375913 decreased the level of miR-27b, increased the level of snail and caused tubulointerstitial fibrosis in mice. In conclusion, the activation of C3a/p38/XBP-1s pathway induces the expression of LOC105375913 in tubular cells, and LOC105375913 increases the level of snail and induces tubulointerstitial fibrosis through competitive binding of miR-27b in tubular cells of FSGS patients.
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Affiliation(s)
- Runhong Han
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, China.,School of Medicine, Southeast University, Nanjing, 210009, China
| | - Shuai Hu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, China
| | - Weisong Qin
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, China
| | - Jingsong Shi
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, China
| | - Caihong Zeng
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, China
| | - Hao Bao
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, China.
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, China.
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Abstract
Acute kidney injury (AKI) is a widespread clinical syndrome directly associated with patient short-term and long-term morbidity and mortality. During the last decade, the incidence rate of AKI has been increasing, the repeated and severe episodes of AKI have been recognized as a major risk factor chronic kidney diseases (CKD) and end-stage kidney disease (ESRD) leading to global disease burden. Proposed pathological processes and risk factors that add to the transition of AKI to CKD and ESRD include severity and frequency of kidney injury, older age, gender, genetics and chronic health conditions like diabetes, hypertension, and obesity. Therefore, there is a great interest in learning about the mechanism of AKI leading to renal fibrosis, the ultimate renal lesions of CKD. Over the last several years, a significant attention has been given to the field of renal fibrosis with impressive progression in knowing the mechanism of renal fibrosis to detailed cellular characterization and molecular pathways implicated in tubulointerstitial fibrosis. Research and clinical trial are underway for emerging biomarkers detecting early kidney injury, predicting kidney disease progression and developing strategies to efficiently treat AKI and to minimize AKI progression to CKD and ESRD. Specific interventions to prevent renal fibrosis are still experimental. Potential therapeutic advances based on those molecular mechanisms will hopefully offer promising insights into the development of new therapeutic interventions for patients in the near future.
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50
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Myofibroblasts in macular fibrosis secondary to neovascular age-related macular degeneration - the potential sources and molecular cues for their recruitment and activation. EBioMedicine 2018; 38:283-291. [PMID: 30473378 PMCID: PMC6306402 DOI: 10.1016/j.ebiom.2018.11.029] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/28/2018] [Revised: 11/14/2018] [Accepted: 11/14/2018] [Indexed: 12/13/2022] Open
Abstract
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in developed countries. Neovascular AMD (nAMD) accounts for 90% of AMD-related vision loss. Although intravitreal injection of VEGF inhibitors can improve vision in nAMD, approximately 1/3 of patients do not benefit from the therapy due to macular fibrosis. The molecular mechanism underlying the transition of the neovascular lesion to a fibrovascular phenotype remains unknown. Here we discussed the clinical features and risk factors of macular fibrosis secondary to nAMD. Myofibroblasts are key cells in fibrosis development. However, fibroblasts do not exist in the macula. Potential sources of myofibroblast precursors, the molecular cues in the macular microenvironment that recruit them and the pathways that control their differentiation and activation in macular fibrosis were also discussed. Furthermore, we highlighted the challenges in macular fibrosis research and the urgent need for better animal models for mechanistic and therapeutic studies.
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