Urinary complement proteins in IgA nephropathy progression from a relative quantitative proteomic analysis

Aim IgA nephropathy (IgAN) is one of the leading causes of end-stage renal disease (ESRD). Urine testing is a non-invasive way to track the biomarkers used for measuring renal injury. This study aimed to analyse urinary complement proteins during IgAN progression using quantitative proteomics. Methods In the discovery phase, we analysed 22 IgAN patients who were divided into three groups (IgAN 1-3) according to their estimated glomerular filtration rate (eGFR). Eight patients with primary membranous nephropathy (pMN) were used as controls. Isobaric tags for relative and absolute quantitation (iTRAQ) labelling, coupled with liquid chromatography-tandem mass spectrometry, was used to analyse global urinary protein expression. In the validation phase, western blotting and parallel reaction monitoring (PRM) were used to verify the iTRAQ results in an independent cohort (N = 64). Results In the discovery phase, 747 proteins were identified in the urine of IgAN and pMN patients. There were different urine protein profiles in IgAN and pMN patients, and the bioinformatics analysis revealed that the complement and coagulation pathways were most activated. We identified a total of 27 urinary complement proteins related to IgAN. The relative abundance of C3, the membrane attack complex (MAC), the complement regulatory proteins of the alternative pathway (AP), and MBL (mannose-binding lectin) and MASP1 (MBL associated serine protease 2) in the lectin pathway (LP) increased during IgAN progression. This was especially true for MAC, which was found to be involved prominently in disease progression. Alpha-N-acetylglucosaminidase (NAGLU) and α-galactosidase A (GLA) were validated by western blot and the results were consistent with the iTRAQ results. Ten proteins were validated in a PRM analysis, and these results were also consistent with the iTRAQ results. Complement factor B (CFB) and complement component C8 alpha chain (C8A) both increased with the progression of IgAN. The combination of CFB and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) also showed potential as a urinary biomarker for monitoring IgAN development. Conclusion There were abundant complement components in the urine of IgAN patients, indicating that the activation of AP and LP is involved in IgAN progression. Urinary complement proteins may be used as biomarkers for evaluating IgAN progression in the future.

[1]  Xinzhou Zhang,et al.  IgA nephropathy with mimicking Fabry disease: A case report and literature review , 2022, Medicine.

[2]  Zhanzheng Zhao,et al.  ICAM-1 related long noncoding RNA is associated with progression of IgA nephropathy and fibrotic changes in proximal tubular cells , 2022, Scientific Reports.

[3]  Byung Chul Yu,et al.  Urinary C5b-9 as a Prognostic Marker in IgA Nephropathy , 2022, Journal of clinical medicine.

[4]  V. Varshavsky,et al.  [Morphological characteristics of renal changes in Fabry disease]. , 2022, Arkhiv patologii.

[5]  Yu Zhang,et al.  The Role of Renal Macrophage, AIM, and TGF-β1 Expression in Renal Fibrosis Progression in IgAN Patients , 2021, Frontiers in Immunology.

[6]  M. Woodward,et al.  Changes in GFR and Albuminuria in Routine Clinical Practice and the Risk of Kidney Disease Progression. , 2021, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[7]  Fang Xu,et al.  Proteomics applications in biomarker discovery and pathogenesis for abdominal aortic aneurysm , 2021, Expert review of proteomics.

[8]  M. Artola,et al.  Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions , 2021, Biomolecules.

[9]  H. Rennke,et al.  Deposition of the Membrane Attack Complex in Healthy and Diseased Human Kidneys , 2021, Frontiers in Immunology.

[10]  B. Rovin,et al.  Safety, Tolerability and Efficacy of Narsoplimab, a Novel MASP-2 Inhibitor for the Treatment of IgA Nephropathy , 2020, Kidney international reports.

[11]  P. Cravedi,et al.  Complement and Complement Targeting Therapies in Glomerular Diseases , 2019, International journal of molecular sciences.

[12]  M. Józsi,et al.  Regulation of regulators: Role of the complement factor H-related proteins. , 2019, Seminars in immunology.

[13]  E. Gutiérrez,et al.  The role of complement in IgA nephropathy. , 2019, Molecular immunology.

[14]  E. Fateen,et al.  Identification of Three Novel Homozygous NAGLU Mutations in Egyptian Patients with Sanfilippo Syndrome B , 2019, Meta Gene.

[15]  F. Wang,et al.  Complement activation products in the circulation and urine of primary membranous nephropathy , 2019, BMC Nephrology.

[16]  Xiangmei Chen,et al.  Comprehensive Analysis of Individual Variation in the Urinary Proteome Revealed Significant Gender Differences* , 2019, Molecular & Cellular Proteomics.

[17]  E. Verderio,et al.  Spotlight on the Transglutaminase 2-Heparan Sulfate Interaction , 2019, Medical sciences.

[18]  Wei Sun,et al.  Analysis of the differential urinary protein profile in IgA nephropathy patients of Uygur ethnicity , 2018, BMC Nephrology.

[19]  Hong Zhang,et al.  Circulating complement factor H-related protein 5 levels contribute to development and progression of IgA nephropathy. , 2018, Kidney international.

[20]  Z. Niemir,et al.  The role of the alternative pathway of complement activation in glomerular diseases , 2018, Clinical and Experimental Medicine.

[21]  Kiran K. Katta,et al.  Endothelial heparan sulfate deficiency reduces inflammation and fibrosis in murine diabetic nephropathy , 2018, Laboratory Investigation.

[22]  S. Thiel,et al.  Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin–Associated Serine Protease-3 (MASP-3) and Increased Glomerular Factor H–Related Protein-5 (FHR5) Deposition , 2017, Kidney international reports.

[23]  F. Berven,et al.  Glomerular abundance of complement proteins characterized by proteomic analysis of laser-captured microdissected glomeruli associates with progressive disease in IgA nephropathy , 2017, Clinical Proteomics.

[24]  Ying Sun,et al.  A comprehensive analysis and annotation of human normal urinary proteome , 2017, Scientific Reports.

[25]  Mark Haas,et al.  Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. , 2017, Kidney international.

[26]  P. Andrew,et al.  Lectin pathway effector enzyme mannan‐binding lectin‐associated serine protease‐2 can activate native complement C3 in absence of C4 and/or C2 , 2017, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  M. Alfadhel,et al.  Rare genetic variant in the CFB gene presenting as atypical hemolytic uremic syndrome and immune complex diffuse membranoproliferative glomerulonephritis, with crescents, successfully treated with eculizumab , 2017, Pediatric Nephrology.

[28]  K. Kurokawa,et al.  The staphylococcal surface-glycopolymer wall teichoic acid (WTA) is crucial for complement activation and immunological defense against Staphylococcus aureus infection. , 2016, Immunobiology.

[29]  J. Floege,et al.  Primary glomerulonephritides , 2016, The Lancet.

[30]  J. Novak,et al.  Markers for the progression of IgA nephropathy , 2016, Journal of Nephrology.

[31]  Chen Shao,et al.  Differential urinary glycoproteome analysis of type 2 diabetic nephropathy using 2D-LC–MS/MS and iTRAQ quantification , 2015, Journal of Translational Medicine.

[32]  G. Berry,et al.  Galactose metabolism and health , 2015, Current opinion in clinical nutrition and metabolic care.

[33]  G. von Heijne,et al.  Tissue-based map of the human proteome , 2015, Science.

[34]  B. Kuster,et al.  Mass-spectrometry-based draft of the human proteome , 2014, Nature.

[35]  Linghong Huang,et al.  Syndecan-4 knockout leads to reduced extracellular transglutaminase-2 and protects against tubulointerstitial fibrosis. , 2014, Journal of the American Society of Nephrology : JASN.

[36]  Pedro M. Coutinho,et al.  The carbohydrate-active enzymes database (CAZy) in 2013 , 2013, Nucleic Acids Res..

[37]  D. G. Sandor,et al.  The role of complement in membranous nephropathy. , 2013, Seminars in nephrology.

[38]  S. Rodríguez de Córdoba,et al.  C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation. , 2013, The Journal of clinical investigation.

[39]  E. Goicoechea de Jorge,et al.  Dimerization of complement factor H-related proteins modulates complement activation in vivo , 2013, Proceedings of the National Academy of Sciences.

[40]  M. Józsi,et al.  Factor H-related Protein 4 Activates Complement by Serving as a Platform for the Assembly of Alternative Pathway C3 Convertase via Its Interaction with C3b Protein , 2012, The Journal of Biological Chemistry.

[41]  B. Julian,et al.  The pathophysiology of IgA nephropathy. , 2011, Journal of the American Society of Nephrology : JASN.

[42]  F. Schena,et al.  Altered modulation of WNT-beta-catenin and PI3K/Akt pathways in IgA nephropathy. , 2010, Kidney international.

[43]  C. Schmid,et al.  A new equation to estimate glomerular filtration rate. , 2009, Annals of internal medicine.

[44]  M. Mann,et al.  Universal sample preparation method for proteome analysis , 2009, Nature Methods.

[45]  J. Styk,et al.  Physiological research. , 2008, Physiological research.

[46]  A. Minagar,et al.  Inflammatory cytokines induce MAdCAM-1 in murine hepatic endothelial cells and mediate alpha-4 beta-7 integrin dependent lymphocyte endothelial adhesion In Vitro , 2007, BMC Physiology.

[47]  J. Kriegsmann,et al.  IgA nephropathy in two adolescent sisters heterozygous for Fabry disease , 2006, Pediatric Nephrology.

[48]  M. Rastaldi,et al.  Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease. , 2006, Journal of the American Society of Nephrology : JASN.

[49]  G. Krissansen,et al.  Bioassay detects soluble MAdCAM‐1 in body fluids , 2004, Immunology and cell biology.

[50]  M. Nagata,et al.  Staphylococcus aureus cell envelope antigen is a new candidate for the induction of IgA nephropathy. , 2004, Kidney international.

[51]  T. Koji,et al.  Intraglomerular Synthesis of Complement C3 and Its Activation Products in IgA Nephropathy , 2001, Nephron.

[52]  B. Heintz,et al.  VCAM-1, ICAM-1, and E-Selectin in IgA Nephropathy and Schönlein-Henoch Syndrome: Differences between Tissue Expression and Serum Concentration , 1999, Nephron.

[53]  M. Briskin,et al.  Human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) demonstrates structural and functional similarities to the alpha 4 beta 7-integrin binding domains of murine MAdCAM-1, but extreme divergence of mucin-like sequences. , 1996, Journal of immunology.

[54]  Y. Tofuku,et al.  Glomerular deposition and serum levels of complement control proteins in patients with IgA nephropathy. , 1984, Clinical nephrology.