Urinary complement proteins in IgA nephropathy progression from a relative quantitative proteomic analysis. 2023

Xia Niu, and Shuyu Zhang, and Chen Shao, and Zhengguang Guo, and Jianqiang Wu, and Jianling Tao, and Ke Zheng, and Wenling Ye, and Guangyan Cai, and Wei Sun, and Mingxi Li
Core Facility of Instruments, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.

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. 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). 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. 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.

UI MeSH Term Description Entries
D007668 Kidney Body organ that filters blood for the secretion of URINE and that regulates ion concentrations. Kidneys
D003165 Complement System Proteins Serum glycoproteins participating in the host defense mechanism of COMPLEMENT ACTIVATION that creates the COMPLEMENT MEMBRANE ATTACK COMPLEX. Included are glycoproteins in the various pathways of complement activation (CLASSICAL COMPLEMENT PATHWAY; ALTERNATIVE COMPLEMENT PATHWAY; and LECTIN COMPLEMENT PATHWAY). Complement Proteins,Complement,Complement Protein,Hemolytic Complement,Complement, Hemolytic,Protein, Complement,Proteins, Complement,Proteins, Complement System
D005922 Glomerulonephritis, IGA A chronic form of glomerulonephritis characterized by deposits of predominantly IMMUNOGLOBULIN A in the mesangial area (GLOMERULAR MESANGIUM). Deposits of COMPLEMENT C3 and IMMUNOGLOBULIN G are also often found. Clinical features may progress from asymptomatic HEMATURIA to END-STAGE KIDNEY DISEASE. Berger Disease,Immunoglobulin A Nephropathy,Nephropathy, IGA,Berger's Disease,IGA Glomerulonephritis,IGA Nephropathy,Iga Nephropathy 1,Nephritis, IGA Type,Bergers Disease,Glomerulonephritides, IGA,IGA Type Nephritis,Nephropathy 1, Iga,Nephropathy, Immunoglobulin A
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D015415 Biomarkers Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, ENVIRONMENTAL EXPOSURE and its effects, disease diagnosis; METABOLIC PROCESSES; SUBSTANCE ABUSE; PREGNANCY; cell line development; EPIDEMIOLOGIC STUDIES; etc. Biochemical Markers,Biological Markers,Biomarker,Clinical Markers,Immunologic Markers,Laboratory Markers,Markers, Biochemical,Markers, Biological,Markers, Clinical,Markers, Immunologic,Markers, Laboratory,Markers, Serum,Markers, Surrogate,Markers, Viral,Serum Markers,Surrogate Markers,Viral Markers,Biochemical Marker,Biologic Marker,Biologic Markers,Clinical Marker,Immune Marker,Immune Markers,Immunologic Marker,Laboratory Marker,Marker, Biochemical,Marker, Biological,Marker, Clinical,Marker, Immunologic,Marker, Laboratory,Marker, Serum,Marker, Surrogate,Serum Marker,Surrogate End Point,Surrogate End Points,Surrogate Endpoint,Surrogate Endpoints,Surrogate Marker,Viral Marker,Biological Marker,End Point, Surrogate,End Points, Surrogate,Endpoint, Surrogate,Endpoints, Surrogate,Marker, Biologic,Marker, Immune,Marker, Viral,Markers, Biologic,Markers, Immune
D015433 Glomerulonephritis, Membranous A type of glomerulonephritis that is characterized by the accumulation of immune deposits (COMPLEMENT MEMBRANE ATTACK COMPLEX) on the outer aspect of the GLOMERULAR BASEMENT MEMBRANE. It progresses from subepithelial dense deposits, to basement membrane reaction and eventual thickening of the basement membrane. Heymann Nephritis,Membranous Glomerulopathy,Nephropathy, Membranous,Extramembranous Glomerulopathy,Idiopathic Membranous Glomerulonephritis,Idiopathic Membranous Nephropathy,Membranous Glomerulonephropathy,Membranous Nephropathy,Glomerulonephritides, Idiopathic Membranous,Glomerulonephritides, Membranous,Glomerulonephritis, Idiopathic Membranous,Glomerulonephropathy, Membranous,Glomerulopathy, Extramembranous,Glomerulopathy, Membranous,Idiopathic Membranous Glomerulonephritides,Membranous Glomerulonephritides,Membranous Glomerulonephritides, Idiopathic,Membranous Glomerulonephritis,Membranous Glomerulonephritis, Idiopathic,Membranous Nephropathy, Idiopathic,Nephritis, Heymann,Nephropathy, Idiopathic Membranous
D015938 Complement Membrane Attack Complex A product of COMPLEMENT ACTIVATION cascade, regardless of the pathways, that forms transmembrane channels causing disruption of the target CELL MEMBRANE and cell lysis. It is formed by the sequential assembly of terminal complement components (COMPLEMENT C5B; COMPLEMENT C6; COMPLEMENT C7; COMPLEMENT C8; and COMPLEMENT C9) into the target membrane. The resultant C5b-8-poly-C9 is the "membrane attack complex" or MAC. Complement Complex C5b-9,Membrane Attack Complex,C 5b-9,C5b-8-poly-C9,C5b-9,Cytolytic Terminal Complement Complex,Terminal Complement Complex,C5b 8 poly C9,Complement Complex C5b 9,Complement Complex, Terminal,Complex, Terminal Complement
D037102 Lectins Proteins that share the common characteristic of binding to carbohydrates. Some ANTIBODIES and carbohydrate-metabolizing proteins (ENZYMES) also bind to carbohydrates, however they are not considered lectins. PLANT LECTINS are carbohydrate-binding proteins that have been primarily identified by their hemagglutinating activity (HEMAGGLUTININS). However, a variety of lectins occur in animal species where they serve diverse array of functions through specific carbohydrate recognition. Animal Lectin,Animal Lectins,Isolectins,Lectin,Isolectin,Lectin, Animal,Lectins, Animal
D040901 Proteomics The systematic study of the complete complement of proteins (PROTEOME) of organisms. Peptidomics

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