Complement components, proteolysis‑related, and cell communication‑related proteins detected in urine proteomics are associated with IgA nephropathy

IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. It was first described in 1968 by Jean Berger and Nicole Hinglais as the presence of intercapillary deposits of IgA. Despite this simple description, patients with IgAN may present very broad clinical features ranging from the isolated presence of IgA in the mesangium without clinical or biological manifestations to rapidly progressive kidney failure. These features are associated with a variety of histological lesions, from the discrete thickening of the mesangial matrix to diffuse cell proliferation. Immunofluorescence on IgAN kidney specimens shows the isolated presence of IgA or its inconsistent association with IgG and complement components. This clinical heterogeneity of IgAN clearly echoes its complex and multifactorial pathophysiology in humans, inviting further analyses of its various aspects through the use of experimental models. Small-animal models of IgAN provide the most pertinent strategies for studying the multifactorial aspects of IgAN pathogenesis and progression. Although only primates have the IgA1 subclass, several murine models have been developed in which various aspects of immune responses are deregulated and which are useful in the understanding of IgAN physiopathology as well as in the assessment of IgAN therapeutic approaches. In this manuscript, we review all murine IgAN models developed since 1968 and discuss their remarkable contribution to understanding the disease.

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The OspE-Related Proteins Inhibit Complement Deposition and Enhance Serum Resistance ofBorrelia burgdorferi, the Lyme Disease Spirochete

Infection and Immunity ◽

10.1128/iai.01274-10 ◽

2011 ◽

Vol 79 (4) ◽

pp. 1451-1457 ◽

Cited By ~ 30

Author(s):

Melisha R. Kenedy ◽

Darrin R. Akins

Keyword(s):

Lyme Disease ◽

Mutant Strain ◽

Membrane Attack Complex ◽

Factor H ◽

Serum Resistance ◽

Complement Components ◽

Complement Inhibitors ◽

Related Proteins ◽

Complement Deposition

ABSTRACTBorrelia burgdorferi, the Lyme disease spirochete, binds the host complement inhibitors factor H (FH) and FH-like protein 1 (FHL-1). Binding of FH/FHL-1 by theB. burgdorferiproteins CspA and the OspE-related proteins is thought to enhance resistance to serum-mediated killing. While previous reports have shown that CspA confers serum resistance inB. burgdorferi, it is unclear whether the OspE-related proteins are relevant inB. burgdorferiserum resistance when OspE is expressed on the borrelial surface. To assess the role of the OspE-related proteins, we overexpressed them in a serum-sensitive CspA mutant strain. OspE overexpression enhanced serum resistance of the CspA-deficient organisms. Furthermore, FH was more efficiently bound to theB. burgdorferisurface when OspE was overexpressed. Deposition of complement components C3 and C5b-9 (the membrane attack complex), however, was reduced on the surface of the OspE-overexpressing strain compared to that on the CspA mutant strain. These data demonstrate that OspE proteins expressed on the surface ofB. burgdorferibind FH and protect the organism from complement deposition and subsequent serum-mediated destruction.

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Effects of Periostracum Cicadae on Cytokines and Apoptosis Regulatory Proteins in IgA Nephropathy Rat Model

10.20944/preprints201805.0337.v1 ◽

2018 ◽

Author(s):

Lu Yang ◽

Yan Wang ◽

Aobulikasimu Nuerbiye ◽

Ping Cheng ◽

Jin-Hui Wang ◽

...

Keyword(s):

Iga Nephropathy ◽

Interleukin 1 ◽

Periodic Acid ◽

Immunoglobulin A ◽

Blood Stasis ◽

Lavage Fluid ◽

Enzyme Linked Immunosorbent Assay ◽

Periodic Acid Schiff ◽

Protein Levels ◽

Related Proteins

Periostracum cicadae, the cast-off shell of the cicada Cryptotympana pustulata Fabricius, is used in traditional Chinese medicine for its diaphoretic, anticonvulsive, sedative, antipyretic, and antiallergic effects. However, the exact pathogenesis of immunoglobulin A nephropathy (IgAN) remains unclear, thereby hindering investigations to identify novel therapeutic agents. A rat IgAN model was established by administration of bovine serum albumin, lipopolysaccharide, and carbon tetrachloride, which simultaneously established blood stasis and a heat syndrome model. The animals were sacrificed to detect changes in protein levels in urine and blood. Immunofluorescence was performed to assess IgA deposition in the glomeruli. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin 6 (IL-6) levels were measured in bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assay. Hematology and eosin, periodic acid-Schiff, TUNEL, and immunohistochemical staining were performed to evaluate histopathological changes in kidney tissues. Additionally, target-related proteins were measured by western blotting. Periostracum cicadae resulted in a reduction in blood and urine protein levels. Serum TNF-α, IL-1β, and IL-6 levels significantly decreased in the periostracum cicadae-treated groups compared to the IgAN group. Furthermore, a reduction in MCP-1, TLR4, and IgA expression levels and a dose- dependent increase in caspace-3 expression were observed in response to periostracum cicadae treatment. TGF-β1 levels decreased, whereas that of Fas increased in the kidney tissues of the periostracum cicadae-treated groups. The findings of the present study indicate that periostracum cicadae induces apoptosis and improves kidney inflammation and fibrosis in IgA nephropathy rat models.

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microRNA-630 Regulates Underglycosylated IgA1 Production in the Tonsils by Targeting TLR4 in IgA Nephropathy

Frontiers in Immunology ◽

10.3389/fimmu.2020.563699 ◽

2020 ◽

Vol 11 ◽

Author(s):

Chan Liu ◽

Mu-Yao Ye ◽

Wen-Zhe Yan ◽

Xiao-Fei Peng ◽

Li-Yu He ◽

...

Keyword(s):

Iga Nephropathy ◽

Molecular Mechanisms ◽

Mononuclear Cells ◽

Immunohistochemical Analysis ◽

Bioinformatic Analysis ◽

Cell Culture Supernatant ◽

Mechanism Study ◽

Complement Components ◽

Mesangial Area ◽

Primary Glomerular Disease

IgA nephropathy (IgAN) is the most common primary glomerular disease. The characteristic pathology involves immune complexes formed by the deposition of IgA1 and underglycosylated IgA1 aggregates in the mesangial area, which may be accompanied by the deposition of IgG and/or IgM and complement components. However, the molecular mechanisms of IgAN remain unclear. In the present study, microarray analysis showed that the expression of microRNA-630 (miR-630) was significantly reduced in palatal tonsils from IgAN patients compared with chronic tonsillitis. Additionally, bioinformatic analysis showed that Toll-like receptor 4 (TLR4) was the predicted target gene of miR-630 and was regulated by miR-630. When miR-630 was overexpressed in palatal tonsil mononuclear cells from IgAN patients, the expression of TLR4 was reduced and the content of IgA1 in the cell culture supernatant was decreased, and the level of galactosylation in the IgA1 hinge region was increased. Moreover, immunohistochemical analysis showed that the expression of TLR4 in IgAN patients was significantly increased. After knocking down the expression of TLR4, both the concentration of IgA1 and the binding force of IgA1 with broad bean lectin were significantly reduced in IgAN. Furthermore, the mechanism study demonstrated that TLR4 might regulate the expression of IL-1β and IL-8 through NF-κB signaling pathway to modulate the concentration of IgA1 and the glycosylation level of IgA1. This interesting finding may offer new insight into the molecular mechanism of IgAN.

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Vesicles Shed by Pathological Murine Adipocytes Spread Pathology: Characterization and Functional Role of Insulin Resistant/Hypertrophied Adiposomes

International Journal of Molecular Sciences ◽

10.3390/ijms21062252 ◽

2020 ◽

Vol 21 (6) ◽

pp. 2252 ◽

Cited By ~ 5

Author(s):

Tamara Camino ◽

Lago-Baameiro Nerea ◽

Bravo Belén ◽

Sueiro Aurelio ◽

Couto Iván ◽

...

Keyword(s):

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Metabolic Diseases ◽

Cell Communication ◽

Cell Of Origin ◽

Insulin Resistant ◽

Cell Tissue ◽

Theoretical Mass ◽

Adipocyte Cell ◽

Related Proteins

Extracellular vesicles (EVs) have recently emerged as a relevant way of cell to cell communication, and its analysis has become an indirect approach to assess the cell/tissue of origin status. However, the knowledge about their nature and role on metabolic diseases is still very scarce. We have established an insulin resistant (IR) and two lipid (palmitic/oleic) hypertrophied adipocyte cell models to isolate EVs to perform a protein cargo qualitative and quantitative Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH) analysis by mass spectrometry. Our results show a high proportion of obesity and IR-related proteins in pathological EVs; thus, we propose a panel of potential obese adipose tissue EV-biomarkers. Among those, lipid hypertrophied vesicles are characterized by ceruloplasmin, mimecan, and perilipin 1 adipokines, and those from the IR by the striking presence of the adiposity and IR related transforming growth factor-beta-induced protein ig-h3 (TFGBI). Interestingly, functional assays show that IR and hypertrophied adipocytes induce differentiation/hypertrophy and IR in healthy adipocytes through secreted EVs. Finally, we demonstrate that lipid atrophied adipocytes shed EVs promote macrophage inflammation by stimulating IL-6 and TNFα expression. Thus, we conclude that pathological adipocytes release vesicles containing representative protein cargo of the cell of origin that are able to induce metabolic alterations on healthy cells probably exacerbating the disease once established.

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Myelin sheaths are formed with proteins that originated in vertebrate lineages

Neuron Glia Biology ◽

10.1017/s1740925x09990238 ◽

2008 ◽

Vol 4 (2) ◽

pp. 137-152 ◽

Cited By ~ 11

Author(s):

Robert M. Gould ◽

Todd Oakley ◽

Jared V. Goldstone ◽

Jason C. Dugas ◽

Scott T. Brady ◽

...

Keyword(s):

Cell Communication ◽

Proteolipid Protein ◽

Myelin Protein ◽

Myelinated Fiber ◽

Peripheral Myelin Protein 22 ◽

Peripheral Myelin Protein ◽

Myelin Sheaths ◽

Protein Zero ◽

Related Proteins ◽

Low Molecular Weight Proteins

All vertebrate nervous systems, except those of agnathans, make extensive use of the myelinated fiber, a structure formed by coordinated interplay between neuronal axons and glial cells. Myelinated fibers, by enhancing the speed and efficiency of nerve cell communication allowed gnathostomes to evolve extensively, forming a broad range of diverse lifestyles in most habitable environments. The axon-covering myelin sheaths are structurally and biochemically novel as they contain high portions of lipid and a few prominent low molecular weight proteins often considered unique to myelin. Here we searched genome and EST databases to identify orthologs and paralogs of the following myelin-related proteins: (1) myelin basic protein (MBP), (2) myelin protein zero (MPZ, formerly P0), (3) proteolipid protein (PLP1, formerly PLP), (4) peripheral myelin protein-2 (PMP2, formerly P2), (5) peripheral myelin protein-22 (PMP22) and (6) stathmin-1 (STMN1). Although widely distributed in gnathostome/vertebrate genomes, neither MBP nor MPZ are present in any of nine invertebrate genomes examined. PLP1, which replaced MPZ in tetrapod CNS myelin sheaths, includes a novel ‘tetrapod-specific’ exon (see also Möbius et al., 2009). Like PLP1, PMP2 first appears in tetrapods and like PLP1 its origins can be traced to invertebrate paralogs. PMP22, with origins in agnathans, and STMN1 with origins in protostomes, existed well before the evolution of gnathostomes. The coordinated appearance of MBP and MPZ with myelin sheaths and of PLP1 with tetrapod CNS myelin suggests interdependence – new proteins giving rise to novel vertebrate structures.

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Systems Biology Modeling of the Complement System Under Immune Susceptible Pathogens

Frontiers in Physics ◽

10.3389/fphy.2021.603704 ◽

2021 ◽

Vol 9 ◽

Author(s):

Nehemiah T. Zewde ◽

Rohaine V. Hsu ◽

Dimitrios Morikis ◽

Giulia Palermo

Keyword(s):

Complement System ◽

Membrane Attack Complex ◽

Factor H ◽

Immunoglobulin M ◽

The Body ◽

Complement Components ◽

Invasive Pathogens ◽

Time Profiles ◽

Related Proteins ◽

The Complement System

The complement system is assembled from a network of proteins that function to bring about the first line of defense of the body against invading pathogens. However, complement deficiencies or invasive pathogens can hijack complement to subsequently increase susceptibility of the body to infections. Moreover, invasive pathogens are increasingly becoming resistant to the currently available therapies. Hence, it is important to gain insights into the highly dynamic interaction between complement and invading microbes in the frontlines of immunity. Here, we developed a mathematical model of the complement system composed of 670 ordinary differential equations with 328 kinetic parameters, which describes all three complement pathways (alternative, classical, and lectin) and includes description of mannose-binding lectin, collectins, ficolins, factor H-related proteins, immunoglobulin M, and pentraxins. Additionally, we incorporate two pathogens: (type 1) complement susceptible pathogen and (type 2) Neisseria meningitidis located in either nasopharynx or bloodstream. In both cases, we generate time profiles of the pathogen surface occupied by complement components and the membrane attack complex (MAC). Our model shows both pathogen types in bloodstream are saturated by complement proteins, whereas MACs occupy <<1.0% of the pathogen surface. Conversely, the MAC production in nasopharynx occupies about 1.5–10% of the total N. meningitidis surface, thus making nasal MAC levels at least about eight orders of magnitude higher. Altogether, we predict complement-imbalance, favoring overactivation, is associated with nasopharynx homeostasis. Conversely, orientating toward complement-balance may cause disruption to the nasopharynx homeostasis. Thus, for sporadic meningococcal disease, our model predicts rising nasal levels of complement regulators as early infection biomarkers.

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Complement factor H–related proteins in IgA nephropathy—sometimes a gentle nudge does the trick

Kidney International ◽

10.1016/j.kint.2017.05.025 ◽

2017 ◽

Vol 92 (4) ◽

pp. 790-793 ◽

Cited By ~ 5

Author(s):

Joshua M. Thurman ◽

Jennifer Laskowski

Keyword(s):

Iga Nephropathy ◽

Factor H ◽

Complement Factor H ◽

Complement Factor ◽

Related Proteins

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POS0110 ASSOCIATION OF miR-155 AND miR-34a EXPRESSION IN LUPUS NEPHRITIS RENAL TISSUE WITH DISEASE ONSET AND OUTCOMES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3761 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 266.1-266

Author(s):

C. Di Mario ◽

L. Petricca ◽

M. R. Gigante ◽

S. Costanzi ◽

G. Vischini ◽

...

Keyword(s):

Lupus Nephritis ◽

Disease Activity ◽

Iga Nephropathy ◽

Lupus Erythematosus ◽

Clinical Laboratory ◽

Demographic Data ◽

Renal Involvement ◽

Disease Onset ◽

Control Group ◽

Complement Components

Background:Epigenetic factors such as non-coding RNA (miRNA) have been shown to be deregulated in Systemic Lupus Erythematosus (SLE). In mouse models, different miRNAs have been associated with lupus nephritis (LN), one of the most severe manifestations of the disease1.Objectives:To evaluate the expression of miR-155 and miR-34a in renal tissues as biomarkers of organ involvement and inflammatory tissue activity in patients with LN.Methods:Thirty-two SLE patients with LN (age: 32.2 ± 9.2 years) with active renal involvement undergoing ultrasound-guided renal biopsy were enrolled between 2010 and 2019. The nephritic manifestation was present in 13 (41%) patients at disease onset (early-LN SLE), while 19 (59%) patients showed a renal involvement after disease onset (long-LN SLE, mean disease duration at LN onset: 7.3 ± 5.7 years). Twelve age-matched patients with IgA nephropathy were enrolled as control group. Clinical, laboratory and demographic data were collected for each patient. Disease activity was recorded using SLEDAI-2K and renal activity, using the total SLEDAI-2K fraction including the items related to the renal involvement. MiR-155 and miR-34a expression in renal tissues was carried out by extraction of total RNA from paraffin-preserved biopsies and was evaluated, after a retrotrascription protocol, using real-time PCR by relative quantification considering the ΔCt (Ct miRNA- Ct housekeeping gene)2.Results:MiR-155 and miR-34a expression in renal tissues was higher in LN-SLE patients as compared to IgA nephropathy patients (ΔCt miR-155: 9.4 ± 10.1 vs 21.9 ± 3.6, p<0.01; ΔCt miR-34a: 10.1 ± 9.8 vs 19.2 ± 3.1, p=0.02). MiR-155 and miR-34a expression in LN-SLE patients renal tissues was comparable in the different histological classes. Furthermore, a direct correlation was observed between the expression of miR-155 and miR-34a (r = 0.91, p <0.001). Dividing patients based on nephritic onset, SLE patients with long-LN showed higher expression of miR-155 (ΔCt 6.1 ± 8.7) and miR-34a (ΔCt 7.1 ± 9.0) as compared to patients with early-LN (miR-155: ΔCt 13.4 ± 10.6 p = 0.08; miR-34a: ΔCt 15.1 ± 9.5 p = 0.02) or patients with IgA nephropathy (miR-155 p<0.01 and miR-34a p<0.01). Moreover, in early-LN SLE it was observed an inverse correlation between miR-34a expression and C3 and C4 complement components (r=-0.7.2; p=0.05 and r=-0.86; p=0.01, respectively) and a direct correlation between miR-155 and 24h-UP (r=0,67; p=0.03). Considering SLE patients with early-LN, the expression of miR-34a was slightly significant in patients who had relapsed (ΔCt 8.2 ± 11.4 vs ΔCt 18.4 ± 7.9 p = 0.08), although no correlation emerged between the expression of miR-155 and miR-34a at the time of the biopsy and with disease activity indices.Conclusion:MiR-155 and miR-34a may represent tissue biomarkers of inflammatory activation in SLE patients with LN; in particular, the higher expression of these miRNA in long-LN and the correlation between miR-155 expression with p24h-UP in early-LN could indicate a possible role of these biomarkers in renal involvement in patients with SLE with later renal onset. The increased expression of miR-34a could give indications of a disease recurrence suggesting a closer monitoring of patients.References:[1]Leiss H et al. Plosone 2017.[2]Alivernini S et al. Nat Commun 2018.Disclosure of Interests:None declared

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