• glomerulonephritis
• iga nephropathy
• igan
• renal cell carcinoma
• renal mass

• IgA nephropathy
• end-stage kidney disease
• prognosis
• systemic immune inflammation index

• Adult
• Female
• Humans
• Male
• Biomarkers/blood
• Biopsy
• Disease Progression
• Glomerular Filtration Rate
• Glomerulonephritis, IGA/complications
• Glomerulonephritis, IGA/immunology
• Glomerulonephritis, IGA/blood
• Glomerulonephritis, IGA/pathology
• Inflammation/blood
• Inflammation/immunology
• Kaplan-Meier Estimate
• Kidney/pathology
• Kidney/immunology
• Kidney Failure, Chronic/immunology
• Prognosis
• Proportional Hazards Models
• Retrospective Studies
• Risk Factors
• ROC Curve

• Four-hit hypothesis
• IgA nephropathy
• inflammation
• pathogenesis
• treatments

• APRIL
• BAFF
• IgA nephropathy
• RNA interference
• clinical trials
• complement
• gut
• monoclonal antibodies

The glomerulus is the functional unit for filtration of blood and formation of primary urine. This intricate structure is composed of the endothelium with its glycocalyx facing the blood, the glomerular basement membrane and the podocytes facing the urinary space of Bowman's capsule. The mesangial cells are the central hub connecting and supporting all these structures. The components as a unit ensure a high permselectivity hindering large plasma proteins from passing into the urine while readily filtering water and small solutes. There has been a long-standing interest and discussion regarding the functional contribution of the different cellular components but the mesangial cells have been somewhat overlooked in this context. The mesangium is situated in close proximity to all other cellular components of the glomerulus and should be considered important in pathophysiological events leading to glomerular disease. This review will highlight the role of the mesangium in both glomerular function and intra-glomerular crosstalk. It also aims to explain the role of the mesangium as a central component involved in disease onset and progression as well as signaling to maintain the functions of other glomerular cells to uphold permselectivity and glomerular health.

• DKD
• IgAN
• crosstalk
• glomerular barrier
• glomerular diseases
• glomerulus
• mesangial cells

• IgA nephropathy
• immunology
• mucosa
• mucosa-kidney axis
• treatment

IgA nephropathy is caused by deposition of circulatory IgA1 in the kidney. Hypogalactosylated IgA1 has the propensity to form poly-IgA aggregates that are prone to deposition. Herein, we purified poly-IgA from the plasma of patients with IgA nephropathy and showed that the complex is susceptible to reducing conditions, suggesting intermolecular disulfide connections between IgA units. We sought to find the cysteine residue(s) that form intermolecular disulfide. Naturally assembled dimeric IgA, also known as secretory IgA, involves a J chain subunit connected with 2 IgA1 molecules via their penultimate cysteine-471 residue on a “tailpiece” segment of IgA heavy chain. It is plausible that, with the absence of J chain, the cysteine residue of mono-IgA1 might aberrantly form a disulfide bond in poly-IgA formation. Mutagenesis confirmed that cysteine-471 is capable of promoting IgA aggregation. These discoveries prompted us to test thiol-based drugs for stabilizing cysteine. Specifically, the cystine-reducing drug cysteamine used for treatment of cystinosis showed a remarkable potency in preventing self-aggregation of IgA. When administrated to rat and mouse models of IgA nephropathy, cysteamine significantly reduced glomerular IgA deposition. Collectively, our results reveal a potentially novel molecular mechanism for aberrant formation of IgA aggregates, to which the repurposed cystinosis drug cysteamine was efficacious in preventing renal IgA deposition.

• Autoimmune diseases
• Autoimmunity

IgA nephropathy, initially described in 1968 as a kidney disease with glomerular “intercapillary deposits of IgA-IgG”, has no disease-specific treatment and is a common cause of kidney failure. Clinical observations and laboratory analyses suggest that IgA nephropathy is an autoimmune disease wherein the kidneys are damaged as innocent bystanders due to deposition of IgA1-IgG immune complexes from the circulation. A multi-hit hypothesis for the pathogenesis of IgA nephropathy describes four sequential steps in disease development. Specifically, patients with IgA nephropathy have elevated circulating levels of IgA1 with some O-glycans deficient in galactose (galactose-deficient IgA1) and these IgA1 glycoforms are recognized as autoantigens by unique IgG autoantibodies, resulting in formation of circulating immune complexes, some of which deposit in glomeruli and activate mesangial cells to induce kidney injury. This proposed mechanism is supported by observations that (i) glomerular immunodeposits in patients with IgA nephropathy are enriched for galactose-deficient IgA1 glycoforms and the corresponding IgG autoantibodies; (ii) circulatory levels of galactose-deficient IgA1 and IgG autoantibodies predict disease progression; and (iii) pathogenic potential of galactose-deficient IgA1 and IgG autoantibodies was demonstrated in vivo. Thus, a better understanding of the structure–function of these immunoglobulins as autoantibodies and autoantigens will enable development of disease-specific treatments.

• IgA nephropathy
• IgA1
• O-glycosylation
• autoantibody
• immune complex

ADAMTS5 is upregulated in human IgA nephropathy lesions.

In IgA nephropathy (IgAN), IgA immune complexes are deposited in the mesangium and drive inflammation and extracellular matrix (ECM) remodelling. The functional links between IgA deposition, inflammation, and matrix remodelling are not well characterized. We recently performed urine liquid chromatography–tandem mass spectrometry proteomics and identified multiple ECM glycoproteins whose expression and function in IgAN is unclear. None of the urine glycoproteins was regulated in IgAN transcriptomics, indicating that tissue remodelling rather than increased expression might contribute to their presence in urine. To investigate this, we examined the IgAN expression profile of metalloproteinases, enzymes involved in the remodelling of ECM proteins, and noted that the proteoglycanase ADAMTS5 was upregulated in IgAN kidneys. ADAMTS5 accumulated in areas of inflammation, and ADAMTS5⁺ cells were seen in the tubulointerstitium and glomeruli. The enzyme was expressed by CD64⁺ cells and its expression was increased by IL-1 and LPS. Analysis of myeloid cell transcriptomics revealed that ADAMTS5 is enriched in human classical monocytes. ADAMTS5⁺ cells were present in areas of matrix remodelling and associated with ECM proteins lumican, versican, and collagen-4. Liquid chromatography–tandem mass spectrometry proteomics of kidney explants digested with ADAMTS5, identified multiple kidney proteins affected by ADAMTS5 and revealed specific proteolysis of complement C3 and fibronectin associated with IgA on immune complexes. ADAMTS5 processing of immune complex proteins reduced binding to cultured mesangial cells. ADAMTS5 is associated with interstitial inflammatory cells in IgAN and other kidney lesions and fragments relevant extracellular proteins. The proteolytic enzyme might be a new translational target relevant to inflammation and scarring in kidney disease.

• IgA nephropathy
• Neutrophil-to-lymphocyte ratio
• Progression

• C3 glomerulonephritis
• C3 glomerulopathy
• C3 nephritic factor
• C3GN
• C3bBb
• Complement
• Dense deposit disease
• Eculizumab
• FHR
• Factor H
• Factor H-related protein
• Hemolytic uremic syndrome
• IgA glomerulonephritis
• IgA nephropathy
• Membranoproliferative glomerulonephritis
• Plasmapheresis
• Proteinuria
• Sialic acid
• Streptococcus
• aHUS

• CD37
• IL-6
• IgA nephropathy
• glomerulonephritis

• Animals
• Antigens, CD/blood
• Antigens, CD/immunology
• Disease Models, Animal
• Female
• Gene Expression Regulation
• Glomerulonephritis, IGA/blood
• Glomerulonephritis, IGA/genetics
• Glomerulonephritis, IGA/physiopathology
• Humans
• Immunoglobulin A/blood
• Immunoglobulin A/immunology
• Kupffer Cells/metabolism
• Kupffer Cells/pathology
• Male
• Mice
• Mice, Transgenic
• Receptors, Fc/blood
• Receptors, Fc/immunology

• National Basic Research Program of China
• National Natural Science Foundation of China

• ANCA
• IgA nephropathy
• complement activation
• crescentic glomerulonephritis

• Auto antibodies
• Complement in renal diseases
• Genome-wide association studies
• Immunoglobulin A
• Immunoglobulin A galactosylation
• Mesangial linked growth factors

Detailed analytical ultracentrifugation and X-ray/neutron scattering data and a new atomistic modelling approach revealed asymmetric extended solution structures for human IgA1 that account for its receptor-binding function. IgA1 with different hinge O-galactosylation patterns showed similar structures.

Native IgA1, for which no crystal structure is known, contains an O-galactosylated 23-residue hinge region that joins its Fab and Fc regions. IgA nephropathy (IgAN) is a leading cause of chronic kidney disease in developed countries. Because IgA1 in IgAN often has a poorly O-galactosylated hinge region, the solution structures of monomeric IgA1 from a healthy subject and three IgAN patients with four different O-galactosylation levels were studied. Analytical ultracentrifugation showed that all four IgA1 samples were monomeric with similar sedimentation coefficients, s⁰_20,w. X-ray scattering showed that the radius of gyration (R_g) slightly increased with IgA1 concentration, indicating self-association, although their distance distribution curves, P(r), were unchanged with concentration. Neutron scattering indicated similar R_g values and P(r) curves, although IgA1 showed a propensity to aggregate in heavy water buffer. A new atomistic modelling procedure based on comparisons with 177000 conformationally-randomized IgA1 structures with the individual experimental scattering curves revealed similar extended Y-shaped solution structures for all four differentially-glycosylated IgA1 molecules. The final models indicated that the N-glycans at Asn²⁶³ were folded back against the Fc surface, the C-terminal tailpiece conformations were undefined and hinge O-galactosylation had little effect on the solution structure. The solution structures for full-length IgA1 showed extended hinges and the Fab and Fc regions were positioned asymmetrically to provide ample space for the functionally-important binding of two FcαR receptors to its Fc region. Whereas no link between O-galactosylation and the IgA1 solution structure was detected, an increase in IgA1 aggregation with reduced O-galactosylation may relate to IgAN.

• X-ray scattering
• analytical ultracentrifugation
• antibody
• constrained modelling
• human immunoglobulin A1 (IgA1)
• immunoglobulin A (IgA) nephropathy
• neutron scattering

Renal mesangial cells (RMCs) constitute a population of cells in glomerular mesangium. Inflammatory cytokines produced by RMCs play a vital role in renal inflammation. miRNAs are key regulators of inflammatory cytokine expression. The abnormal expression of renal miRNAs and the consequent changes in inflammatory signal transduction are closely associated with renal inflammation. However, our knowledge of the functions of renal miRNAs is still limited. In this study, we investigated the role of miR-744 in type I interferon (IFN) signaling pathway in primary human RMCs. We show that overexpression of miR-744 enhances IFN-induced CCL2, CCL5, CXCL10, and IL6 expression specifically in RMCs. We found that the activation of TYK2, STAT1 and STAT3 was significantly enhanced by miR-744. miR-744 also enhanced the activation of non-classical signal components, such as ERK and p38. We then identified PTP1B, a ubiquitously expressed phosphatase, as the target of miR-744 that is responsible for enhancing type I IFN response. Finally, miR-744 expression was induced by type I IFN in RMCs. Collectively, our data indicate that by targeting PTP1B, miR-744 plays a feed-forward role in regulating type I IFN signaling pathway. These findings give us new insights into the functions of renal miRNAs in regulating important signaling pathways.

• Animals
• Bone Marrow Transplantation
• Female
• Fluorescent Antibody Technique/methods
• Glomerular Mesangium/immunology
• Glomerular Mesangium/pathology
• Glomerulonephritis, IGA/immunology
• Glomerulonephritis, IGA/pathology
• Glomerulonephritis, IGA/therapy
• Humans
• Immunoglobulin A/immunology
• Mice
• Mice, Inbred BALB C
• Microscopy, Electron/methods
• Proteinuria/immunology
• Proteinuria/pathology

• immunoglobulin A nephropathy
• isobaric tags for relative and absolute quantification technology
• proteomic
• tandem mass spectrometry

• Adolescent
• Angiotensin-Converting Enzyme 2
• Biopsy
• Cells, Cultured
• Child
• Creatinine/blood
• Female
• Glomerular Filtration Rate
• Glomerulonephritis, IGA/diagnosis
• Glomerulonephritis, IGA/enzymology
• Humans
• Kidney/metabolism
• Kidney Glomerulus/enzymology
• Kidney Glomerulus/metabolism
• Male
• Mesangial Cells/enzymology
• Peptidyl-Dipeptidase A/metabolism
• RNA, Messenger/metabolism
• Regression Analysis
• Renin-Angiotensin System

The association between sarcoidosis and glomerular diseases has not been extensively investigated in a large series and the potential features of this uncommon association remain to be determined.

We retrospectively identified 26 patients with biopsy-proven glomerular lesions that occurred in a sarcoidosis context. Potential remission of glomerular disease and sarcoidosis under specific treatment (steroid and/or immunosuppressive agents) was recorded for all patients. Demographic, clinical and biological characteristics were assessed at the time of kidney biopsy for each patient. Therapeutic data were analyzed for all patients.

Glomerular disease occurred after the diagnosis of sarcoidosis in 11 of 26 cases (42%) (mean delay of 9.7 years). In six patients (23%), the glomerulopathy preceded the sarcoidosis diagnosis (mean delay 8 years). In the last nine patients (35%), both conditions occurred simultaneously. The most frequent glomerular disease occurring in sarcoidosis patients was membranous nephropathy in eleven cases. Other glomerular lesions included IgA nephropathy in six cases, focal segmental glomerulosclerosis in four patients, minimal change nephrotic syndrome for three patients and proliferative lupus nephritis in two patients. Granulomatous interstitial nephritis was associated with glomerular disease in six patients and was exclusively found in patients in whom the both disease occurred simultaneously. In nine patients with simultaneous glomerular and sarcoidosis diseases, we observed a strong dissociation between glomerular disease and sarcoidosis in terms of steroid responsiveness. At the end of the follow-up (mean of 8.4 years), six patients had reached end-stage renal disease and three patients had died.

A wide spectrum of glomerular lesions is associated with sarcoidosis. The close temporal relationship observed in some patients suggests common causative molecular mechanisms of glomerular injury but complete remission of both diseases in response to exclusive steroid therapy is infrequent.

• Acetylglucosaminidase/urine
• Adolescent
• Albuminuria/urine
• Alpha-Globulins/urine
• Analysis of Variance
• Area Under Curve
• Biomarkers/urine
• Biopsy
• Child
• Child, Preschool
• Female
• Glomerulonephritis, Membranoproliferative/complications
• Glomerulonephritis, Membranoproliferative/metabolism
• Glomerulonephritis, Membranoproliferative/pathology
• Glomerulonephritis, Membranoproliferative/urine
• Glomerulosclerosis, Focal Segmental/complications
• Glomerulosclerosis, Focal Segmental/pathology
• Glomerulosclerosis, Focal Segmental/urine
• Humans
• Immunoglobulin A/metabolism
• Immunoglobulin G/urine
• Immunoglobulin M/metabolism
• Kidney Tubules/pathology
• Male
• Mesangial Cells/pathology
• Predictive Value of Tests
• ROC Curve
• Severity of Illness Index
• Transferrin/urine
• beta 2-Microglobulin/urine

• chromatin immunoprecipitation
• histone h3 lysine 4
• iga nephropathy
• quantitative methylation-specific pcr
• trimethylation

• Adult
• Case-Control Studies
• Chromatin Immunoprecipitation
• Female
• Glomerulonephritis, IGA/genetics
• Glomerulonephritis, IGA/metabolism
• Histones/metabolism
• Humans
• Leukocytes, Mononuclear/metabolism
• Lysine/metabolism
• Male
• Methylation
• Oligonucleotide Array Sequence Analysis/methods
• Real-Time Polymerase Chain Reaction
• Young Adult

• Animals
• Antigens, CD/metabolism
• Antigens, Neoplasm/metabolism
• Autoantibodies/chemistry
• Cell Membrane/metabolism
• Female
• Glomerulonephritis, IGA/metabolism
• Glycoproteins/metabolism
• Immune System
• Immunoglobulin A/metabolism
• Inflammation
• Kidney/pathology
• Kidney Glomerulus/metabolism
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Tetraspanins

• Adult
• Aged
• B-Lymphocytes/immunology
• B-Lymphocytes/pathology
• Binding Sites
• Carbohydrate Sequence
• Case-Control Studies
• Cell Differentiation
• Enzyme-Linked Immunosorbent Assay
• Female
• Galactose/chemistry
• Glomerulonephritis, IGA/immunology
• Glomerulonephritis, IGA/pathology
• Glycosylation
• Humans
• Immunoglobulin A/blood
• Immunoglobulin A/chemistry
• Immunoglobulin D/blood
• Immunoglobulin D/chemistry
• Lectins
• Male
• Middle Aged
• Molecular Sequence Data

In order to determine the glycosylation pattern for IgD, and to examine whether there are changes in the pattern of IgD and IgA1 O-glycosylation in patients with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) during acute febrile attacks and during periods of quiescence, serum was obtained from 20 patients with HIDS and 20 control subjects. In the HIDS group, serum was obtained either during an acute febrile episode (n = 9) or during a period of quiescence (n = 11). The O-glycosylation profiles of native and desialylated IgA1 and IgD were measured in an ELISA-type system using the lectins Helix aspersa and peanut agglutinin, which bind to alternative forms of O-glycan moieties. IgD is more heavily O-galactosylated and less O-sialylated than IgA1 in healthy subjects. HIDS is associated with more extensive O-galactosylation of IgD and a reduction in O-sialylation of both IgD and IgA1. These changes are present both during acute febrile attacks and periods of quiescence. The T cell IgD receptor is a lectin with binding affinity for the O-glycans of both IgD and IgA1. The observed changes in IgD and IgA1 O-glycosylation are likely to have a significant effect on IgD/IgA1–T cell IgD receptor interactions including basal immunoglobulin synthesis, and possibly myeloid IgD receptor-mediated cytokine release.