Molecular basis of IgA nephropathy

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and remains an important cause of end-stage renal failure. However, the basic molecular mechanism(s) underlying abnormal IgA synthesis, selective mesangial deposition with ensuing mesangial cell proliferation and extracellular matrix expansion remains poorly understood. Notably, the severity of tubulointerstitial lesions better predicts the renal progression than the degree of glomerular lesions. The task of elucidating the molecular basis of IgAN is made especially challenging by the fact that both environmental and genetic components likely contribute to the development and progression of IgAN. This review will summarize the earlier works on the structure of the IgA molecule, mechanisms of mesangial IgA deposition and pathophysiologic effects of IgA on mesangial cells following mesangial deposition. Recently, a series of important advances in the area of communication between the glomerular mesangium and renal tubular cells have emerged. These novel findings regarding the molecular pathogenesis of IgAN will be helpful in designing future directions for therapy.     

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A 20-year-old man with a 10-year history of glomerulonephritis presented with a purpuric rash on his legs. A renal biopsy specimen obtained when he was 11 years old had shown mesangial glomerulonephritis; staining 9 years later for IgA had negative results. A second renal biopsy, performed when the rash was present, revealed mesangial glomerulonephritis and mesangial deposits of IgA; biopsies of the involved skin showed leukocytoclastic vasculitis. In this case isolated glomerulonephritis appeared to change to a multisystem illness, with a different immunologic character, through one of several possible pathogenetic mechanisms.     

Downregulated expression in high IgA (HIGA) mice and the renal protective role of meprinbeta

This study discusses the critical role of the metalloproteinase meprinbeta in the progression of glomerulonephritis. Using a microarray technique, the gene expression profiles in glomeruli isolated from high serum IgA (HIGA) mice with a purity of 97% or greater were examined. HIGA mice are a valid model of human IgA nephropathy (IgAN), with the typical pathological features of this condition, including a consistently high serum IgA level as well as dominant mesangial IgA deposition and mesangial enlargement. Among the many upregulated/downregulated genes after the development of IgAN, the downregulation of meprinbeta was intriguing. The expression level of the meprinbeta gene at 40 weeks of age was 52% of that observed at 8 weeks of age (prior to the development of IgAN), although in the control BALB/c mice, a 2.19-fold elevation was seen. These results were also confirmed by semi-quantitative RT-PCR and immunostaining analyses. As meprinbeta is a subunit of metalloproteinase meprins (meprin A, meprin B) and meprins are capable of proteolytically degrading extracellular matrix (ECM) components and proteolytically processing bioactive peptides, the downregulation of meprinbeta may contribute to the progression of glomerulonephritis and the eventual glomerular scarring. This working hypothesis was examined using an in vivo meprinbeta inhibition study. The inhibition of meprins by actinonin exacerbated some parameters of renal injury in mice afflicted with anti-glomerular basement membrane (anti-GBM) antibody-associated nephritis. These in vitro and in vivo results suggest that meprinbeta may play a protective role against the progression of renal injury through the degradation of ECM and bioactive peptides.     

Insulin-like growth factor binding protein-1 levels are increased in patients with IgA nephropathy

The mechanisms underlying the pathogenesis of immunoglobulin A (IgA) nephropathy (IgAN) are not well understood. In this study, we examined gene expression profiles in kidneys obtained from mice with high serum IgA levels (HIGA mice), which exhibit features of human IgAN. Female inbred HIGA, established from the ddY line, were used in these experiments. Serum IgA levels, renal IgA deposition, mesangial proliferation, and glomerulosclerosis were increased in 32-week-old HIGA mice in comparison to ddY animals. By microarray analysis, five genes were observed to be increased by more than 2.5-fold in 32-week-old HIGA in comparison to 16-week-old HIGA; these same five genes were decreased more than 2.5-fold in 32-week-old ddY in comparison to 16-week-old ddY mice. Of these five genes, insulin-like growth factor (IGF) binding protein (IGFBP)-1 exhibited differential expression between these mouse lines, as confirmed by quantitative RT-PCR. In addition, serum IGFBP-1 levels were significantly higher in patients with IgAN than in healthy controls. In patients with IgAN, these levels correlated with measures of renal function, such as estimated glomerular filtration rate (eGFR), but not with sex, age, serum IgA, C3 levels, or IGF-1 levels. Pathologically, serum IGFBP-1 levels were significantly associated with the severity of renal injury, as assessed by mesangial cell proliferation and interstitial fibrosis. These results suggest that increased IGFBP-1 levels are associated with the severity of renal pathology in patients with IgAN.     

Pathogenic significance of IgA receptor interactions in IgA nephropathy

IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, frequently progresses to renal failure. The pathogenesis of this disease involves the deposition of undergalactosylated IgA1 complexes in the glomerular mesangium. How the IgA1 complexes are generated and why they are deposited in the mesangium remains unclear. We propose a model wherein two types of IgA receptors participate in sequential steps to promote the development of IgAN, with FcalphaRI (CD89) being initially involved in the formation of circulating IgA-containing complexes and, subsequently, transferrin receptor (CD71) in mediating mesangial deposition of IgA1 complexes.     

Suppression of adiponectin by aberrantly glycosylated IgA1 in glomerular mesangial cells in vitro and in vivo

The pathogenesis of IgA nephropathy (IgAN) may be associated with the mesangial deposition of aberrantly glycosylated IgA1. To identify mediators affected by aberrantly glycosylated IgA1 in cultured human mesangial cells (HMCs), we generated enzymatically modified desialylated and degalactosylated (deSial/deGal) IgA1. The state of deglycosylated IgA1 was confirmed by lectin binding to Helix aspersa (HAA) and Sambucus nigra (SNA). In the cytokine array analysis, 52 proteins were upregulated and 34 were downregulated in HMCs after stimulation with deSial/deGal IgA1. Among them, the secretion of adiponectin was suppressed in HMCs after stimulation with deSial/deGal IgA1. HMCs expressed mRNAs for adiponectin and its type 1 receptor, but not the type 2 receptor. Moreover, we revealed a downregulation of adiponectin expression in the glomeruli of renal biopsy specimens from patients with IgAN compared to those with lupus nephritis. We also demonstrated that aberrantly glycosylated IgA1 was deposited in the mesangium of patients with IgAN by dual staining of HAA and IgA. Moreover, the urinary HAA/SNA ratio of lectin binding was significantly higher in IgAN compared to other kidney diseases. Since adiponectin has anti-inflammatory effects, including the inhibition of adhesion molecules and cytokines, these data suggest that the local suppression of this adipokine by aberrantly glycosylated IgA1 could be involved in the regulation of glomerular inflammation and sclerosis in IgAN.     

天然免疫分子在糖基化异常IgA致肾小球足细胞损伤中的免疫调节作用

IgA肾病(IgA nephropathy,IgAN)位居各类肾小球疾病之首,是一组以IgA为主的免疫球蛋白在肾小球系膜区沉积为特征的免疫介导性肾小球疾病,也是引起患者终末期肾衰竭最常见的病因之一。足细胞是继系膜细胞与IgA肾病关系的新近关注热点,其系一类位于基底膜最外层的上皮细胞,并是构成肾小球滤过屏障的核心成份。目前认为,足细胞损伤及其生物学行为在IgA肾病等疾病起始进展乃至终末期肾衰中起关键作用。近年伴随着对上皮细胞尤其细胞转分化(EMT)现象在足细胞损伤机制中重要意义的认识,人们注意到糖基化异常IgA在足细胞EMT发生中的诱发作用,以及足细胞EMT过程中的病生理调控机制与IgA肾病等肾小球疾病发生发展的关系。为此,该文进一步基于足细胞的生物学特性以及免疫调节新的视角,探讨天然免疫分子在糖基化异常IgA致足细胞损伤中的调控作用,拟为进一步阐释IgA肾病发病机制及其相关研究乃至临床治疗提供新的思路。     

The long pentraxin PTX3 is synthesized in IgA glomerulonephritis and activates mesangial cells

The long pentraxin PTX3 has been recently involved in amplification of the inflammatory reactions and regulation of innate immunity. In the present study we evaluated the expression and role of PTX3 in glomerular inflammation. PTX3 expression was investigated in the IgA, type I membranoproliferative, and diffuse proliferative lupus glomerulonephritis, which are characterized by inflammatory and proliferative lesions mainly driven by resident mesangial cells, and in the membranous glomerulonephritis and the focal segmental glomerular sclerosis, where signs of glomerular inflammation are usually absent. We found an intense staining for PTX3 in the expanded mesangial areas of renal biopsies obtained from patients with IgA glomerulonephritis. The pattern of staining was on glomerular mesangial and endothelial cells. Scattered PTX3-positive cells were also detected in glomeruli of type I membranoproliferative glomerulonephritis. The concomitant expression of CD14 suggests an inflammatory origin of these cells. Normal renal tissue and biopsies from patients with the other glomerular nephropathies studied were mainly negative for PTX3 expression in glomeruli. However, PTX3-positive cells were detected in the interstitium of nephropathies showing inflammatory interstitial injury. In vitro, cultured human mesangial cells synthesized PTX3 when stimulated with TNF-alpha and IgA and exhibited specific binding for recombinant PTX3. Moreover, stimulation with exogenous PTX3 promoted mesangial cell contraction and synthesis of the proinflammatory lipid mediator platelet-activating factor. In conclusion, we provide the first evidence that mesangial cells may both produce and be a target for PTX3. The detection of this long pentraxin in the renal tissue of patients with glomerulonephritis suggests its potential role in the modulation of glomerular and tubular injury.     

Pathogenesis of Berger's disease: recent advances on the involvement of immunoglobulin A and their receptors

Immunoglobulin A (IgA) nephropathy or Berger's disease is the most common form of primary glomerulonephritis in the world and one of the first cause of end-stage renal failure. IgA nephropathy is characterized by the accumulation in mesangial areas of immune complexes containing polymeric IgA1. While epidemiology and clinical studies of IgA nephropathy are well established, the mechanism(s) underlying disease development is poorly understood. The pathogenesis of this disease involves the deposition of polymeric and undergalactosylated IgA1 in the mesangium. Quantitative and structural changes of IgA1 play a key role in the development of the disease due to functional abnormalities of two IgA receptors: The FcalphaR (CD89) expressed by blood myeloid cells and the transferrin receptor (CD71) on mesangial cells. Abnormal IgA induce the release of soluble CD89 which is responsible for the formation of circulating IgA complexes. These complexes may be trapped by CD71 that is overexpressed on mesangial cells in IgA nephropathy patients allowing pathogenic IgA complex formation.     

Triptolide promotes autophagy to inhibit mesangial cell proliferation in IgA nephropathy via the CARD9/p38 MAPK pathway

BackgroundMesangial cell proliferation is the most basic pathological feature of immunoglobulin A nephropathy (IgAN); however, the specific underlying mechanism and an appropriate therapeutic strategy are yet to be unearthed. This study aimed to investigate the therapeutic effect of triptolide (TP) on IgAN and the mechanism by which TP regulates autophagy and proliferation of mesangial cells through the CARD9/p38 MAPK pathway.MethodsWe established a TP‐treated IgAN mouse model and produced IgA1‐induced human mesangial cells (HMC) and divided them into control, TP, IgAN, and IgAN+TP groups. The levels of mesangial cell proliferation (PCNA, cyclin D1, cell viability, and cell cycle) and autophagy (P62, LC3 II, and autophagy flux rate) were measured, with the autophagy inhibitor 3‐Methyladenine used to explore the relationship between autophagy and proliferation. We observed CARD9 expression in renal biopsies from patients and analyzed its clinical significance. CARD9 siRNA and overexpression plasmids were constructed to investigate the changes in mesangial cell proliferation and autophagy as well as the expression of CARD9 and p‐p38 MAPK/p38 MAPK following TP treatment.ResultsAdministering TP was safe and effectively alleviated mesangial cell proliferation in IgAN mice. Moreover, TP inhibited IgA1‐induced HMC proliferation by promoting autophagy. The high expression of CARD9 in IgAN patients was positively correlated with the severity of HMC proliferation. CARD9/p38 MAPK was involved in the regulation of HMC autophagy and proliferation, and TP promoted autophagy to inhibit HMC proliferation by downregulating the CARD9/p38 MAPK pathway in IgAN.ConclusionTP promotes autophagy to inhibit mesangial cell proliferation in IgAN via the CARD9/p38 MAPK pathway.

The proliferation of glomerular mesangial cells is the most basic pathological feature for IgA nephropathy (IgAN). Galactose‐deficient IgA1 (Gd‐IgA1) immune complex deposition activates mesangial cells to mediate specific intracellular signal transduction, promotes mesangial cell proliferation, and initiates kidney damage. Autophagy is involved in mesangial cell proliferation. CARD9 is a risk gene for IgAN. The triptolide (TP), purified from Tripterygium wilfordii hook F., promotes autophagy to inhibit mesangial cell proliferation in IgAN via the CARD9/p38 MAPK pathway.     

Glomerular lesions in HIV-infected patients: a Yale University Department of Medicine Residency Peer-Teaching Conference.

HIV-associated nephropathy (HIVAN) is a clinicopathologic entity characterized by heavy proteinuria, absence of edema and an irreversible decline in renal function. Findings on renal biopsy include: collapsed glomerular capillaries; visceral glomerular epitheliosis; microcystic tubules; mesangial prominence; and endothelial tubuloreticular inclusions. Early in the AIDS epidemic, HIVAN was the predominant glomerular lesion observed in HIV-infected patients. It is being increasingly recognized, especially in Caucasian populations, that a variety of immune complex-mediated lesions such as membranoproliferative glomerulonephritis, proliferative glomerulonephritis and IgA nephropathy are associated with HIV infection. In this review we present two cases: one patient whose first presentation of AIDS was end-stage renal disease, who on biopsy was found to have HIVAN, and the second, who was infected with HIV, and on biopsy was found to have hepatitis C-related hepatitis C related membranoproliferative glomerulonephritis. We also review the current literature on HIVAN and HIV-associated immune complex diseases (HIVICDs). Each case illustrates an important clinical point. The first that renal disease can be the first manifestation of HIV infection and the second that HIV-infected patients may develop immune complex related renal diseases, some of which may be potentially treatable.     

Decoy receptor 3 inhibits renal mononuclear leukocyte infiltration and apoptosis and prevents progression of IgA nephropathy in mice

The progression of IgA nephropathy (IgAN), the most frequent type of primary glomerulonephritis, is associated with high levels of mononuclear leukocyte infiltration into the kidney. These cells consist mainly of T cells and macrophages. Our previous study showed that a decoy receptor 3 (DCR3) gene therapy can prevent the development of a mouse autoimmune glomerulonephritis model by its potent immune modulating effects (Ka SM, Sytwu HK, Chang DM, Hsieh SL, Tsai PY, Chen A. J Am Soc Nephrol 18: 2473-2485, 2007). Here, we tested the hypothesis that DCR3 might prevent the progression of IgAN, an immune complex-mediated primary glomerulonephritis, by inhibiting T cell activation, renal T cell/macrophage infiltration, and protecting the kidney from apoptosis. We used a progressive IgAN (Prg-IgAN) model in B cell-deficient mice, because the mice are characterized by a dramatic proliferation of activated T cells systemically and progressive NF-κB activation in the kidney. We treated the animals with short-term gene therapy with DCR3 plasmids by hydrodynamics-based gene delivery. When the mice were euthanized on day 21, we found that, compared with empty vector-treated (disease control) Prg-IgAN mice, DCR3 gene therapy resulted in 1) systemic inhibition of T cell activation and proliferation; 2) lower serum levels of proinflammatory cytokines; 3) improved proteinuria, renal function, and renal pathology (inhibiting the development of marked glomerular proliferation, crescent formation, glomerulosclerosis, and interstitial inflammation); 5) suppression of T cell and macrophage infiltration into the periglomerular interstitium of the kidney; and 5) a reduction in apoptotic figures in the kidney. On the basis of these findings, DCR3 might be useful therapeutically in preventing the progression of IgAN.     

IL-6 and its role in IgA nephropathy development

IL-6 is considered one of the well characterized cytokines exhibiting homeostatic, pro- and anti-inflammatory activities, depending on the receptor variant and the induced intracellular cis- or trans-signaling responses. IL-6-activated pathways are involved in the regulation of cell proliferation, survival, differentiation, and cell metabolism changes.Deviations in IL-6 levels or abnormal response to IL-6 signaling are associated with several autoimmune diseases including IgA nephropathy (IgAN), one of most frequent primary glomerulonephritis worldwide. IgAN is associated with increased plasma concentration of IL-6 and increased plasma concentration of aberrantly galactosylated IgA1 immunoglobulin (Gd-IgA1). Gd-IgA1 is specifically recognized by autoantibodies, leading to the formation of circulating immune complexes (CIC) with nephritogenic potential, since CIC deposited in the glomerular mesangium induce mesangial cells proliferation and glomerular injury. Infection of the upper respiratory or digestive tract enhances IL-6 production and in IgAN patients is often followed by the macroscopic hematuria.This review recapitulates general aspects of IL-6 signaling and summarizes experimental evidences about IL-6 involvement in the etiopathogenesis of IgA nephropathy through the production of Gd-IgA1 and regulation of mesangial cell proliferation.     

Dual Involvement of Growth Arrest-Specific Gene 6 in the Early Phase of Human IgA Nephropathy

Background

Gas6 is a growth factor that causes proliferation of mesangial cells in the development of glomerulonephritis. Gas6 can bind to three kinds of receptors; Axl, Dtk, and Mer. However, their expression and functions are not entirely clear in the different glomerular cell types. Meanwhile, representative cell cycle regulatory protein p27 has been reported to be expressed in podocytes in normal glomeruli with decreased expression in proliferating glomeruli, which inversely correlated with mesangial proliferation in human IgA nephropathy (IgAN).

Methods

The aim of this study is to clarify Gas6 involvement in the progression of IgAN. Expression of Gas6/Axl/Dtk was examined in 31 biopsy proven IgAN cases. We compared the expression levels with histological severity or clinical data. Moreover, we investigated the expression of Gas6 and its receptors in cultured podocytes.

Results

In 28 of 31 cases, Gas6 was upregulated mainly in podocytes. In the other 3 cases, Gas6 expression was induced in endothelial and mesangial cells, which was similar to animal nephritis models. Among 28 podocyte type cases, the expression level of Gas6 correlated with the mesangial hypercellularity score of IgAN Oxford classification and urine protein excretion. It also inversely correlated with p27 expression in glomeruli. As for the receptors, Axl was mainly expressed in endothelial and mesangial cells, while Dtk was expressed in podocytes. In vitro, Dtk was expressed in cultured murine podocytes, and the expression of p27 was decreased by Gas6 stimulation.

Conclusions

Gas6 was uniquely upregulated in either endothelial/mesangial cells or podocytes in IgAN. The expression pattern can be used as a marker to classify IgAN. Gas6 has a possibility to be involved in not only mesangial proliferation via Axl, but also podocyte injury via Dtk in IgAN.     

Role of glomerular proteoglycans in IgA nephropathy

Mesangial matrix expansion is a prominent feature of the most common form of glomerulonephritis, IgA nephropathy (IgAN). To find molecular markers and improve the understanding of the disease, the gene and protein expression of proteoglycans were investigated in biopsies from IgAN patients and correlated to clinical and morphological data. We collected and microdissected renal biopsies from IgAN patients (n = 19) and from healthy kidney donors (n = 14). Patients were followed for an average time of 4 years and blood pressure was according to target guidelines. Distinct patterns of gene expression were seen in glomerular and tubulo-interstitial cells. Three of the proteoglycans investigated were found to be of special interest and upregulated in glomeruli: perlecan, decorin and biglycan. Perlecan gene expression negatively correlated to albumin excretion and progress of the disease. Abundant decorin protein expression was found in sclerotic glomeruli, but not in unaffected glomeruli from IgAN patients or in controls. Transforming growth factor beta (TGF-β), known to interact with perlecan, decorin and biglycan, were upregulated both on gene and protein level in the glomeruli. This study provides further insight into the molecular mechanisms involved in mesangial matrix expansion in IgAN. We conclude that perlecan is a possible prognostic marker for patients with IgAN. In addition, the up-regulation of biglycan and decorin, as well as TGF-β itself, indicate that regulation of TGF-β, and other profibrotic markers plays a role in IgAN pathology.     

Isolated glomerulonephritis with mesangial IgA deposits.

Mesangial deposits of IgA, occurring in the absence of systemic disease known to be associated with nephritis, were detected by immunofluorescence microscopy in renal biopsy specimens from 25 patients (4% of 630 specimens studied). Associated deposits of C3 were always present, usually with IgG, but IgM deposits were less common and C1q was never seen. On light microscopy most of the biopsy specimens showed mesangial of focal nuclear proliferation though some were normal. Fifteen of the 25 patients presented with macroscopic haematuria, which was usually recurrent and preceded by a sore throat, whereas the remaining, and usually older, patients presented with persistent proteinuria and were more likely to have impaired renal function. This incidence of "mesangial IgA disease" is less than that reported by French workers. There was a significantly high incidence of familial renal disease among these patients. No abnormalities of serum complement or IgA concentration were found.     

The Kinetics of Glomerular Deposition of Nephritogenic IgA

Whether IgA nephropathy is attributable to mesangial IgA is unclear as there is no correlation between intensity of deposits and extent of glomerular injury and no clear mechanism explaining how these mesangial deposits induce hematuria and subsequent proteinuria. This hinders the development of a specific therapy. Thus, precise events during deposition still remain clinical challenge to clarify. Since no study assessed induction of IgA nephropathy by nephritogenic IgA, we analyzed sequential events involving nephritogenic IgA from IgA nephropathy-prone mice by real-time imaging systems. Immunofluorescence and electron microscopy showed that serum IgA from susceptible mice had strong affinity to mesangial, subepithelial, and subendothelial lesions, with effacement/actin aggregation in podocytes and arcade formation in endothelial cells. The deposits disappeared 24-h after single IgA injection. The data were supported by a fluorescence molecular tomography system and real-time and 3D in vivo imaging. In vivo imaging showed that IgA from the susceptible mice began depositing along the glomerular capillary from 1 min and accumulated until 2-h on the first stick in a focal and segmental manner. The findings indicate that glomerular IgA depositions in IgAN may be expressed under the balance between deposition and clearance. Since nephritogenic IgA showed mesangial as well as focal and segmental deposition along the capillary with acute cellular activation, all glomerular cellular elements are a plausible target for injury such as hematuria.     

Deletion of the miR-25/93/106b cluster induces glomerular deposition of immune complexes and renal fibrosis in mice

IgA nephropathy (IgAN), the most common form of primary glomerulonephritis, is caused by immune system dysfunction and affects only the kidneys. miRNA was involved in IgAN, in which their roles are still unknown. Herein, we found increased glomerular medulla size, proteinuria, kidney artery resistance, kidney fibrosis and immune complex deposition in 5-month miR-25/93/106b cluster knockout (miR-TKO) mice. In vitro, the inhibition of miR-25 cluster could promote cell proliferation and increase fibrosis-related protein and transferrin receptor (TFRC) expression in human renal glomerular mesangial cell (HRMC). Luciferase assay revealed that inhibition of miR-93/106b cluster could upregulate Ccnd1 expression through direct binding with the 3’UTR of Ccnd1. Conversely, inhibition of Ccnd1 expression prevented miR-93/106b-induced effect in HRMC. These findings suggested that miR-25 cluster played an important role in the progression of IgAN, which provided new insights into the pathogenesis and treatment of IgAN.     

Synergistic Effect of Mesangial Cell-Induced CXCL1 and TGF-β1 in Promoting Podocyte Loss in IgA Nephropathy

Podocyte loss has been reported to relate to disease severity and progression in IgA nephropathy (IgAN). However, the underlying mechanism for its role in IgAN remain unclear. Recent evidence has shown that IgA1 complexes from patients with IgAN could activate mesangial cells to induce soluble mediator excretion, and further injure podocytes through mesangial-podocytic cross-talk. In the present study, we explored the underlying mechanism of mesangial cell-induced podocyte loss in IgAN. We found that IgA1 complexes from IgAN patients significantly up-regulated the expression of CXCL1 and TGF-β1 in mesangial cells compared with healthy controls. Significantly higher urinary levels of CXCL1 and TGF-β1 were also observed in patients with IgAN compared to healthy controls. Moreover, IgAN patients with higher urinary CXCL1 and TGF-β1 presented with severe clinical and pathological manifestations, including higher 24-hour urine protein excretion, lower eGFR and higher cresentic glomeruli proportion. Further in vitro experiments showed that increased podocyte death and reduced podocyte adhesion were induced by mesangial cell conditional medium from IgAN (IgAN-HMCM), as well as rhCXCL1 together with rhTGF-β1. In addition, the over-expression of CXCR2, the receptor for CXCL1, by podocytes was induced by IgAN-HMCM and rhTGF-β1, but not by rhCXCL1. Furthermore, the effect of increased podocyte death and reduced podocyte adhesion induced by IgAN-HMCM and rhCXCL1 and rhTGF-β1 was rescued partially by a blocking antibody against CXCR2. Moreover, we observed the expression of CXCR2 in urine exfoliated podocytes in IgAN patients. Our present study implied that IgA1 complexes from IgAN patients could up-regulate the secretion of CXCL1 and TGF-β1 in mesangial cells. Additionally, the synergistic effect of CXCL1 and TGF-β1 further induced podocyte death and adhesion dysfunction in podocytes via CXCR2. This might be a potential mechanism for podocyte loss observed in IgAN.     

Difference in IgA1 O-glycosylation between IgA deposition donors and IgA nephropathy recipients

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis, and disease recurrence often occurs after transplantation. On the other hands, Asymptomatic IgA deposition (IgAD) is occasionally observed in donated kidney. It is recognized that IgAD does not progress to IgAN, but the mechanism has not demonstrated yet. In IgAN, aberrant IgA1 O-glycan structure in the hinge region (HR) of serum IgA is suggested as one of the most convincing key mediators. However, little is known about IgA1 O-glycan structure in IgAD patients. Herein, we investigated the prevalence of IgAD in living renal transplant donors in our cohort. IgAD was observed in 21(13.0%) among 161 renal transplant donors and have statistically significant blood relationship with IgAN recipients (28.6% in relatives vs. 9.8% in non-relatives, respectively; p?=?0.0073). Next, we evaluated the IgA1 O-glycan structure of serum IgA from IgAN recipients (n?=?26), IgAD donors (n?=?17), and non-IgAD helthy donors (n?=?27) using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI–TOF MS). The numbers of GalNAc and Gal and the Gal/GalNAc ratio in the HR of the IgAN recipients had significantly lower comparing to the IgAD and non-IgAD healthy donors. The decreased Gal/GalNAc ratio in IgAN recipients means the increased ratio of galactose-deficient IgA1. To the best of our knowledge, this is the first report to compare the O-glycan structures in IgAN recipients and IgAD donors using MALDI–TOF MS. We concluded that IgAD was more common in IgAN related donors. Overall, decreased GalNAc and Gal contents in HR could play a material pathogenic role in IgAN.