Endothelial injury by circulating IgA1 complex through the activation of mesangial cells in IgA nephropathy

Abstract Background: Renal arteriolar microangiopathic (MA) lesions were common in IgA nephropathy (IgAN) and their presence was an independent risk factor for kidney failure. Endothelial injury is regarded as the most important cause of MA lesions. The deposition of circulating IgA1 complex (cIgA1) in the glomerular mesangium has been regarded as the most important mechanism to induce the injury of podocyte and tubular epithelium. Whether cIgA1 can induce vascular endothelial injury is not clear.Methods: Blood of 59 IgAN patients and 19 healthy controls was collected, pending the measurement of Willebrand factor (vWF) and soluble vascular cell adhesion molecule 1 (sVCAM1) and Heparin-binding EGF-like growth factor (HB-EGF) by ELISA. cIgA1 was isolated from 12 primary IgAN patients who had not been treated with steroids or immunosuppressants and 10 healthy controls. Then, IgA-HMC medium (IgA-HMCM) was prepared by collecting the cell culture supernatants of growth-arrested HMCs grown in medium containing cIgA1. Human umbilical vein endothelial cells (HUVECs) were cultured with the IgA-HMCM in the presence or absence of Panax notoginseng saponins (PNS), which are anti-inflammatory bioactive components of the Chinese medicinal herb Panax notoginseng. The protein levels of interleukin-6 (IL-6) and chemokine (C-X-C motif) ligand 1 (CXCL1) in IgA-HMCM and vWF, sVCAM1 and HB-EGF in HUVEC medium were determined by ELISA. Results: IgAN patients had higher levels of vWF, sVCAM-1 and HB-EGF than that in healthy controls. cIgA1 from IgAN patients (IgAN-cIgA1) induced significantly higher expression levels of IL-6 and CXCL1 in HMCM than cIgA1 from healthy controls. vWF, sVCAM1 and HB-EGF levels induced by conditioned IgAN-cIgA1-treated HMCM (IgAN-HMCM) were significantly higher than the levels induced by conditioned cIgA1-treated HMCM from healthy controls (HC-HMCM). After HUVECs were cultured in PNS and IgAN-HMCM, the levels of vWF, sVCAM1 and HB-EGF were significantly lower in the culture supernatants of cells cultured in PNS and IgAN-HMCM than in that of cells cultured in IgAN-HMCM alone. Conclusion: cIgA1 could activate mesangial cells and, in turn, induce the injury of endothelial cells by inflammation factors in vitro.

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Faculty Opinions recommendation of Spleen tyrosine kinase is important in the production of proinflammatory cytokines and cell proliferation in human mesangial cells following stimulation with IgA1 isolated from IgA nephropathy patients.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718077294.793513964 ◽

2016 ◽

Author(s):

Kar Neng Lai

Keyword(s):

Cell Proliferation ◽

Tyrosine Kinase ◽

Iga Nephropathy ◽

Proinflammatory Cytokines ◽

Mesangial Cells ◽

Spleen Tyrosine Kinase ◽

Human Mesangial Cells

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Mesangial Cells Stimulated by Immunoglobin A1 from IgA Nephropathy Upregulates Transforming Growth Factor-β1 Synthesis in Podocytes Via Renin-Angiotensin System Activation

Archives of Medical Research ◽

10.1016/j.arcmed.2010.05.003 ◽

2010 ◽

Vol 41 (4) ◽

pp. 255-260 ◽

Cited By ~ 8

Author(s):

Cheng Wang ◽

Xun Liu ◽

Hui Peng ◽

Ying Tang ◽

Hua Tang ◽

...

Keyword(s):

Growth Factor ◽

Iga Nephropathy ◽

Transforming Growth Factor ◽

Mesangial Cells ◽

Renin Angiotensin System ◽

Transforming Growth Factor Β1 ◽

Angiotensin System ◽

Renin Angiotensin ◽

System Activation

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MO262THE SINGLE-CELL TRANSCRIPTOMICS OF HUMAN IGA NEPHROPATHY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab104.0020 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Yong Zhong ◽

Xiangcheng Xiao

Keyword(s):

Gene Expression ◽

Single Cell ◽

Signaling Pathways ◽

Iga Nephropathy ◽

Molecular Mechanisms ◽

Mesangial Cells ◽

Therapeutic Targets ◽

Cell Types ◽

Receptor Crosstalk ◽

Overt Proteinuria

Abstract Background and Aims The exact molecular mechanisms underlying IgA nephropathy (IgAN) remains incompletely defined. Therefore, it is necessary to further elucidate the mechanism of IgA nephropathy and find novel therapeutic targets. Method Single-cell RNA sequencing (scRNA-seq) was applied to kidney biopsies from 4 IgAN and 1 control subjects to define the transcriptomic landscape at the single-cell resolution. Unsupervised clustering analysis of kidney specimens was used to identify distinct cell clusters. Differentially expressed genes and potential signaling pathways involved in IgAN were also identified. Results Our analysis identified 14 cell subsets in kidney biopsies from IgAN patients, and analyzed changing gene expression in distinct renal cell types. We found increased mesangial expression of several novel genes including MALAT1, GADD45B, SOX4 and EDIL3, which were related to proliferation and matrix accumulation and have not been reported in IgAN previously. The overexpressed genes in tubule cells of IgAN were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling and NOD-like receptor signaling. Moreover, the receptor-ligand crosstalk analysis revealed potential interactions between mesangial cells and other cells in IgAN. Specifically, IgAN with overt proteinuria displayed elevated genes participating in several signaling pathways which may be involved in pathogenesis of progression of IgAN. Conclusion The comprehensive analysis of kidney biopsy specimen demonstrated different gene expression profile, potential pathologic ligand-receptor crosstalk, signaling pathways in human IgAN. These results offer new insight into pathogenesis and identify new therapeutic targets for patients with IgA nephropathy.

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Mass spectrometry-based circulating IgA1 complexes screening driven identification of IgA-alpha-1-microglobulin complex in IgA nephropathy

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa352 ◽

2020 ◽

Author(s):

Boyang Xu ◽

Li Zhu ◽

Qingsong Wang ◽

Yanfeng Zhao ◽

Meng Jia ◽

...

Keyword(s):

Mass Spectrometry ◽

Iga Nephropathy ◽

Cell Injury ◽

Mesangial Cell ◽

Mesangial Cells ◽

Independent Population ◽

Tubulointerstitial Lesions ◽

Noninvasive Biomarker

Abstract Background IgA nephropathy (IgAN) is characterized by predominant IgA deposition in the glomerular mesangium. Previous studies proved that renal-deposited IgA in IgAN came from circulating IgA1-containing complexes (CICs). Methods To explore the composition of CICs in IgAN, we isolated CICs from IgAN patients and healthy controls, and then quantitatively analyzed them by mass spectrometry. Meanwhile, the isolated CICs were used to treat human mesangial cells to monitor mesangial cell injury. Taken together the proteins content and injury effects, the key constituent in CICs was identified. Then, the circulating levels of identified key constituent-IgA complex were detected in an independent population by an in-house-developed ELISA. Results By comparing the proteins of CICs between IgAN patients and controls, we found that 14 proteins showed significantly different levels. Among them, alpha-1-microglobulin content in CICs was associated with not only in vitro mesangial cell proliferation and MCP-1 secretion but also in vivo eGFR levels and tubulointerstitial lesions in IgAN patients. Moreover, we found alpha-1-microglobulin was prone to bind aberrant glycosylated IgA1. Additionally, an elevated circulating IgA-alpha-1-microglobulin complex levels were detected in an independent IgAN population, and IgA-alpha-1-microglobulin complex levels were correlated with hypertension, eGFR levels and Oxford-T scores in these IgAN patients. Conclusions Our results suggest that the IgA-alpha-1-microglobulin complex is an important constituent in CICs, and that circulating IgA-alpha-1-microglobulin complex detection might serve as a potential noninvasive biomarker detection method for IgAN.

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