BAFF is involved in the pathogenesis of IgA nephropathy by activating the TRAF6/NF‑κB signaling pathway in glomerular mesangial cells

Cao, Yihan; Lu, Guoyuan; Chen, Xiaolan; Xu, Chen; Guo, Naifeng; Li, Wenwen

doi:10.3892/mmr.2019.10870

Cited by 11 publications

(9 citation statements)

References 39 publications

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“…Abnormalities in the production of BAFF are closely associated with B-cell-mediated autoimmune diseases, including IgAN. Serum levels of BAFF were reportedly significantly higher in patients with IgAN than those in controls; these levels were positively correlated with the severity of histopathological damage such as mesangial hypercellularity and segmental glomerulosclerosis, thus indicating that serum BAFF levels could be a noninvasive biomarker for monitoring the disease severity and a potential therapeutic target in IgAN ( Xin et al, 2013 ; Li et al, 2014 ; Cao et al, 2020 ).…”

Section: Regulation Of Immune Response In Iganmentioning

confidence: 97%

An Update on Targeted Treatment of IgA Nephropathy: An Autoimmune Perspective

Huang

2021

Front. Pharmacol.

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Immunoglobulin (Ig) A nephropathy (IgAN) is the commonest form of primary glomerulonephritis worldwide and is, considered a significant cause of end-stage renal disease in young adults. The precise pathogenesis of IgAN is unclear. The clinical and pathological features vary significantly between individuals and races, which makes treating IgAN difficult. Currently, the therapeutic strategies in IgAN are still optimal blood pressure control and proteinuria remission to improve the renal function in most cases. Immunosuppressive drugs such as corticosteroids can be considered in patients with persistent proteinuria and a high risk of renal function decline; however, they include a high toxicity profile. Therefore, the safety and selectivity of medications are critical concerns in the treatment of IgAN. Various pharmacological therapeutic targets have emerged based on the evolving understanding of the autoimmune pathogenesis of IgAN, which involves the immune response, mucosal immunity, renal inflammation, complement activation, and autophagy; treatments based on these mechanisms have been explored in preclinical and clinical studies. This review summarizes the progress concerning targeted therapeutic strategies and the relevant autoimmune pathogenesis in IgAN.

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Section: Regulation Of Immune Response In Iganmentioning

confidence: 97%

An Update on Targeted Treatment of IgA Nephropathy: An Autoimmune Perspective

Huang

2021

Front. Pharmacol.

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“…In addition to direct interaction between Gd-IgA and mesangial cells, there are several other factors enhancing mesangial cell proliferation, ECM production, and cytokine release from mesangial cells. B cell-activating factor belonging to the TNF family (BAFF), which is generally vital for B-cell survival, proliferation, and activation, could also target BAFF receptors on mesangial cells to promote proliferation through Akt activation ( 51 ) and enhance fibroblast factors expression like connective tissue growth factor (CTGF) and fibronectin (FN) in mesangial cells through tumor necrosis factor receptor-associated factor 6 (TRAF6)/NF-κB signaling pathway ( 52 ). ADAMTS5, one member of the metalloproteinase family, was upregulated in infiltrated monocytes in IgAN tubulointerstitium and glomeruli (but not in the tissue-resident macrophages), which affected multiple ECM proteins ( 53 ) including basement membrane components and basement membrane-binding integrins.…”

Section: Mesangial Cellmentioning

confidence: 99%

Molecular insight in intrarenal inflammation affecting four main types of cells in nephrons in IgA nephropathy

2023

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Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis and the leading cause of kidney failure in the world. The current widely accepted framework for its pathogenesis is the “multi-hit hypothesis.” In this review, we mainly discussed the intrarenal inflammation in IgAN, which is initiated by immune complex deposition with complement molecule activation, by focusing on four main types of cells in nephrons including mesangial cells, endothelial cells, podocytes, and tubular epithelial cells (TECs). Galactose-deficient IgA1 (Gd-IgA1)-containing immune complexes deposit in the mesangium and activate complement molecules and mesangial cells. Activation of mesangial cells by Gd-IgA1 deposition with enhanced cellular proliferation, extracellular matrix (ECM) expansion, and inflammatory response plays a central role in the pathogenesis of IgAN. Regional immune complex deposition and mesangial–endothelial crosstalk result in hyperpermeability of endothelium with loss of endothelial cells and infiltration barrier proteins, and recruitment of inflammatory cells. Podocyte damage is mainly derived from mesangial–podocyte crosstalk, in which tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), renin-angiotensin-aldosterone system (RAAS), and micro-RNAs are the major players in podocyte apoptosis and disorganization of slit diaphragm (SD) related to proteinuria in patients with IgAN. In addition to filtrated proteins into tubulointerstitium and mesangial–tubular crosstalk involved in the injury of TECs, retinoic acid has been discovered innovatively participating in TEC injury.

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“…Of great importance, the PCR cycles were: Pretreatment for 10 min at 95˚C, 96˚C for 15 sec, 64˚C for 45 sec (45 cycles), 96˚C for 15 sec, 64˚C for 1 min, 95˚C for 15 sec, a final extension at 75˚C for 10 min and held at 4˚C. The relative gene expression of BTK and TNF-α was calculated using the 2 -∆∆Cq method (27) and normalized with β-actin. The primer sequence, designed by Invitrogen (Thermo Fisher Scientific, Inc.), used for BTK was F, 5'-TGTTGAAACAGT GGTTCCTGA-3' and R, 5'-TGCTCCATTTCACTGGAC TCT-3'; TNF-α was F, 5'-CAGCCTCTTCTCCTTCCTGA-3' and R, 5'-GGAAGACCCCTCCCAGATAGA-3' and β-actin was F, 5'-ATGGGCCAGAAAGATGCCTATGT-3' and R, 5'-ATGCCAGGGAACATAGTTGAGCC-3' .…”

Section: Development Of Collagen-induced Arthritis (Cia) Mouse Modelmentioning

confidence: 99%

Synergistic effect of Bruton's tyrosine kinase and TNF‑α in the regulation of rheumatoid arthritis and underlying mechanisms

Du¹

2021

Exp Ther Med

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The presence of Bruton's tyrosine kinase (BTK) in macrophages has been recommended as a promising therapeutic target for rheumatoid arthritis (RA). In addition, activated macrophages in the inflamed joints of patients with RA can also produce a plethora of cytokines, such as TNF-α. The aim of the present study was to investigate the potential role of BTK and TNF-α in the regulation of RA. The results demonstrated that higher levels of BTK and TNF-α were observed in macrophages in inflamed RA joints compared with those in normal joint tissues. Subsequently, the role of BTK and TNF-α in the regulation of cellular process in inflammatory macrophages was analyzed. It was demonstrated that aberrant expression of BTK and TNF-α in inflammatory macrophages can lead to higher cell proliferation rates. Once the expression of BTK or TNF-α was restricted by using short interfering (si)RNAs (siBTK or siTNF-α), the activity of inflammatory macrophages was significantly downregulated. Of note, when the expression of BTK and TNF-α was simultaneously decreased, the proliferation rate of inflammatory macrophages was inhibited to the greatest extent. Subsequently, the underlying mechanisms through which BTK and TNF-α can regulate RA were investigated. The results demonstrated that BTK mainly regulated the ERK/JNK pathway, while TNF-α mainly affected the inactive rhomboid protein 2/B-cell-activating factor pathway. Finally, animal experiments demonstrated that simultaneous silencing of both BTK and TNF-α can significantly alleviate the symptoms associated with RA.

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BAFF is involved in the pathogenesis of IgA nephropathy by activating the TRAF6/NF‑κB signaling pathway in glomerular mesangial cells

Cited by 11 publications

References 39 publications

An Update on Targeted Treatment of IgA Nephropathy: An Autoimmune Perspective

An Update on Targeted Treatment of IgA Nephropathy: An Autoimmune Perspective

Molecular insight in intrarenal inflammation affecting four main types of cells in nephrons in IgA nephropathy

Synergistic effect of Bruton's tyrosine kinase and TNF‑α in the regulation of rheumatoid arthritis and underlying mechanisms

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