Anti-dsDNA antibody induces soluble fibronectin secretion by proximal renal tubular epithelial cells and downstream increase of TGF-β1 and collagen synthesis

Yung, Susan; Ng, Claudia Y.C.; Ho, Sau Kwan; Cheung, Kwok Fan; Chan, Kwok Wah; Zhang, Qing; Chau, Michael; Chan, Tak Mao

doi:10.1016/j.jaut.2015.01.008

Cited by 52 publications

(43 citation statements)

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“…Previous studies showed that anti-dsDNA IgG enhances the production of proinflammatory cytokines and fibrotic factors in cultured mesangial and tubular cells (12, 13). Consistently, we found that the profibrotic factors including TGF-β1, PDGFB, and CTGF have higher mRNA levels in kidneys of anti-dsDNA IgG-injected SCID mice.…”

Section: Discussionmentioning

confidence: 99%

Anti-Double-Stranded DNA IgG Participates in Renal Fibrosis through Suppressing the Suppressor of Cytokine Signaling 1 Signals

et al. 2017

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Suppressor of cytokine signaling 1 (SOCS1) participates in renal fibrosis by downregulating Janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1)-mediated cytokine signaling. Recently, it was found that anti-double-stranded DNA (dsDNA) IgG induces the synthesis of profibrotic cytokines by renal cells. To explore the potential effect of anti-dsDNA IgG on SOCS1-mediated renal fibrosis, kidney tissues were collected from patients with lupus nephritis (LN) as well as MRL/lpr lupus-prone mice. The SOCS1 expression was evaluated in tissue samples. In addition, SCID mice were injected with anti-dsDNA IgG, followed by evaluation of SOCS1 levels. Renal resident cells were cultured in vitro, receiving the stimulation of anti-dsDNA IgG and then the measurement of SOCS1, JAK2, STAT1α, and profibrotic cytokines. Moreover, the binding of anti-dsDNA IgG to SOCS1 kinase inhibitory region (KIR) peptide was analyzed by surface plasmon resonance. We found that SOCS1 expression was inhibited, but JAK2/STAT1 activation was prominent in the kidney tissues of patients with LN, MRL/ lpr mice, or anti-dsDNA IgG-injected SCID mice. The cultured renal cells also showed SOCS1 downregulation, JAK2/STAT1 activation, and profibrotic cytokine promotion upon anti-dsDNA IgG stimulation. Surprisingly, anti-dsDNA IgG showed high affinity to KIR peptide and competed with JAK2 loop for KIR. Additionally, a DNA-mimicking peptide (ALW) blocked the binding of anti-dsDNA IgG to KIR, and even partially abrogated the activation of JAK2/STAT1α signals and the expression of profibrotic cytokines in SCID mice. In conclusion, anti-dsDNA IgG downregulates SOCS1 expression, activates JAK2/STAT1 signals, and contributes to renal fibrosis; its peptide blockade may restore the SOCS1 inhibitory effect on the production of profibrotic cytokine, and finally ameliorate renal fibrosis in LN.

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Section: Discussionmentioning

confidence: 99%

Anti-Double-Stranded DNA IgG Participates in Renal Fibrosis through Suppressing the Suppressor of Cytokine Signaling 1 Signals

et al. 2017

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“…There is evidence that in addition to contributing to immune complex formation, pathogenic anti-dsDNA antibodies can bind to resident renal cells and induce downstream apoptotic, inflammatory, and fibrotic processes 10, 12, 14– 20 . There is increasing evidence to suggest that the pathogenic potential of anti-dsDNA antibodies is not dependent on its interaction with dsDNA per se since dsDNA is poorly immunogenic 21 but is instead reliant on its poly-reactive nature and ability to bind to cross-reactive antigens on the surface of resident renal cells or constituents of their extracellular matrix 22– 24 .…”

Section: Overview Of Lupus Nephritis Pathogenesismentioning

confidence: 99%

“…We reported that anti-dsDNA antibodies isolated from patients with LN during nephritic flare can induce secretion of pro-inflammatory mediators such as IL-6, IL-8, TNF-α, and MCP-1 through distinct MAPK pathways in cultured PTECs 14, 39 and contribute to the establishment of chemotactic gradients that permit infiltration of immune cells into the tubulo-interstitium. Bi-directional communication occurs between mesangial cells and PTECs, and inflammatory responses occurring in either kidney compartment induced by anti-dsDNA antibodies can provoke a response in the other compartment 10 .…”

Section: Recent Knowledge On Renal Inflammation In Lupus Nephritismentioning

confidence: 99%

“…Intra-glomerular fibronectin expression is increased in patients and mice with active LN 15, 16 and co-localizes with IgG deposition, suggesting an association between autoantibody deposition and matrix protein accumulation 16 . We reported that anti-dsDNA antibodies can induce both soluble and fibrillar fibronectin synthesis in mesangial cells and PTECs through increased PKC and MAPK signaling and TGF-β1, MCP-1, IL-6, IL-8, and TNF-α secretion 14, 16 . Our observation that pro-inflammatory mediators can also contribute to increased fibrogenesis highlights their multi-faceted functions during pathogenesis.…”

Section: Recent Knowledge On Renal Fibrosis In Lupus Nephritismentioning

confidence: 99%

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Recent advances in the understanding of renal inflammation and fibrosis in lupus nephritis

2017

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Lupus nephritis is a potentially reversible cause of severe acute kidney injury and is an important cause of end-stage renal failure in Asians and patients of African or Hispanic descent. It is characterized by aberrant exaggerated innate and adaptive immune responses, autoantibody production and their deposition in the kidney parenchyma, triggering complement activation, activation and proliferation of resident renal cells, and expression of pro-inflammatory and chemotactic molecules leading to the influx of inflammatory cells, all of which culminate in destruction of normal nephrons and their replacement by fibrous tissue. Anti-double-stranded DNA (anti-dsDNA) antibody level correlates with disease activity in most patients. There is evidence that apart from mediating pathogenic processes through the formation of immune complexes, pathogenic anti-dsDNA antibodies can bind to resident renal cells and induce downstream pro-apoptotic, pro-inflammatory, or pro-fibrotic processes or a combination of these. Recent data also highlight the critical role of macrophages in acute and chronic kidney injury. Though clinically effective, current treatments for lupus nephritis encompass non-specific immunosuppression and the anti-inflammatory action of high-dose corticosteroids. The clinical and histological impact of novel biologics targeting pro-inflammatory molecules remains to be investigated. Insight into the underlying mechanisms that induce inflammatory and fibrotic processes in the kidney of lupus nephritis could present opportunities for more specific novel treatment options to improve clinical outcomes while minimizing off-target untoward effects. This review discusses recent advances in the understanding of pathogenic mechanisms leading to inflammation and fibrosis of the kidney in lupus nephritis in the context of established standard-of-care and emerging therapies.

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“…Anti-Sm trig other auto-antibodies to be produced in an abundant, and then result in the more severe lupus manifestations. 23 In this research, QUE did not reduce the anti-Sm level significantly. The same effect also happened to the positive control group which received cyclophosphamide.…”

Section: Foxp3 + T Cells ± Sd (%)mentioning

confidence: 50%

FOXP3 Modulation of Quercetin-3-O-rhamnoside and its Impacts on Lupus Nephritis Mice

Indriyanti¹,

Soeroso²,

Khotib³

2018

JYP

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Background: Quercetin-3-O-rhamnoside (QUE) has anti-inflammatory and anti-oxidative effects which probably beneficially used in lupus. Objective: This research was focused on analyzing the effects of QUE on FOXP3 modulation to result in an anti-inflammatory outcome in the kidney of severe lupus mice. Methods: This research used Pristane-induced female BALB/c lupus mice, and the biomarkers involved in were CD4 + CD25+ T reg cells, FOXP3 T cells, anti-Sm, IL-6, and histopathology assessment of the kidney of lupus mice. The QUE group was treated and compared to the negative control which received placebo, and the positive control which received cyclophosphamide. Results: QUE increased the number of CD4 + CD25 + T reg cells (negative control: 3.01±3.43%; QUE: 18.77±5.12%; positive control: 3.26±11.09%), and FOXP3 significantly (p<0.05) (negative control: 1.14±0.54%; QUE: 2.00±1.45%; positive control: 1.73±1.14%). The antiSm level did not decrease, meanwhile the IL-6 decreased significantly, and the histopathological assessment of the kidney reveal the repairing effects of QUE on glomeruli. Conclusion: QUE has an anti-inflammatory activity which reduces the severity of lupus nephritis signs in lupus mice by initially increasing the CD4 + CD25+ and FOXP3 + Tregs numbers. QUE is potential to be further developed as a safe treatment choice for lupus nephritis. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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Anti-dsDNA antibody induces soluble fibronectin secretion by proximal renal tubular epithelial cells and downstream increase of TGF-β1 and collagen synthesis

Cited by 52 publications

References 64 publications

Anti-Double-Stranded DNA IgG Participates in Renal Fibrosis through Suppressing the Suppressor of Cytokine Signaling 1 Signals

Anti-Double-Stranded DNA IgG Participates in Renal Fibrosis through Suppressing the Suppressor of Cytokine Signaling 1 Signals

Recent advances in the understanding of renal inflammation and fibrosis in lupus nephritis

FOXP3 Modulation of Quercetin-3-O-rhamnoside and its Impacts on Lupus Nephritis Mice

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