AGE-RAGE signal generates a specific NF-κB RelA “barcode” that directs collagen I expression

Peng, Yunqian; Kim, Ji Min; Park, Hal Sol; Yang, Annie; Islam, Celia; Lakatta, Edward G.; Li, Lin

doi:10.1038/srep18822

Cited by 37 publications

(34 citation statements)

References 59 publications

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“…Most importantly, collagen I diminished to a level below the one registered in BSA and nonimmune murine IgG exposed cells, suggesting RAGE may be involved (via NF-κB signaling) in steady state collagen I expression in these cells. Recently, collagen type I expression was shown to be induced in a very specific manner by NF-κB p65 via the AGEs-RAGE axis [ 59 ]. This is in accordance with our findings which showed that anti-RAGE antibody treatment severely diminished NF-κB p65 ( Fig 4 ).…”

Section: Resultsmentioning

confidence: 99%

RAGE and TGF-β1 Cross-Talk Regulate Extracellular Matrix Turnover and Cytokine Synthesis in AGEs Exposed Fibroblast Cells

et al. 2016

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AGEs accumulation in the skin affects extracellular matrix (ECM) turnover and triggers diabetes associated skin conditions and accelerated skin aging. The receptor of AGEs (RAGE) has an essential contribution to cellular dysfunction driven by chronic inflammatory responses while TGF-β1 is critical in both dermal homeostasis and inflammation. We investigated the contribution of RAGE and TGF-β1 to the modulation of inflammatory response and ECM turnover in AGEs milieu, using a normal fibroblast cell line. RAGE, TGF-β1, collagen I and III gene and protein expression were upregulated after exposure to AGEs-BSA, and MMP-2 was activated. AGEs-RAGE was pivotal in NF-κB dependent collagen I expression and joined with TGF-β1 to stimulate collagen III expression, probably via ERK1/2 signaling. AGEs-RAGE axis induced upregulation of TGF-β1, TNF-α and IL-8 cytokines. TNF-α and IL-8 were subjected to TGF-β1 negative regulation. RAGE’s proinflammatory signaling also antagonized AGEs-TGF-β1 induced fibroblast contraction, suggesting the existence of an inhibitory cross-talk mechanism between TGF-β1 and RAGE signaling. RAGE and TGF-β1 stimulated anti-inflammatory cytokines IL-2 and IL-4 expression. GM-CSF and IL-6 expression appeared to be dependent only on TGF-β1 signaling. Our data also indicated that IFN-γ upregulated in AGEs-BSA milieu in a RAGE and TGF-β1 independent mechanism. Our findings raise the possibility that RAGE and TGF-β1 are both involved in fibrosis development in a complex cross-talk mechanism, while also acting on their own individual targets. This study contributes to the understanding of impaired wound healing associated with diabetes complications.

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Section: Resultsmentioning

confidence: 99%

RAGE and TGF-β1 Cross-Talk Regulate Extracellular Matrix Turnover and Cytokine Synthesis in AGEs Exposed Fibroblast Cells

et al. 2016

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“…Both of these pathways activate NF κ B, which would allow for the conclusion that RAGE signaling increases NF κ B activity [ 69 ]. An increase in NF κ B transcription activity can lead to an increase in mRNA expression of type I collagen a1 and a2 in murine VSMCs treated with AGEs as shown in Peng et al [ 70 ]. Collectively, AGE-induced RAGE signaling affects the activity of NF κ B in VSMCs, which can lead to remodeling of the type I collage in the ECM or to a change in cell morphology.…”

Section: Age-rage Signaling and Oxidative Stress In Vascular Calcimentioning

confidence: 99%

The Role of AGE/RAGE Signaling in Diabetes-Mediated Vascular Calcification

Kay

Simpson

Stewart

2016

Journal of Diabetes Research

257

170

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AGE/RAGE signaling has been a well-studied cascade in many different disease states, particularly diabetes. Due to the complex nature of the receptor and multiple intersecting pathways, the AGE/RAGE signaling mechanism is still not well understood. The purpose of this review is to highlight key areas of AGE/RAGE mediated vascular calcification as a complication of diabetes. AGE/RAGE signaling heavily influences both cellular and systemic responses to increase bone matrix proteins through PKC, p38 MAPK, fetuin-A, TGF-β, NFκB, and ERK1/2 signaling pathways in both hyperglycemic and calcification conditions. AGE/RAGE signaling has been shown to increase oxidative stress to promote diabetes-mediated vascular calcification through activation of Nox-1 and decreased expression of SOD-1. AGE/RAGE signaling in diabetes-mediated vascular calcification was also attributed to increased oxidative stress resulting in the phenotypic switch of VSMCs to osteoblast-like cells in AGEs-induced calcification. Researchers found that pharmacological agents and certain antioxidants decreased the level of calcium deposition in AGEs-induced diabetes-mediated vascular calcification. By understanding the role the AGE/RAGE signaling cascade plays diabetes-mediated vascular calcification will allow for pharmacological intervention to decrease the severity of this diabetic complication.

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“…However, we found increased activation of the NF-κB pathway as demonstrated by the increased p-IκB/t-IκB ratio in association with decreased c-Met phosphorylation, as well as increased levels of TNFα and IL-6 in crizotinib-treated mice compared to control counterparts. TNF family cytokines can activate the NF-κB signaling pathway and NF-κB activation can induce collagen expression and cause tissue fibrosis in a TGFβ-independent fashion [ 35 , 36 , 37 ]. The NF-κB pathway may also cause tissue fibrosis by promoting differentiation of epithelial cells to fibroblasts [ 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Renal Injury during Long-Term Crizotinib Therapy

Yasuma

Kobayashi

D’Alessandro-Gabazza

et al. 2018

IJMS

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Crizotinib is highly effective against anaplastic lymphoma kinase-positive and c-ros oncogen1-positive non-small cell lung cancer. Renal dysfunction is associated with crizotinib therapy but the mechanism is unknown. Here, we report a case of anaplastic lymphoma kinase positive non-small cell lung cancer showing multiple cysts and dysfunction of the kidneys during crizotinib administration. We also present results demonstrating that long-term crizotinib treatment induces fibrosis and dysfunction of the kidneys by activating the tumor necrosis factor-α/nuclear factor-κB signaling pathway. In conclusion, this study shows the renal detrimental effects of crizotinib, suggesting the need of careful monitoring of renal function during crizotinib therapy.

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AGE-RAGE signal generates a specific NF-κB RelA “barcode” that directs collagen I expression

Cited by 37 publications

References 59 publications

RAGE and TGF-β1 Cross-Talk Regulate Extracellular Matrix Turnover and Cytokine Synthesis in AGEs Exposed Fibroblast Cells

RAGE and TGF-β1 Cross-Talk Regulate Extracellular Matrix Turnover and Cytokine Synthesis in AGEs Exposed Fibroblast Cells

The Role of AGE/RAGE Signaling in Diabetes-Mediated Vascular Calcification

Renal Injury during Long-Term Crizotinib Therapy

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