High glucose induces and activates Toll-like receptor 4 in endothelial cells of diabetic retinopathy

Wang, Lu; Wang, Jing; Jia, Fang; Zhou, Hongyan; Liu, Xialin; Su, Shao Bo

doi:10.1186/s13098-015-0086-4

Cited by 67 publications

(49 citation statements)

References 36 publications

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“…Pahwa et al found that TLR4 mediate hyperglycemia induced macrovascular aortic endothelial cell inflammation and perturbation of the endothelial glycocalyx [47]. And high glucose could also induce and activate TLR4 in endothelial cells of diabetic retinopathy [48, 49]. The present study demonstrated that TLR4 knock-down curbed the abnormal proliferation of mesangial cells induced by hyperglycemia, which was in accordance with the others reports.…”

Section: Discussionsupporting

confidence: 91%

High Glucose Induces Mouse Mesangial Cell Overproliferation via Inhibition of Hydrogen Sulfide Synthesis in a TLR-4-Dependent Manner

Ding¹,

Chen²,

Li³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Overproliferation of mesangial cells was believed to play an important role in the progress of diabetic nephropathy, one of the primary complications of diabetes. Hydrogen sulfide (H₂S), a well-known and pungent gas with the distinctive smell of rotten eggs, was discovered to play a protective role in diabetic nephropathy. Methods: MTT assay was used to examine the viability of mesangial cells. Small interfering RNA was used to knock down the expression of TLR4 while specific inhibitor LY294002 to suppress the function of PI3K. H₂S generation rate was determined by a H₂S micro-respiration sensor. Results: Glucose of 25mM induced significant mesangial cells proliferation, which was accomplished by significantly inhibited endogenous H₂S synthesis. And exogenous H₂S treatment by NaHS markedly mitigated the overproliferation of mouse mesangial cells. Furthermore, it was found that H₂S deficiency could result in TLR4 activation. And H₂S supplementation remarkably inhibited TLR4 expression and curbed the mesangial cell overproliferation. Besides, PI3K/Akt pathway inhibition also significantly ameliorated the cell overproliferation. Conclusion: High glucose (HG) induces mouse mesangial cell overproliferation via inhibition of hydrogen sulfide synthesis in a TLR-4-dependent manner. And PI3K/Akt pathway might also play a vital part in the HG-induced mesangial cell overproliferation.

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Section: Discussionsupporting

confidence: 91%

High Glucose Induces Mouse Mesangial Cell Overproliferation via Inhibition of Hydrogen Sulfide Synthesis in a TLR-4-Dependent Manner

Ding¹,

Chen²,

Li³

et al. 2017

Cell Physiol Biochem

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“…The inflammatory response produces numerous inflammatory mediators to accelerate the apoptosis of endothelial cells, and vascular permeability [5]. The endothelial cell activation in response to inflammatory stimuli is an initial event in diabetic retinopathy [6] and atherosclerosis [7]. …”

Section: Introductionmentioning

confidence: 99%

Interactions of TLR4 and PPARγ, Dependent on AMPK Signalling Pathway Contribute to Anti-Inflammatory Effects of Vaccariae Hypaphorine in Endothelial Cells

Sun¹,

Zhu²,

Lin³

et al. 2017

Cell Physiol Biochem

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Background /Aims: Accumulating evidence indicates that endothelial inflammation is one of the critical determinants in pathogenesis of atherosclerotic cardiovascular disease. Our previous studies had demonstrated that Vaccariae prevented high glucose or oxidative stress-triggered endothelial dysfunction in vitro. Very little is known about the potential effects of hypaphorine from Vaccariae seed on inflammatory response in endothelial cells. Methods: In the present study, we evaluated the anti-inflammatory effects of Vaccariae hypaphorine (VH) on lipopolysaccharide (LPS)-challenged endothelial EA.hy926 cells. The inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemoattractant protein 1 (MCP-1) and vascular cellular adhesion molecule-1 (VCAM-1) were measured by real-time PCR (RT-PCR). The expressions of adenosine monophosphate-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), toll-like receptor 4 (TLR4), peroxisome proliferator-activated receptor γ (PPARγ) were detected by Western blotting or immunofluorescence. Results: We showed that LPS stimulated the expressions of TNF-α, IL-1β, MCP-1, VCAM-1 and TLR4, but attenuated the phosphorylation of AMPK and ACC as well as PPARγ protein levels, which were reversed by VH pretreatment. Moreover, we observed that LPS-upregulated TLR4 protein expressions were inhibited by PPARγ agonist pioglitazone, and the downregulated PPARγ expressions in response to LPS were partially restored by knockdown of TLR4. The negative regulation loop between TLR4 and PPARγ response to LPS was modulated by AMPK agonist AICAR (5-Aminoimidazole-4-carboxamide riboside or acadesine) or A769662. Conclusions: Taken together, our results suggested that VH ameliorated LPS-induced inflammatory cytokines production in endothelial cells via inhibition of TLR4 and activation of PPARγ, dependent on AMPK signalling pathway.

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“…In addition to responding to the foreign pattern recognition molecules, TLR4 binds to a range of endogenous ligands such as high-mobility group chromatin protein B1 (HMGB1) which was reported to play a significant role in many angiogenesis-related conditions (37)(38)(39). TLR4 is highly expressed and activated in hypoxic and ischemic ocular diseases such as ROP and diabetic retinopathy (40,41). TLR4 2/2 mice presented with significantly attenuated NV and avascular areas in the OIR model (25), consistent with the results from the pharmacologic inhibitor TAK-242.…”

Section: Discussionmentioning

confidence: 99%

Role of TLR4‐MAP4K4 signaling pathway in models of oxygen‐induced retinopathy

Chen

Zhang

et al. 2018

FASEB j.

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Retinopathy of prematurity is a vision‐threatening condition, and therapies based on antagonizing VEGF may elicit serious side effects in premature infants. Mechanisms of retinal angiogenesis, particularly the signaling pathways independent of VEGF, remain elusive. The goals of our study were to explore TLR4‐mediated signaling pathways in human retinal microvascular endothelial cells (HRMECs) and to examine the effects of TLR4 antagonists in models of oxygen‐induced retinopathy (OIR). Our results show that intravitreal injection of the TLR4 antagonist TAK‐242 reduced areas of nonperfusion, inhibited aberrant angiogenesis, and improved vascular density in the retina of OIR mice. The effects were further potentiated by the anti‐VEGF antibody ranibizumab. In cultured HRMECs, the TLR4 agonist LPS up‐regulated TLR4/MAPKK kinase kinase 4 (MAP4K4) signaling, and promoted cell proliferation and migration, and reduced barrier functions of the cells. Down‐regulation of MAP4K4 in HRMECs abolished the proangiogenic effects by LPS. Our data suggest that the TLR4–MAP4K4 pathway can regulate retinal neovascularization via mechanisms independent of VEGF.—Chen, W., Zhang, J., Zhang, P., Hu, F., Jiang, T., Gu, J., Chang, Q. Role of TLR4‐MAP4K4 signaling pathway in models of oxygen‐induced retinopathy. FASEB J. 33, 3451–3464 (2019). http://www.fasebj.org

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High glucose induces and activates Toll-like receptor 4 in endothelial cells of diabetic retinopathy

Cited by 67 publications

References 36 publications

High Glucose Induces Mouse Mesangial Cell Overproliferation via Inhibition of Hydrogen Sulfide Synthesis in a TLR-4-Dependent Manner

High Glucose Induces Mouse Mesangial Cell Overproliferation via Inhibition of Hydrogen Sulfide Synthesis in a TLR-4-Dependent Manner

Interactions of TLR4 and PPARγ, Dependent on AMPK Signalling Pathway Contribute to Anti-Inflammatory Effects of Vaccariae Hypaphorine in Endothelial Cells

Role of TLR4‐MAP4K4 signaling pathway in models of oxygen‐induced retinopathy

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