Association of the TLR4 signaling pathway in the retina of streptozotocin-induced diabetic rats

Wang, Yanling; Wang, Kang; Yu, Shanshan; Li, Qian; Li, Na; Lin, Pingping; Li, Mingming; Guo, Jian-You

doi:10.1007/s00417-014-2832-y

Cited by 36 publications

(31 citation statements)

References 37 publications

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“…Furthermore, microglia express Toll-like receptor 4 (TLR4) (96,97), which is involved in the pathogenesis of different types of retinal degeneration (91,(96)(97)(98)(99). TLR4 activation has been shown to induce IL-18 mRNA and protein activation in renal tubular epithelial cells during renal obstruction (100).…”

Section: Discussionmentioning

confidence: 99%

“…Since cultured cells can have altered properties compared to their properties in their in vivo state, it may be that culturing conditions primed endothelial cells to respond pathologically to increasing RBP4 levels in our previous study. Interestingly, hyperglycemia increases TLR4 expression in endothelial cells (101) and the retinas of rats with STZ-induced diabetes (99), which could prime the endothelium to respond to proinflammatory levels of RBP4 during diabetes. Further studies are necessary to determine whether the elevation n.s., not significant by Student's t test; *, P Ͻ 0.05 by Student's t test; **, P Ͻ 0.01 by Student's t test; ***, P Ͻ 0.001 by Student's t test.…”

Section: Discussionmentioning

confidence: 99%

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Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism

Otalora

Martin

et al. 2015

Molecular and Cellular Biology

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Serum retinol-binding protein 4 (RBP4) is the sole specific transport protein for retinol in the blood, but it is also an adipokine with retinol-independent, proinflammatory activity associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. Moreover, two separate studies reported that patients with proliferative diabetic retinopathy have increased serum RBP4 levels compared to patients with mild or no retinopathy, yet the effect of increased levels of RBP4 on the retina has not been studied. Here we show that transgenic mice overexpressing RBP4 (RBP4-Tg mice) develop progressive retinal degeneration, characterized by photoreceptor ribbon synapse deficiency and subsequent bipolar cell loss. Ocular retinoid and bisretinoid levels are normal in RBP4-Tg mice, demonstrating that a retinoid-independent mechanism underlies retinal degeneration. Increased expression of pro-interleukin-18 (pro-IL-18) mRNA and activated IL-18 protein and early-onset microglia activation in the retina suggest that retinal degeneration is driven by a proinflammatory mechanism. Neither chronic systemic metabolic disease nor other retinal insults are required for RBP4 elevation to promote retinal neurodegeneration, since RBP4-Tg mice do not have coincident retinal vascular pathology, obesity, dyslipidemia, or hyperglycemia. These findings suggest that elevation of serum RBP4 levels could be a risk factor for retinal damage and vision loss in nondiabetic as well as diabetic patients. S erum retinol-binding protein 4 (RBP4) is the sole specific transport protein for vitamin A (retinol) in the blood (1-4).The eye is the organ most dependent on the RBP4-mediated delivery of retinol to maintain optimal function, as RBP4 loss of function in either mice or humans impairs retinal function, leading to visual impairment, while other organ systems remain intact (5-7). However, in the past decade numerous clinical studies have linked increased serum levels of RBP4 to disease, including obesity (8, 9), insulin resistance (8-13), type 2 diabetes (9, 13), and cardiovascular disease (hypertension, atherosclerosis, stroke) (14-18). This appears to be more than a spurious correlation, since recent studies have demonstrated that RBP4 is an adipokine (adipose-derived cytokine) with retinoid-independent, proinflammatory activity that contributes to the development of insulin resistance (13,(19)(20)(21). Moreover, a human single nucleotide polymorphism that increases RBP4 promoter activity confers a 2-fold increase for the risk of type 2 diabetes (22, 23).Several studies have provided mechanistic insights into RBP4-induced insulin resistance. Mice with genetic or pharmacologic elevation of RBP4 levels develop insulin resistance (13), whereas lowering of RBP4 levels improves insulin sensitivity in mice (13,24). RBP4 inhibits insulin signaling in adipocytes indirectly by activating proinflammatory cytokine production in macrophages through retinol-independent and Toll-like receptor 4 (TLR4)-and c-Jun N-terminal kinase (JNK)-dependent ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism

Otalora

Martin

et al. 2015

Molecular and Cellular Biology

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“…This was associated with decreased phosphorylation of NFkB, IL-6, and other inflammatory pathways [17]. Furthermore, work in the streptozotocin-induced diabetic rat showed that diabetes increased TLR4 signaling, leading to increased levels of key inflammatory mediators [18]. Taken together, there is literature to demonstrate localization and activation of TLR4 signaling in the retina, leading to retinopathy-associated complications.…”

Section: 0 Introductionmentioning

confidence: 99%

TLR4 regulates insulin-resistant proteins to increase apoptosis in the mouse retina

et al. 2017

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Objective and Design Work in multiple organs has suggested that toll-like receptor 4 (TLR4) may play a role in insulin resistance. Additional studies have shown a negative role for TLR4 on retinal health. We have previously reported that β-adrenergic receptors can regulate both TLR4 signal transduction, as well as insulin signaling in the retina and in retinal endothelial cells (REC). Thus, we hypothesized that TLR4 would regulate retinal insulin signaling. Materials and Methods We used endothelial cell specific TLR4 knockout mice, as well as TLR4 overexpressing mice for these studies. Methods Western blotting and ELISA analyses were done for investigations of insulin receptor, insulin receptor substrate 1 (IRS-1) serine 307, and Akt phosphorylation, as well as cleaved caspase 3 levels in the mouse retina. Results We found that loss of TLR4 led to increased insulin receptor and Akt phosphorylation, as well as decreased IRS-1Ser307 levels. In support of these results, TLR4 overexpression decreased insulin signaling and the cleavage of caspase 3. Conclusions Therefore, these results suggest that TLR4 plays a key role in insulin signaling in the retina. Reduction of TLR4 levels may be protective to the retina.

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“…Inhibition of any of these factors shows promise in reducing retinal stress-associated neuronal and vascular damage [4–8]. Additionally, the role of the innate immune system may also contribute to retinal damage associated with diabetes, specifically toll-like receptor 4 (TLR4) [9, 10]. TLR4 is one of a class of pathogen-associated molecular pattern receptors [11].…”

Section: Introductionmentioning

confidence: 99%

Toll-Like Receptor 4 Reduces Occludin and Zonula Occludens 1 to Increase Retinal Permeability Both in vitro<b> </b>and in vivo

Liu¹,

Jiang²,

Steinle³

2017

J Vasc Res

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We reported that β-adrenergic receptors regulate toll-like receptor 4 (TLR4) signaling in the retina of diabetic mice and in retinal endothelial cells (REC) and Müller cells. We hypothesized that TLR4 regulates retinal permeability both in vitro and in vivo in the retinal vasculature. We used REC cultured in normal and high-glucose conditions and TLR4 siRNA treatments for cell culture studies of permeability and protein analyses of tumor necrosis factor α, occludin, and zonula occludens 1 (ZO-1). We used endothelial cell (EC)-specific Cre-Lox TLR4 knockout mice to study retinal permeability and neuronal and vascular changes following exposure to ocular ischemia/reperfusion (I/R) used as a retinal stressor. We found that the loss of TLR4 in the EC led to the reduced permeability following I/R and fewer degenerate capillaries. Retinal permeability was increased in REC grown in high-glucose conditions but was inhibited by TLR4 siRNA treatment. High-glucose culture conditions significantly reduced occludin and ZO-1 levels in REC, and TLR4 siRNA treatment restored levels to baseline. In conclusion, these studies demonstrate that TLR4 in EC strongly regulates retinal permeability and neuronal and vascular changes following exposure to stressors such as I/R.

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Association of the TLR4 signaling pathway in the retina of streptozotocin-induced diabetic rats

Cited by 36 publications

References 37 publications

Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism

Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism

TLR4 regulates insulin-resistant proteins to increase apoptosis in the mouse retina

Toll-Like Receptor 4 Reduces Occludin and Zonula Occludens 1 to Increase Retinal Permeability Both in vitro<b> </b>and in vivo

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