The effect of spleen tyrosine kinase inhibitor R406 on diabetic retinopathy in experimental diabetic rats

Su, Xian; Ren, Qi; Liu, Junru; Yin, Li; Liang, Na; Meng, Lingling; Sun, Ryan

doi:10.1007/s10792-020-01422-4

Cited by 4 publications

(6 citation statements)

References 36 publications

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“…Oral administration of the SYK inhibitor R406 to STZ diabetic rats was previously found to reduce diabetes-induced retinal VEGF expression. 14 In coordination with reducing VEGF levels in the retina of STZ diabetic rats, SYK inhibition reduces retinal vascular permeability, prevents the appearance of acellular capillaries, and restores expression of tight junction proteins. 14 An important caveat to these benefits is that systemic delivery of R406 reduced fasting blood glucose concentrations in STZ diabetic rats; thus, it was unclear if the protective effects on DR pathology were achieved through SYK inhibition in specific retinal cells or secondary to improved glucose homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“… 14 In coordination with reducing VEGF levels in the retina of STZ diabetic rats, SYK inhibition reduces retinal vascular permeability, prevents the appearance of acellular capillaries, and restores expression of tight junction proteins. 14 An important caveat to these benefits is that systemic delivery of R406 reduced fasting blood glucose concentrations in STZ diabetic rats; thus, it was unclear if the protective effects on DR pathology were achieved through SYK inhibition in specific retinal cells or secondary to improved glucose homeostasis. More recently, conditional SYK deletion in microglia was found to reduce microglial activation and proinflammatory cytokine expression in the retina of STZ diabetic mice.…”

Section: Discussionmentioning

confidence: 99%

“… 13 SYK inhibition in STZ diabetic rats was recently found to reduce retinal vascular permeability, prevent the appearance of acellular capillaries, and restore expression of tight junction proteins. 14 Importantly, the benefits of SYK inhibition were attributed, at least in part, to normalization of VEGF expression in the retina of STZ diabetic rats. A role for SYK in regulation of HIF1 has been previously demonstrated in splenocytes and macrophages.…”

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confidence: 99%

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Spleen Tyrosine Kinase Contributes to Müller Glial Expression of Proangiogenic Cytokines in Diabetes

Yerlikaya

Toro

Sunilkumar

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose Neuroglial dysfunction occurs early in the progression of diabetic retinopathy. In response to diabetes or hypoxia, Müller glia secrete cytokines and growth factors that contribute to disease progression. This study was designed to examine common signaling pathways activated in Müller glia by both type 1 and pre-/type 2 diabetes. Methods RiboTag ( Pdgfra -cre;HA-Rpl22) mice were used to compare the impact of streptozotocin (STZ) and a high-fat, high-sucrose (HFHS) diet on ribosome association of mRNAs in Müller glia by RNA sequencing analysis. Human MIO-M1 Müller cells were exposed to either hyperglycemic or hypoxic culture conditions. Genetic manipulation and pharmacologic inhibition were used to interrogate signaling pathways. Results Association of mRNAs encoding triggering receptor expressed on myeloid cells 2 (TREM2), DNAX-activating protein 12 kDa (DAP12), and colony stimulating factor 1 receptor (CSF1R) with ribosomes isolated from Müller glia was upregulated in both STZ diabetic mice and mice fed an HFHS diet. The TREM2/DAP12 receptor-adaptor complex signals in coordination with CSF1R to activate spleen tyrosine kinase (SYK). SYK activation was enhanced in the retina of diabetic mice and in human MIO-M1 Müller cell cultures exposed to hyperglycemic or hypoxic culture conditions. DAP12 knockdown reduced SYK autophosphorylation in Müller cells exposed to hyperglycemic or hypoxic conditions. SYK inhibition or DAP12 knockdown suppressed hypoxia-induced expression of the transcription factor hypoxia-inducible factor 1⍺ (HIF1⍺), as well as expression of vascular endothelial growth factor and angiopoietin-like 4. Conclusions The findings support TREM2/DAP12 receptor-adaptor complex signaling via SYK to promote HIF1α stabilization and increased angiogenic cytokine production by Müller glia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Spleen Tyrosine Kinase Contributes to Müller Glial Expression of Proangiogenic Cytokines in Diabetes

Yerlikaya

Toro

Sunilkumar

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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“…Syk and its downstream signaling pathways in the microglia were reported to mediate neuroinflammatory injury in ischemic stroke 22 and microglial cell dysfunction in Alzheimer's disease. 23 Although a previous publication indicated that the Syk inhibitor R406 could ameliorate DR in diabetic rats, 8 the relationship between microglial Syk and DR was still largely unknown. Therefore, our current study focused mainly on the role of microglial Syk in the progression of DR, and proved that deletion of microglial Syk could effectively delay the development of DR.…”

Section: Discussionmentioning

confidence: 99%

“…7 Furthermore, Syk inhibitor R406 ameliorated DR by reducing retinal inflammation via inhibiting the activation of nuclear factor kappa-lightchain-enhancer of activated B cells in streptozotocin (STZ)-induced diabetic rats. 8 However, the cellular and molecular mechanisms of microglial Syk in DR as well as its role in microglial activation remained largely unknown. Therefore, in this study, we used Cx3cr1 CreERT2 ; Syk fl/fl mice to knockout microglial Syk in the retina followed by the STZ injection to induce DR in mice, and combined with in vitro studies, explored the role of microglial Syk in microglial activation, as well as the development of DR.…”

Section: Introductionmentioning

confidence: 99%

Spleen Tyrosine Kinase Mediates Microglial Activation in Mice With Diabetic Retinopathy

Liu

Xu²,

Gao

2021

Trans. Vis. Sci. Tech.

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Diabetic retinopathy (DR) is a leading cause of blindness in developed countries, in which microglial activation is involved. However, the mechanism of microglial activation in DR remains largely unknown.Methods: We used Cx3cr1 CreERT2 ; Syk fl/fl mice to knockout microglial spleen tyrosine kinase (Syk) in the retina of mice (cKO mice) after streptozotocin injection to induce diabetes. We also isolated primary retinal microglia from wild-type and cKO mice, respectively, to explore the role of microglial Syk in DR. Results:The deletion of microglial Syk in the retina of mice or in the primary retinal microglia inhibited microglial activation and inflammatory response, eventually leading to the improvement of DR by regulating the expressions of interferon regulatory factor 8 (Irf8) and Pu.1 both in vivo and in vitro. Conclusions:The deletion of microglial Syk in the retina effectively ameliorated microglial activation-induced DR, suggesting the potential of microglial Syk as a therapeutic target for DR.Translational Relevance: Microglial spleen tyrosine kinase might serve as a potential therapeutic target for diabetic retinopathy.

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A dual-targeting therapeutic nanobubble for imaging-guided atherosclerosis treatment

Lin,

Chen,

et al. 2024

Materials Today Bio

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The effect of spleen tyrosine kinase inhibitor R406 on diabetic retinopathy in experimental diabetic rats

Cited by 4 publications

References 36 publications

Spleen Tyrosine Kinase Contributes to Müller Glial Expression of Proangiogenic Cytokines in Diabetes

Spleen Tyrosine Kinase Contributes to Müller Glial Expression of Proangiogenic Cytokines in Diabetes

Spleen Tyrosine Kinase Mediates Microglial Activation in Mice With Diabetic Retinopathy

A dual-targeting therapeutic nanobubble for imaging-guided atherosclerosis treatment

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