Transcription factor SP1 mediates hyperglycemia-induced upregulation of roundabout4 in retinal microvascular endothelial cells

Xie, Jia’nan; Gong, Qiang; Liu, Xin; Liu, Zaoxia; Tian, Rui; Cheng, Yan; Su, Guanfang

doi:10.1016/j.gene.2017.03.027

Cited by 33 publications

(34 citation statements)

References 39 publications

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“…Recently, the SP1 mRNA was shown to be expressed at high levels in the epiretinal membranes of subjects with proliferative diabetic retinopathy (PDR), and the SP1 protein colocalized with VEGF [77], suggesting that SP1 may be involved in the mechanism regulating Robo4 expression under hyperglycemic conditions. In human retinal ECs (HRECs) transfected with SP1 siRNA and cultured under hyperglycemic conditions, the level of the Robo4 mRNA was significantly decreased, similar to the level in the normal glucose control group [59]. Moreover, transfection with a Robo4 siRNA decreased Robo4 expression less than transfection of the SP1 siRNA, and SP1 expression was not affected.…”

Section: E26 Transformation-specific Variantmentioning

confidence: 78%

“…Under hypoxic conditions, HIF-1α positively regulated the transcription of Robo4 to promote the invasion and proliferation of HRECs [117]. Under hyperglycemic conditions, increased transcription of SP1 up-regulated the levels of Robo4 to increase the migration, permeability and angiogenesis of HRECs [59]. A similar increase in VEGF and Robo4 expression in diabetic retinas suggested that Robo4 might work together with VEGF to modulate the progression of DR. MicroRNAs represent a new therapeutic target for DR treatment, as miR-15a-5p inhibits the increase in VEGF and Robo4 levels in diabetic rats to delay the development of DR [118].…”

Section: Robo4 and Ocular Neovascularizationmentioning

confidence: 97%

“…Based on these results, SP1 unidirectionally regulates Robo4 expression at the transcriptional level. Subsequent ChIP assays showed that the additional SP1 binding site at positions −1912/−1908 was activated under hyperglycemic conditions to increase Robo4 expression ( Figure 3) [59]. Inhibition of the SP1/Robo4 pathway by siRNAs prevents retinal vascular endothelial permeability and angiogenesis induced by a high-glucose environment and thus may serve as a therapeutic strategy for diabetic retinopathy (DR) in the future.…”

Section: E26 Transformation-specific Variantmentioning

confidence: 99%

“…The proximal promoter of Robo4, to which GA-binding protein (GABP) and specificity protein 1 (SP1) bind, determines the basal promoter activity. Under pathological conditions, some static transcription factor-binding motifs are activated [58,59], inducing the abnormal expression of Robo4. Epigenetic control of gene transcription includes DNA methylation, histone modification, and chromatin remodeling.…”

Section: Transcriptional Factors and Epigenetic Modificationmentioning

confidence: 99%

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Regulatory mechanisms of Robo4 and their effects on angiogenesis

et al. 2019

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Roundabout4 (Robo4) is a transmembrane receptor that belongs to the Roundabout (Robo) family of axon guidance molecules. Robo4 is an endothelial-specific receptor that participates in endothelial cell migration, proliferation, and angiogenesis and the maintenance of vasculature homeostasis. The purpose of this review is to summarize and analyze three main mechanisms related to the expression and function of Robo4 during developmental and pathological angiogenesis. In this review, static shear stress and the binding of transcription factors such as E26 transformation-specific variant 2 (ETV2) and Slit3 induce Robo4 expression and activate Robo4 during tissue and organ development. Robo4 interacts with Slit2 or UNC5B to maintain vascular integrity, while a disturbed flow and the expression of transcription factors in inflammatory or neoplastic environments alter Robo4 expression levels, although these changes have uncertain functions. Based on the mechanisms described above, we discuss the aberrant expression of Robo4 in angiogenesis-related diseases and propose antiangiogenic therapies targeting the Robo4 signaling pathway for the treatment of ocular neovascularization lesions and tumors. Finally, although many problems related to Robo4 signaling pathways remain to be resolved, Robo4 is a promising and potentially valuable therapeutic target for treating pathological angiogenesis and developmental defects in angiogenesis.

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Section: E26 Transformation-specific Variantmentioning

confidence: 78%

Section: Robo4 and Ocular Neovascularizationmentioning

confidence: 97%

Section: E26 Transformation-specific Variantmentioning

confidence: 99%

Section: Transcriptional Factors and Epigenetic Modificationmentioning

confidence: 99%

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Regulatory mechanisms of Robo4 and their effects on angiogenesis

et al. 2019

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“…Previous studies have demonstrated a positive relation between hyperglycemia and the levels of VCAM-1 and ICAM-1 both on endothelial cells as well as in the circulation of humans and mice. 40,41 Although hyperglycemia seemingly increases the expression of Robo4 in endothelial cells in vitro, 42 no evidence so far existed about the regulation of its circulating levels under hyperglycemic conditions in vivo. The potential mechanisms regulating the release of Robo4 remain elusive.…”

Section: Discussionmentioning

confidence: 99%

Robo4‐mediated pancreatic endothelial integrity decreases inflammation and islet destruction in autoimmune diabetes

et al. 2020

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In Type 1 Diabetes Mellitus (T1DM), leukocyte infiltration of the pancreatic islets and the resulting immune-mediated destruction of beta cells precede hyperglycemia and clinical disease symptoms. In this context, the role of the pancreatic endothelium as a barrier for autoimmunity-and inflammation-related destruction of the islets is not well studied. Here, we identified Robo4, expressed on endothelial cells, as a regulator of pancreatic vascular endothelial permeability during autoimmune diabetes. Circulating levels of Robo4 were upregulated in mice subjected to the Multiple Low-Dose Streptozotocin (MLDS) model of diabetes. Upon MLDS induction, Robo4-deficiency resulted in increased pancreatic vascular permeability, leukocyte infiltration to the islets and islet apoptosis, associated with reduced insulin levels and faster diabetes development. On the contrary, in vivo administration of Slit2 in mice modestly delayed the emergence of hyperglycaemia and ameliorated islet inflammation in MLDS-induced diabetes. Thus, Robo4-mediated endothelial barrier integrity reduces insulitis and islet destruction in autoimmune diabetes. Our findings highlight the importance of the endothelium as gatekeeper of pancreatic inflammation during

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Inhibitor of growth 4 affects hypoxia‐induced migration and angiogenesis regulation in retinal pigment epithelial cells

Yang

Gong

et al. 2019

Journal Cellular Physiology

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Inhibitor of growth 4 (ING4), a potential tumor suppressor, is implicated in cell migration and angiogenesis. However, its effects on diabetic retinopathy (DR) have not been elucidated. In this study, we aimed to evaluate ING4 expression in normal and diabetic rats and clarify its effects on hypoxia‐induced dysfunction in human retinal pigment epithelial (ARPE‐19) cells. A Type 1 diabetic model was generated by injecting rats intraperitoneally with streptozotocin and then killed them 4, 8, or 12 weeks later. ING4 expression in retinal tissue was detected using western blot analysis, reverse transcription quantitative real‐time polymerase chain reaction (RT‐qPCR), and immunohistochemistry assays. After transfection with an ING4 overexpression lentiviral vector or small interfering RNA (siRNA), ARPE‐19 migration under hypoxia was tested using wound healing and transwell assays. The angiogenic effect of conditioned medium (CM) from ARPE‐19 cells was examined by assessing human retinal endothelial cell (HREC) capillary tube formation. Additionally, western blot analysis and RT‐qPCR were performed to investigate the signaling pathways in which ING4, specificity protein 1 (Sp1), matrix metalloproteinase 2 (MMP‐2), MMP‐9, and vascular endothelial growth factor A (VEGF‐A) were involved. Here, we found that ING4 expression was significantly reduced in the diabetic rats’ retinal tissue. Silencing ING4 aggravated hypoxia‐induced ARPE‐19 cell migration. CM collected from ING4 siRNA‐transfected ARPE‐19 cells under hypoxia promoted HREC angiogenesis. These effects were reversed by ING4 overexpression. Furthermore, ING4 suppressed MMP‐2, MMP‐9, and VEGF‐A expression in an Sp1‐dependent manner in hypoxia‐conditioned ARPE‐19 cells. Overall, our results provide valuable mechanistic insights into the protective effects of ING4 on hypoxia‐induced migration and angiogenesis regulation in ARPE‐19 cells. Restoring ING4 may be a novel strategy for treating DR.

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Transcription factor SP1 mediates hyperglycemia-induced upregulation of roundabout4 in retinal microvascular endothelial cells

Cited by 33 publications

References 39 publications

Regulatory mechanisms of Robo4 and their effects on angiogenesis

Regulatory mechanisms of Robo4 and their effects on angiogenesis

Robo4‐mediated pancreatic endothelial integrity decreases inflammation and islet destruction in autoimmune diabetes

Inhibitor of growth 4 affects hypoxia‐induced migration and angiogenesis regulation in retinal pigment epithelial cells

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