ERK5 Contributes to VEGF Alteration in Diabetic Retinopathy

Wu, Yuexiu; Zuo, Yufeng; Chakrabarti, Rana; Feng, Biao; Chen, Shali; Chakrabarti, Subrata

doi:10.1155/2010/465824

Cited by 13 publications

(14 citation statements)

References 47 publications

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“…In keeping with our previous study, 19,20 CAMEK5 increased KLF2, whereas ERK5 siRNA reduced it (data not shown).…”

Section: Glucose-induced Fn Upregulation Is Regulated By Erk5supporting

confidence: 93%

“…18 Our recent studies have demonstrated that ERK5 negatively regulates ET-1 and VEGF expression in diabetic retinopathy. 19,20 FN interacts with ET-1 and VEGF in the pathogenesis of chronic diabetic complications. 8,9 Thus, it is possible that FN is also regulated by ERK5 signaling.…”

Section: Discussionmentioning

confidence: 98%

“…1E), in keeping with previous studies. 19,20 In contrast, FN mRNA and protein in retinal tissue of diabetic rats were elevated (Figs. 1F, 1G).…”

Section: Glucose-induced Fn Upregulation Is Regulated By Erk5mentioning

confidence: 95%

“…They were sacrificed after 1 month of diabetes. The retinas were separated as described before 19,20 and stored at À708C.…”

Section: Animal Experimentsmentioning

confidence: 99%

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ERK5 Regulates Glucose-Induced Increased Fibronectin Production in the Endothelial Cells and in the Retina in Diabetes

Feng²,

Chen³

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Fibronectin (FN) production and deposition in the tissue is a characteristic feature of diabetic retinopathy. ERK5 is a recent member of the mitogen activated protein kinase (MAPK) family, which plays a critical role in cardiovascular development and maintaining endothelial cell integrity. The aim of this study was to investigate the role of ERK5 signaling in glucose-induced FN overproduction.METHODS. Dermal-derived human microvascular endothelial cells (HMVECs) and human retinal microvascular endothelial cells (HRMECs) were used in this study. FN mRNA levels and secreted FN protein levels were measured using real-time PCR and ELISA, respectively. Constitutively active MAPK/ERK kinase 5 (MEK5 [CAMEK5]) adenovirus was used to upregulate ERK5. Dominant negative MEK5 (DNMEK5) and ERK5 siRNA (siERK5) were used to downregulate ERK5. Parallel retinal tissues of diabetic rats were examined. RESULTS.A significant decrease of FN was observed at both protein and mRNA levels following CAMEK5 transduction in basal as well as in high glucose. DNMEK5 transduction led to further enhancement of glucose-induced increased FN expression. siERK5 treatment led to an increase of FN synthesis. Retinal tissues of diabetic rats showed FN upregulation and ERK5 downregulation. TGFb1 mRNA and phosphorylated Smad2 were markedly suppressed by CAMEK5 transduction with and without glucose treatment. On the other hand, siERK5 transfection enhanced TGFb1 mRNA expression. Exogenous nerve growth factor supplementation resulted in elevated phosphorylated and total ERK5 with and without glucose treatment. CONCLUSIONS.Our experiments demonstrated a novel mechanism of glucose-induced increased FN production in diabetic retinopathy, which is mediated through decreased ERK5 signaling. (Invest Ophthalmol Vis Sci. 2012;53:8405-8413 Increased FN expression has been demonstrated in several tissues in diabetes. We, and others, have shown increased FN mRNA and protein expression in the retina of diabetic animals. 3,4We have demonstrated that endothelin-1 (ET-1) mediates glucoseinduced increased FN synthesis via activation of nuclear factor-jB (NF-jB), activating protein-1 (AP-1), and transcriptional coactivator p300. [1][2][3]10 We have further shown that ET-1 and TGFb1 are major regulators of FN production. 11 Multiple signaling pathways are involved in molecular changes in the ECs. Several studies have shown that glucose-induced protein kinase C (PKC) and mitogen activated protein kinase (MAPK) activation mediate FN mRNA and protein expression in the ECs.12,13 ERK5 is a new member of MAPK family. 14,15 It remains unknown whether ERK5 regulates FN overproduction in diabetic retinopathy.ERK5, also known as big MAPK1 (BMK1), is the most recently identified member of MAPK family. 14,15 ERK5 shares high homology in the N-terminal kinase domain with ERK1/2, but has a unique long C-terminal, which has a transcriptional activation domain.14,15 MAPK/ERK kinase 5 (MEK5) is the specific MAPK kinase for ERK5 activation, which works through phosphorylation of t...

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“…In keeping with our previous study, 19,20 CAMEK5 increased KLF2, whereas ERK5 siRNA reduced it (data not shown).…”

Section: Glucose-induced Fn Upregulation Is Regulated By Erk5supporting

confidence: 93%

Section: Discussionmentioning

confidence: 98%

“…1E), in keeping with previous studies. 19,20 In contrast, FN mRNA and protein in retinal tissue of diabetic rats were elevated (Figs. 1F, 1G).…”

Section: Glucose-induced Fn Upregulation Is Regulated By Erk5mentioning

confidence: 95%

“…They were sacrificed after 1 month of diabetes. The retinas were separated as described before 19,20 and stored at À708C.…”

Section: Animal Experimentsmentioning

confidence: 99%

See 2 more Smart Citations

ERK5 Regulates Glucose-Induced Increased Fibronectin Production in the Endothelial Cells and in the Retina in Diabetes

Feng²,

Chen³

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…Young et al 19 reported that intracellular VEGF protein in RPE cells was significantly increased under high-glucose conditions by regulating protein kinase C (PKC) isozymes. Wu et al 20 reported that ERK5, a member of the MAPK family, contributes to high-glucose-elevated VEGF production in the retina via the MEF2-KLF2 pathway. It is worthy to note that both PKCa and PKCb were activated via phosphorylation and that ERK was upregulated in our study.…”

Section: Discussionmentioning

confidence: 99%

Elevated cell proliferation and VEGF production by high-glucose conditions in Müller cells involve XIAP

Sun

et al. 2013

Eye

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Purpose Mü ller cells have important roles in the pathogenesis of diabetic retinopathy by promoting cell proliferation and inducing the production of vascular endothelial growth factor (VEGF) under hyperglycemic conditions. The objective of this study was to determine the potential mechanism of Mü ller cell proliferation and VEGF production due to high-glucose conditions. Methods Primary cultured rat Mü ller cells were incubated with medium containing variable concentrations of glucose and/or embelin, a specific inhibitor of X-linked inhibitor of apoptosis protein (XIAP), for 72 h. The proliferation of Mü ller cells was assessed by the MTT assay. The expression and/or phosphorylation of 146 proteins were assessed using protein pathway array. Results High concentrations of glucoseinduced Mü ller cell proliferation and altered expression and/or phosphorylation of 47 proteins that have been identified to have key roles in several important signaling pathways (XIAP, VEGF, HIF1a, NFkB, etc) and are involved in the regulation of cell survival, proliferation, or apoptosis. However, Mü ller cell alterations induced by highglucose conditions were counteracted by the XIAP inhibitor embelin, and 26 proteins/ phosphorylations (out of 47) were restored to their normal levels. Nine proteins, including NFkB p65, p-p38, tumor necrosis factor-a, urokinase-type plasminogen activator, CREB, IL-1b, HCAM, estrogen receptor-a, and p-Stat3, were involved in regulatory networks between XIAP and VEGF. Conclusions The current study suggests that XIAP may be a potential regulator that can mediate a series of pathological changes induced by high-glucose conditions in Mü ller cells. Therefore, embelin could be a potential agent for the prevention and treatment of diabetic retinopathy.

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Classical Signaling Pathways

Hayashi

2014

Neuroprotection and Neuroregeneration for Retinal Diseases

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ERK5 Contributes to VEGF Alteration in Diabetic Retinopathy

Cited by 13 publications

References 47 publications

ERK5 Regulates Glucose-Induced Increased Fibronectin Production in the Endothelial Cells and in the Retina in Diabetes

ERK5 Regulates Glucose-Induced Increased Fibronectin Production in the Endothelial Cells and in the Retina in Diabetes

Elevated cell proliferation and VEGF production by high-glucose conditions in Müller cells involve XIAP

Classical Signaling Pathways

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