Regulated in Development and DNA Damage 1 Is Necessary for Hyperglycemia-induced Vascular Endothelial Growth Factor Expression in the Retina of Diabetic Rodents

Dennis, Michael D.; Kimball, Scot R.; Fort, Patrice E.; Jefferson, Leonard S.

doi:10.1074/jbc.m114.623058

Cited by 51 publications

(68 citation statements)

References 52 publications

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“…GAM attenuated insulin-induced phosphorylation of the mTORC1 substrates p70S6K1 and 4E-BP1 (Fig 1D). We previously demonstrated a similar attenuation of mTORC1 substrate phosphorylation in TR-MUL cells in response to hyperglycemic conditions (13). Notably, the repressive effect of GAM was independent of the glucose concentration in the cell culture medium (Fig 1E).…”

Section: Resultsmentioning

confidence: 62%

“…Furthermore, they are responsible for the synthesis and secretion of a number of hormones, such as the pro-angiogenic cytokine vascular endothelial growth factor (VEGF), that play an essential and causative role in retinal vascular complications (12). Our laboratory recently demonstrated that inhibition of the mTORC1 signaling pathway contributes to Müller cell derived synthesis of VEGF in response to diabetes (13). A key regulator of this effect is the translational repressor 4E-BP1.…”

Section: Introductionmentioning

confidence: 99%

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Glucosamine induces REDD1 to suppress insulin action in retinal Müller cells

Moore

Miller

Dennis

2016

Cellular Signalling

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Resistance to insulin action is a key cause of diabetic complications, yet much remains unknown about the molecular mechanisms that contribute to the defect. Glucose-induced insulin resistance in peripheral tissues such as the retina is mediated in part by the hexosamine biosynthetic pathway (HBP). Glucosamine (GAM), a leading dietary supplement marketed to relieve the discomfort of osteoarthritis, is metabolized by the HBP, and in doing so bypasses the rate-limiting enzyme of the pathway. Thus, exogenous GAM consumption potentially exacerbates the resistance to insulin action observed with diabetes-induced hyperglycemia. In the present study, we evaluated the effect of GAM on insulin action in retinal Müller cells in culture. Addition of GAM to Müller cell culture repressed insulin-induced activation of the Akt/mTORC1 signaling pathway. However, the effect was not recapitulated by chemical inhibition to promote protein O-GlcNAcylation, nor was blockade of O-GlcNAcylation sufficient to prevent the effects of GAM. Instead, GAM induced ER stress and subsequent expression of the protein Regulated in DNA Damage and Development (REDD1), which was necessary for GAM to repress insulin-stimulated phosphorylation of Akt on Thr308. Overall, the findings support a model whereby GAM promotes ER stress in retinal Müller cells, resulting in elevated REDD1 expression and thus resistance to insulin action.

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Section: Resultsmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Glucosamine induces REDD1 to suppress insulin action in retinal Müller cells

Moore

Miller

Dennis

2016

Cellular Signalling

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“…Mice were anesthetized by isoflurane inhalation 16 h after the previous feeding to control for acute effects of diet. Retinas were flash-frozen in liquid nitrogen, and lysates were prepared as previously described (47). Protein concentrations were assessed by the Bradford assay, and supernatants were combined with a 2ϫ Laemmli buffer, boiled for 5 min, and analyzed via Western blotting.…”

Section: Methodsmentioning

confidence: 99%

Activation of the Stress Response Kinase JNK (c-Jun N-terminal Kinase) Attenuates Insulin Action in Retina through a p70S6K1-dependent Mechanism

Miller

Ravi

Martin

et al. 2017

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinDespite recent advances in therapeutics, diabetic retinopathy remains a leading cause of vision impairment. Improvement in the treatment of diabetic retinopathy requires a better understanding of the molecular mechanisms that cause neurovascular complications, particularly in type 2 diabetes. Recent studies demonstrate that rodents fed a high fat diet exhibit retinal dysfunction concomitant with attenuated Akt phosphorylation. The purpose of the present study was to evaluate the impact of a high fat/high sucrose diet on retinal insulin signaling and evaluate the mechanism(s) responsible for the changes. Mice fed a high fat/sucrose diet exhibited attenuated Akt phosphorylation in the retina as compared with mice fed normal chow. Retinas of mice fed a high fat/sucrose diet also exhibited elevated levels of activated JNK as well as enhanced p70S6K1 autoinhibitory domain phosphorylation. In cells, JNK activation enhanced p70S6K1 phosphorylation and mTORC1-dependent activation of the kinase, as evidenced by enhanced phosphorylation of key substrates. Rictor phosphorylation by p70S6K1 was specifically enhanced by the addition of phosphomimetic mutations in the autoinhibitory domain and was more sensitive to inhibition of the kinase as compared with rpS6. Notably, rictor and IRS-1 phosphorylation by p70S6K1 attenuate insulin action through a negative feedback pathway. Indeed, p70S6K1 inhibition prevented the repressive effect of JNK activation on insulin action in retinas. Overall, the results identify the JNK/S6K1 axis as a key molecular mechanism whereby a high fat/sucrose diet impairs insulin action in retina.Diabetic retinopathy is the leading cause of vision loss in working age Americans. Almost everyone with type 1 diabetes and most people with type 2 diabetes develop retinopathy within two decades of disease onset (1). The incidence of type 2 diabetes is rapidly on the rise and accounts for up to 95% of diabetes prevalence (2). However, the overwhelming majority of experimental studies on diabetic retinopathy have been performed using animal models of type 1 diabetes. Development of type 2 diabetes is associated with consumption of a diet containing high fat and sucrose content, which has become extremely common in Western populations (3). Thus, in the present study we set out to investigate potential mechanisms whereby a Western diet contributes to diabetes-induced vision loss.Diabetic retinopathy is caused by a combination of hyperglycemia and a reduction in insulin-mediated signaling, which results in neurovascular changes in the retina. Insulin provides a protective neurotrophic stimulus to retina by activating the protein kinase Akt through a signaling pathway involving the insulin receptor substrate 1/2 (IRS1/2) 2 (4). In response to insulin, the activation loop of Akt is phosphorylated at Thr-308 by phosphoinositide-dependent kinase 1 (PDK1) (5), whereas the C-terminal hydrophobic motif is phosphorylated at Ser-473 by mTORC2 (mammalian target of rapamycin (mTOR) in complex 2) (6...

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“…VEGF is produced by differentiated human RPE cells in vitro and in vivo and also involved in paracrine signaling between the RPE and the CC [40]. Hyperglycemia has been reported to induce the level of VEGF in the retina [41], RPE [42] and retinal endothelial cells [43]. Also, an increased level of VEGF mRNA in retina has been detected in DR and ROP [44].…”

Section: Discussionmentioning

confidence: 99%

Prorenin receptor (PRR)-mediated NADPH oxidase (Nox) signaling regulates VEGF synthesis under hyperglycemic condition in ARPE-19 cells

Haque

Iuvone

et al. 2017

Journal of Receptors and Signal Transduction

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The stimulation of angiotensin II (Ang II), the effector peptide of renin–angiotensin system, has been reported to increase the expression of vascular endothelial growth factor (VEGF) through the activation of the Ang II type 1 receptor (AT1R). In this study, we investigated whether hyperglycemia (HG, 33 mM glucose) in ARPE-19 cells could promote the expression of VEGF independently of Ang II through prorenin receptor (PRR), via an NADPH oxidase (Nox)-dependent mechanism. ARPE-19 cells were treated with the angiotensin converting enzyme (ACE) inhibitor perindopril to block the synthesis of Ang II. Treatment with HG induced VEGF expression in ARPE-19 cells, which was attenuated by pretreatment with the inhibitors of Nox, but not those of nitric oxide synthase, xanthine oxidase and mitochondrial O2 synthesis. In addition, Nox-derived O2− and H2O2 signaling in the regulation of VEGF was determined by using both polyethylene glycol (PEG)-catalase (CAT) and PEG-superoxide dismutase (SOD). We demonstrated that small interfering RNA (siRNA)-mediated knockdown of PRR, Nox2 and Nox4 significantly reduced the HG-induced stimulation of VEGF. On the other hand, Nox4 overexpression significantly potentiated PRR-induced stimulation of VEGF under hyperglycemia in ARPE-19 cells. Furthermore, Nox4 was shown to be associated with enhanced activities of ERK1/2 and NF-κB (p65), indicating their involvement in PRR-induced activation of VEGF under HG in ARPE-19 cells. Our results support the hypothesis that Nox4-derived reactive oxygen species (ROS) signaling is implicated in the hyperglycemia-induced increase of VEGF expression through PRR in ARPE-19 cells. However, further work is needed to evaluate the role of PRR and Nox-s in HG-induced stimulation of VEGF in vivo.

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Regulated in Development and DNA Damage 1 Is Necessary for Hyperglycemia-induced Vascular Endothelial Growth Factor Expression in the Retina of Diabetic Rodents

Cited by 51 publications

References 52 publications

Glucosamine induces REDD1 to suppress insulin action in retinal Müller cells

Glucosamine induces REDD1 to suppress insulin action in retinal Müller cells

Activation of the Stress Response Kinase JNK (c-Jun N-terminal Kinase) Attenuates Insulin Action in Retina through a p70S6K1-dependent Mechanism

Prorenin receptor (PRR)-mediated NADPH oxidase (Nox) signaling regulates VEGF synthesis under hyperglycemic condition in ARPE-19 cells

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