Mechanistic dissection of diabetic retinopathy using the protein-metabolite interactome

Patrick, Ambrose Teru; He, Weilue; Joshua, Madu; Sripathi, Srinivas R.; Choi, Se Hyun; Lee, Kook; Samson, Faith Pwaniyibo; Powell, Folami Lamoke; Bartoli, Manuela; Jee, Donghyun; Gutsaeva, Diana; Jahng, Wan Jin

doi:10.1007/s40200-020-00570-9

Cited by 7 publications

(8 citation statements)

References 114 publications

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“…In contrast to our work, one study found decreased prohibitin mRNA and protein levels in diabetic mice and rats, with increased prohibitin 1 protein levels in aging samples [ 8 ] and ARPE-19 epithelial cells [ 8 ], which is in contrast to our studies of endothelial cells. However, in contrast to this recent paper, others in the same group reported that aging reduced prohibitin 1 mRNA in 2010 [ 9 ]; thus it is unclear why the findings on prohibitin 1 have changed over time.…”

Section: Discussioncontrasting

confidence: 99%

“…In that same paper, the authors reported that early diabetes led to decreased prohibitin 1 levels [ 7 ]. However, a more recent paper showed that the diabetic retina had decreased prohibitin 1 expression, but this paper did not investigate protein levels [ 8 ]. Another work has suggested that prohibitin 1 is regulated by aging and oxidative stress in the eye [ 9 ], suggesting that it may have complex actions in the eye.…”

Section: Introductionmentioning

confidence: 99%

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Prohibitin 1 Regulates Inflammatory Mediators and Reactive Oxygen Species in Retinal Endothelial Cells

Liu

Jiang

Steinle

2022

JCM

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Diabetic retinopathy is associated with increased inflammatory mediator levels. In these studies, we focused on prohibitin 1. We performed western blotting for retinal lysates from diabetic mice and Epac1 floxed and cdh5Cre-Epac1 mice. We also grew primary retinal endothelial cells (REC) in normal (5 mM) and high (25 mM) glucose, and treated some cells with an Epac 1 agonist or prohibitin 1 siRNA. Western blotting was done to confirm knockdown of prohibitin 1 and Epac 1 agonism. We measured the tumor necrosis factor alpha (TNFα), interleukin-1-beta (IL-1β), phosphorylated prohibitin 1, phosphorylated nuclear factor kappa beta (NFkB), high mobility group box 1 (HMGB1) and reactive oxygen species (ROS) levels in REC after transfection with prohibitin 1 siRNA. Results showed that high glucose increased the inflammatory mediators, as well as HMGB1 and ROS. The levels of ROS, HMGB1, and inflammatory pathways were all reduced after cells were transfected with prohibitin 1 siRNA. Epac1 reduced prohibitin 1 phosphorylation. In conclusion, decreased prohibitin 1 significantly reduced the inflammatory mediator and ROS levels in REC. Epac1 regulates the prohibitin 1 levels in REC.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prohibitin 1 Regulates Inflammatory Mediators and Reactive Oxygen Species in Retinal Endothelial Cells

Liu

Jiang

Steinle

2022

JCM

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“…As a result, anti-angiogenic, anti-oxidative, anti-inflammatory, and antiapoptotic strategies remain the most promising methods to treat these irreversible progressive neurologic degenerations. 23 , 24 , 27 …”

Section: Discussionmentioning

confidence: 99%

Dual Switch Mechanism of Erythropoietin as an Antiapoptotic and Pro-Angiogenic Determinant in the Retina

Samson

Sripathi

et al. 2020

ACS Omega

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Constant or intense light degenerates the retina and retinal pigment epithelial cells. Light generates reactive oxygen species and nitric oxide leading to initial reactions of retinal degeneration. Apoptosis is the primary mechanism of abnormal death of photoreceptors, retinal ganglion cells, or retinal pigment epithelium (RPE) in degenerative retinal diseases, including diabetic retinopathy and age-related macular degeneration. The current study evaluated the function of erythropoietin (EPO) on angiogenesis and apoptosis in the retina and RPE under oxidative stress. We determined the pro-angiogenic and antiapoptotic mechanism of EPO under stress conditions using a conditional EPO knockdown model using siRNA, EPO addition, proteomics, immunocytochemistry, and bioinformatic analysis. Our studies verified that EPO protected retinal cells from light-, hypoxia-, hyperoxia-, and hydrogen peroxide-induced apoptosis through caspase inhibition, whereas up-regulated angiogenic reactions through vascular endothelial growth factor (VEGF) and angiotensin pathway. We demonstrated that the EPO expression in the retina and subsequent serine/threonine/tyrosine kinase phosphorylations might be linked to oxidative stress response tightly to determining angiogenesis and apoptosis. Neuroprotective roles of EPO may involve the balance between antiapoptotic and pro-angiogenic signaling molecules, including BCL-xL, c-FOS, caspase-3, nitric oxide, angiotensin, and VEGF receptor. Our data indicate a new therapeutic application of EPO toward retinal degeneration based on the dual roles in apoptosis and angiogenesis at the molecular level under oxidative stress.

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“…Blood-retinal barrier formation, maintenance and enhancement [63,103] Increase in GFAP and reduction/redistribution in occludin expression in retinal vessels [104] Increase in adherent leukocytes in blood vessels [105,106] Increase in macromolecules leakage in outer BRB [107] Decrease in occludin and ZO-1 expression by Müller cell-derived VEGF [108] Leakage resulting from Müller cell ablation [109] Protection against vascular alterations and angiogenesis [110,111] Neurovascular coupling [65,67] Alteration in neurovascular coupling [66] ND ILM formation [41,54] ND Alteration of ILM [112] Better prognostic after foveal sparing ILM peeling in idiopathic macular hole [88] Neural regeneration [113] Intravitreal injected adipose-derived stem cells differentiated into pericytes and integrate retinal vasculature [114] Intravitreal injected multipotent mesenchymal stromal cells prevented retinal ganglion cell loss [115] ND Contribution to the outer retinal barrier, forming OLM [40,49,50] Alteration in occludin content and distribution in diabetic retinas [49,116] Alteration of OLM in DME [117,118] ND Participation in the visual cycle [42,43] Alteration in visual cycle-related proteins [119,120] Involvement of visual cycle proteins with oxidative stress and vascular alterations in DR [121] ND Contribution to photoreceptors integrity [51] Degeneration of photoreceptor cells [122,123] Alteration in morphology [124]…”

Section: Physiological Role Retinal Changes In Hyperglycemia/dm Alter...mentioning

confidence: 99%

Contribution of Müller Cells in the Diabetic Retinopathy Development: Focus on Oxidative Stress and Inflammation

et al. 2022

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Diabetic retinopathy is a neurovascular complication of diabetes and the main cause of vision loss in adults. Glial cells have a key role in maintenance of central nervous system homeostasis. In the retina, the predominant element is the Müller cell, a specialized cell with radial morphology that spans all retinal layers and influences the function of the entire retinal circuitry. Müller cells provide metabolic support, regulation of extracellular composition, synaptic activity control, structural organization of the blood–retina barrier, antioxidant activity, and trophic support, among other roles. Therefore, impairments of Müller actions lead to retinal malfunctions. Accordingly, increasing evidence indicates that Müller cells are affected in diabetic retinopathy and may contribute to the severity of the disease. Here, we will survey recently described alterations in Müller cell functions and cellular events that contribute to diabetic retinopathy, especially related to oxidative stress and inflammation. This review sheds light on Müller cells as potential therapeutic targets of this disease.

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Mechanistic dissection of diabetic retinopathy using the protein-metabolite interactome

Cited by 7 publications

References 114 publications

Prohibitin 1 Regulates Inflammatory Mediators and Reactive Oxygen Species in Retinal Endothelial Cells

Prohibitin 1 Regulates Inflammatory Mediators and Reactive Oxygen Species in Retinal Endothelial Cells

Dual Switch Mechanism of Erythropoietin as an Antiapoptotic and Pro-Angiogenic Determinant in the Retina

Contribution of Müller Cells in the Diabetic Retinopathy Development: Focus on Oxidative Stress and Inflammation

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