scholarly journals Histamine causes an imbalance between pro-angiogenic and anti-angiogenic factors in the retinal pigment epithelium of diabetic retina via H4 receptor/p38 MAPK axis

2020 ◽  
Vol 8 (2) ◽  
pp. e001710
Author(s):  
Byung Joo Lee ◽  
Hye Eun Byeon ◽  
Chang Sik Cho ◽  
Young Ho Kim ◽  
Jin Hyoung Kim ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Retinal Pigment Epithelium ◽  
Regulatory Mechanism ◽  
Histidine Decarboxylase ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Angiogenic Factors ◽  
Mitogen Activated Protein Kinase ◽  
Patients With Diabetes

IntroductionSystemic histaminergic activity is elevated in patients with diabetes mellitus. There are a few studies suggesting that histamine is implicated in the pathogenesis of diabetes, but the exact role of histamine in the development of diabetic retinopathy is unclear. The aim of this study was to investigate the role of histamine receptor H4 (HRH4) in the regulation of retinal pigment epithelium (RPE)-derived pro-angiogenic and anti-angiogenic factors under diabetic conditions.Research design and methodsThe levels of vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), histamine and histidine decarboxylase (HDC) in the serum and vitreous samples of patients with diabetes were compared with those of patients without diabetes. The effect of hyperglycemia on expression levels of HRH4, VEGF, IL-6 and pigment epithelium-derived factor (PEDF) in the RPE was determined. The role of HRH4 in high glucose-induced regulation of VEGF, IL-6 and PEDF in ARPE-19 cells and the underlying regulatory mechanism were verified using an RNA interference-mediated knockdown study.ResultsThe serum and vitreous levels of VEGF, IL-6, histamine and HDC were more increased in patients with diabetic retinopathy than in patients without diabetes. HRH4 was overexpressed in RPE both in vitro and in vivo. Histamine treatment upregulated VEGF and IL-6 and downregulated PEDF expression in ARPE-19 cells cultivated under hyperglycemic conditions. Hyperglycemia-induced phosphorylation of p38 and subsequent upregulation of VEGF and IL-6 and downregulation of PEDF were dampened by small interfering RNA-mediated knockdown of HRH4 in ARPE-19 cells.ConclusionsTaken together, HRH4 was a critical regulator of VEGF, IL-6 and PEDF in the RPE under hyperglycemic conditions and the p38 mitogen-activated protein kinase pathway mediated this regulatory mechanism.

scholarly journals The Impact of Glycemic Control on Retinal Photoreceptor Layers and Retinal Pigment Epithelium in Patients With Type 2 Diabetes Without Diabetic Retinopathy: A Follow-Up Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Fukashi Ishibashi ◽  
Aiko Kosaka ◽  
Mitra Tavakoli
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Retinal Pigment Epithelium ◽  
Glycemic Control ◽  
Pigment Epithelium ◽  
Outer Nuclear Layer ◽  
Retinal Pigment ◽  
Glycemic Variability ◽  
Hba1c Levels

AimsTo establish the sequential changes by glycemic control in the mean thickness, volume and reflectance of the macular photoreceptor layers (MPRLs) and retinal pigment epithelium in patients with type 2 diabetes without diabetic retinopathy.MethodsThirty-one poorly controlled (HbA1c > 8.0%) patients with type 2 diabetes without diabetic retinopathy undergoing glycemic control and 39 control subjects with normal HbA1c levels (< 5.9%) underwent periodical full medical, neurological and ophthalmological examinations over 2 years. Glycemic variability was evaluated by standard deviation and coefficient of variation of monthly measured HbA1c levels and casual plasma glucose. 3D swept source-optical coherence tomography (OCT) and OCT-Explorer-generated enface thickness, volume and reflectance images for 9 subfields defined by Early Treatment Diabetic Retinopathy Study of 4 MPRLs {outer nuclear layer, ellipsoid zone, photoreceptor outer segment (PROS) and interdigitation zone} and retinal pigment epithelium were acquired every 3 months.ResultsGlycemic control sequentially restored the thickness and volume at 6, 4 and 5 subfields of outer nuclear layer, ellipsoid zone and PROS, respectively. The thickness and volume of outer nuclear layer were restored related to the decrease in HbA1c and casual plasma glucose levels, but not related to glycemic variability and neurological tests. The reflectance of MPRLs and retinal pigment epithelium in patients was marginally weaker than controls, and further decreased at 6 or 15 months during glycemic control. The reduction at 6 months coincided with high HbA1c levels.ConclusionGlycemic control sequentially restored the some MPRL thickness, especially of outer nuclear layer. In contrast, high glucose during glycemic control decreased reflectance and may lead to the development of diabetic retinopathy induced by glycemic control. The repeated OCT examinations can clarify the benefit and hazard of glycemic control to the diabetic retinopathy.

scholarly journals Expression and Role of VEGF in the Adult Retinal Pigment Epithelium

2011 ◽  
Vol 52 (13) ◽  
pp. 9478 ◽  
Author(s):  
Knatokie M. Ford ◽  
Magali Saint-Geniez ◽  
Tony Walshe ◽  
Alisar Zahr ◽  
Patricia A. D'Amore
Keyword(s):  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment

Retinal pigment epithelium-secretome: A diabetic retinopathy perspective

Cytokine ◽  
2017 ◽  
Vol 95 ◽  
pp. 126-135 ◽  
Author(s):  
Murugeswari Ponnalagu ◽  
Murali Subramani ◽  
Chaitra Jayadev ◽  
Rohit Shetty ◽  
Debashish Das
Keyword(s):  
Diabetic Retinopathy ◽  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment

scholarly journals Elucidating the mechanism of action of alpha-1-antitrypsin using retinal pigment epithelium cells exposed to high glucose. Potential use in diabetic retinopathy

PLoS ONE ◽  
2020 ◽  
Vol 15 (2) ◽  
pp. e0228895 ◽  
Author(s):  
María Constanza Potilinski ◽  
Gustavo A. Ortíz ◽  
Juan P. Salica ◽  
Emiliano S. López ◽  
Mariano Fernández Acquier ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Retinal Pigment Epithelium ◽  
Mechanism Of Action ◽  
High Glucose ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelium Cells ◽  
Alpha 1 Antitrypsin ◽  
Epithelium Cells ◽  
Potential Use

scholarly journals Mitochondrial Ceramide Effects on the Retinal Pigment Epithelium in Diabetes

2020 ◽  
Vol 21 (11) ◽  
pp. 3830 ◽  
Author(s):  
Yan Levitsky ◽  
Sandra S. Hammer ◽  
Kiera P. Fisher ◽  
Chao Huang ◽  
Travan L. Gentles ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Mitochondrial Function ◽  
High Glucose ◽  
Citrate Synthase ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Intercellular Adhesion Molecule ◽  
Early Event ◽  
Rpe Cells

Mitochondrial damage in the cells comprising inner (retinal endothelial cells) and outer (retinal pigment epithelium (RPE)) blood–retinal barriers (BRB) is known to precede the initial BRB breakdown and further histopathological abnormalities in diabetic retinopathy (DR). We previously demonstrated that activation of acid sphingomyelinase (ASM) is an important early event in the pathogenesis of DR, and recent studies have demonstrated that there is an intricate connection between ceramide and mitochondrial function. This study aimed to determine the role of ASM-dependent mitochondrial ceramide accumulation in diabetes-induced RPE cell damage. Mitochondria isolated from streptozotocin (STZ)-induced diabetic rat retinas (7 weeks duration) showed a 1.64 ± 0.29-fold increase in the ceramide-to-sphingomyelin ratio compared to controls. Conversely, the ceramide-to-sphingomyelin ratio was decreased in the mitochondria isolated from ASM-knockout mouse retinas compared to wild-type littermates, confirming the role of ASM in mitochondrial ceramide production. Cellular ceramide was elevated 2.67 ± 1.07-fold in RPE cells derived from diabetic donors compared to control donors, and these changes correlated with increased gene expression of IL-1β, IL-6, and ASM. Treatment of RPE cells derived from control donors with high glucose resulted in elevated ASM, vascular endothelial growth factor (VEGF), and intercellular adhesion molecule 1 (ICAM-1) mRNA. RPE from diabetic donors showed fragmented mitochondria and a 2.68 ± 0.66-fold decreased respiratory control ratio (RCR). Treatment of immortalized cell in vision research (ARPE-19) cells with high glucose resulted in a 25% ± 1.6% decrease in citrate synthase activity at 72 h. Inhibition of ASM with desipramine (15 μM, 1 h daily) abolished the decreases in metabolic functional parameters. Our results are consistent with diabetes-induced increase in mitochondrial ceramide through an ASM-dependent pathway leading to impaired mitochondrial function in the RPE cells of the retina.

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