Implication of VEGF and aquaporin 4 mediating Müller cell swelling to diabetic retinal edema

Oku, Hidehiro; Horie, Tetsuhiro; Fukumoto, Manabu; Morishita, Seita; Ikeda, Tsunehiko

doi:10.1007/s00417-017-3631-z

Cited by 27 publications

(28 citation statements)

References 36 publications

(39 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our in vitro study mimicked our in vivo study in that high glucose condition increased the cellular volume and TGN-020 depressed the increase. We previously showed that TGN-020 depressed the VEGF-induced cellular swelling of TR-MUL5 cells, indicating that VEGF-induced increase of cellular volume is mediated by AQP4 [22]. Consistently, high glucose condition caused swelling of Müller cells, and ROS was increased in these cells.…”

Section: Discussionmentioning

confidence: 57%

“…AQP4 would also be involved in diabetic retinal edema through vasogenic and cytotoxic mechanisms. Recently, we reported the possibility that AQP4 and VEGF are involved in Müller cell swelling, using diabetic rats and cultured Müller cells [22]. To our knowledge, there is no report related with ROS and AQP4 in diabetic rat retinas.Taken together, it seems that VEGF, ROS, and AQP4 are closely linked in the retina, and that the unbalance between them may contribute to the development of diabetic retinopathy and DME.Several chemical structures with an AQP4 inhibitory effect have been identified.…”

mentioning

confidence: 90%

mentioning

confidence: 90%

See 2 more Smart Citations

Effects of an Aquaporin 4 Inhibitor, TGN-020, on Murine Diabetic Retina

Oosuka

Oku

Horie

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

Purpose: To investigate the effect of a selective aquaporin 4 (AQP4) inhibitor, 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), on the expression of vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS) production, as well as on the retinal edema in diabetic retina. Methods: Intravitreal injections of bevacizumab, TGN-020, or phosphate-buffered saline (PBS) were performed on streptozotocin-induced diabetic rats. Retinal sections were immunostained for anti-glial fibrillary acidic protein (GFAP), anti-AQP4, and anti-VEGF. Protein levels of VEGF from collected retinas were determined by Western blot analysis. In addition, retinal vascular leakage of Evans Blue was observed in the flat-mounted retina from the diabetic rats in the presence or absence of TGN-020. Volumetric changes of rat retinal Müller cells (TR-MUL5; transgenic rat Müller cells) and intracellular levels of ROS were determined using flow cytometry analysis of ethidium fluorescence in the presence or absence of TGN-020 or bevacizumab under physiological and high glucose conditions. Results: In the diabetic retina, the immunoreactivity and protein levels of VEGF were suppressed by TGN-020. AQP4 immunoreactivity was higher than in the control retinas and the expressions of AQP4 were co-localized with GFAP. Similarly to VEGF, AQP4 and GFAP were also suppressed by TGN-020. In the Evans Blue assay, TGN-020 decreased leakage in the diabetic retinas. In the cultured Müller cells, the increase in cell volumes and intracellular ROS production under high glucose condition were suppressed by exposure to TGN-020 as much as by exposure to bevacizumab. Conclusion: TGN-020 may have an inhibitory effect on diabetic retinal edema.

show abstract

Section: Discussionmentioning

confidence: 57%

mentioning

confidence: 90%

See 1 more Smart Citation

Effects of an Aquaporin 4 Inhibitor, TGN-020, on Murine Diabetic Retina

Oosuka

Oku

Horie

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…We did not have plausible explanation for the difference. The positive relationship between the INL thickness and HbA1c levels might be due to the hyperglycemia-induced swelling of Müller cells (36). The HbA1c levels negatively affected the thickness of photoreceptors and positively affected that of the inner retinal layers and RPE.…”

Section: Discussionmentioning

confidence: 97%

Thinning of Macular Neuroretinal Layers Contributes to Sleep Disorder in Patients With Type 2 Diabetes Without Clinical Evidences of Neuropathy and Retinopathy

Ishibashi

Tavakoli

2020

Front. Endocrinol.

View full text Add to dashboard Cite

Aims: To investigate the impact of thinning at individual grids of macular neuroretinal layers, clinical factors, and inadequate light exposure on the specific components of sleep disorder in patients with type 2 diabetes.Methods: One hundred twenty-four patients with type 2 diabetes without clinical evidences of diabetic retinopathy and neuropathy (HbA1c: 8.3%, diabetes duration; 8.7 years) and 54 age-and sex-matched control subjects (HbA1c: 5.6%) underwent detailed clinical, neurological, and ophthalmological examinations. The sleep disorder was assessed by the Pittsburgh Sleep Quality Index Japanese Version (PSQI-J). The temporal structures of daily life were assessed by the Munich Chronotype Questionnaire Japanese Version. The thickness at nine grids defined by the Early Treatment Diabetic Retinopathy Study of nine macular neuroretinal layers was determined by swept-source optical coherence tomography and OCT-Explorer. The associations between the individual components of sleep disorders and the thickness at each grid of macular neuroretinal layers, clinical factors, or the temporal structures of daily life were examined.Results: The prevalence of the sleep disorder, global score, and four individual PSQI-J scores in patients with type 2 diabetes were higher than control subjects. The thickness of two and five grids of two inner retinal layers and four to seven grids of four outer retinal layers in patients with type 2 diabetes was thinner than those in control subjects. The thickness at one to eight grids of four outer retinal layers in type 2 diabetic patients was inversely associated with global score and five individual scores of sleep disorder. The thinning at one to two grids of the inner plexiform layer was related to three high individual scores of sleep disorder. The inappropriate light exposure was associated with the sleep disorder and altered macular neuroretinal layers. The high HbA1c and LDL-cholesterol levels were related to the high global score and two individual scores of sleep disorder, respectively. Ishibashi and Tavakoli Neuroretinal Alterations and Sleep DisorderConclusion: In patients with type 2 diabetes, the thinning at grids of the inner plexiform layer and outer retinal layers was associated with the high scores of specific components of the sleep disorder. The sleep disorder was also related to hyperglycemia, dyslipidemia, and inappropriate light exposure. Keywords: inappropriate light exposure, optical coherence tomography, Pittsburgh sleep quality index Japanese version, sleep disorder, thinning of macular neuroretinal layer, type 2 diabetes Abbreviations: ETDRS, Early Treatment Diabetic Retinopathy Study; GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; IS/OS, junction of inner and outer segment of photoreceptor; OCT, optical coherence tomography; ONL, outer nuclear layer; OPL, outer plexiform layer; OPR, outer segment of photoreceptor/retinal pigment epithelium complex; PSQI-J, Pittsburgh Sleep Quality Index Japanese Version; RNFL, retinal nerve f...

show abstract

“…31 It has been reported that the absorption of fluid from the inner retinal tissues is through the AQP4 channels, and retinal ischemia downregulates the activity of AQP4. 32 This then impairs the fluid clearance leading to retinal edema. 32 We have confirmed that the retinal edema was due to the upregulation of VEGF and the downregulation of AQP4 in the mouse RVO model.…”

Section: Expression Level Of Aqp4 Is Significantly Increased By Earlymentioning

confidence: 99%

Pathophysiological Role of VEGF on Retinal Edema and Nonperfused Areas in Mouse Eyes With Retinal Vein Occlusion

Nishinaka

Inoue

Fuma

et al. 2018

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

PURPOSE. To determine the relationship between retinal morphologic changes and molecules involved in the changes after anti-VEGF treatment in the retina of retinal vein occlusion (RVO) murine model. METHODS. The studies were performed on murine RVO model created by laser irradiation of retinal veins. The site of VEGF expression was determined by immunostaining, and the retinal thickness was measured in the images obtained by optical coherence tomography. The levels of VEGF-related and inflammatory factors after an intravitreal injection of anti-VEGF antibody immediately or 7 days after laser irradiation were determined by Western blotting. RESULTS. The level of VEGF increased in all retinal layers 1 day after laser irradiation, and expression was higher in the partially perfused areas than in the completely nonperfused areas. In eyes with high expression level of VEGF, early administration of anti-VEGF antibody reduced the retinal thickness, and expressions of VEGF and inflammatory factors returned to normal levels. However, the levels of phosphorylated protein kinase B (AKT), extracellular signal-regulated kinase 1 and 2 (ERK1/2), and endothelial nitric oxide synthase (eNOS) were increased by early administration of anti-VEGF antibody. On the other hand, in eyes with low concentration of VEGF, late injection of anti-VEGF antibody induced retinal thinning and the concentrations of phosphorylated AKT, ERK1/2, and eNOS were lower than that in normal group. Furthermore, anti-VEGF antibody lessened the reduction of aquaporin-4. CONCLUSIONS. These findings indicate that the effect of anti-VEGF antibody is most likely dependent on its effect on the intraocular VEGF levels.

show abstract

Implication of VEGF and aquaporin 4 mediating Müller cell swelling to diabetic retinal edema

Abstract: The observed Müller cell swelling is mediated by VEGF and AQP4.

Cited by 27 publications

References 36 publications

Effects of an Aquaporin 4 Inhibitor, TGN-020, on Murine Diabetic Retina

Effects of an Aquaporin 4 Inhibitor, TGN-020, on Murine Diabetic Retina

Thinning of Macular Neuroretinal Layers Contributes to Sleep Disorder in Patients With Type 2 Diabetes Without Clinical Evidences of Neuropathy and Retinopathy

Pathophysiological Role of VEGF on Retinal Edema and Nonperfused Areas in Mouse Eyes With Retinal Vein Occlusion

Contact Info

Product

Resources

About