Intraocular pressure fluctuation and neurodegeneration in the diabetic rat retina.
Ontology highlight
ABSTRACT: Background and purpose
Early retinal neurodegeneration occurs as one of the complications of diabetes even before clinically detectable diabetic vascular retinopathy. The pathogenesis of retinal diabetic neuropathy is still not well understood. We investigated the serial changes or fluctuations in intraocular pressure (IOP) and examined their roles in the pathogenesis of neuronal degeneration in diabetic retina.Experimental approach
Male Sprague Dawley rats with streptozotocin-induced diabetes were treated with ophthalmic preparations of brinzolamide, latanoprost, both drugs (combined treatment) or saline for 8 weeks. IOP was measured daily under general anaesthesia using a rebound tonometer. Antegrade axoplasmic flow in the optic nerve was assessed with a fluorescent substrate. Immunohistochemical staining, TUNEL assays and western blots were also used.Key results
The fluctuation of IOP was higher in the diabetes group than in the normal control or the combined treatment group. Diabetes-induced apoptosis of retinal ganglion cells was decreased by combined treatment. Increased expression of glial fibrillary acidic protein or Iba-1 in the retina or optic nerve head, induced by diabetes, was attenuated only by the combined treatment. Intercellular adhesion molecule-1 was increased in diabetic rats but not in the combined treatment group. Diabetes-induced loss of antegrade axoplasmic transport was partially relieved with combined treatment.Conclusion and implications
Elevated IOP fluctuations seemed to be associated with the gliosis, neuroinflammation, and neurodegeneration induced by diabetes. The loss of retinal ganglion cells might be relieved by IOP-lowering medication. The improvement of unstable perfusion pressure could play a role in neuroprotection in the diabetic retina.
SUBMITTER: Jung KI
PROVIDER: S-EPMC7279969 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:ObjectiveTo characterize the 24-h habitual-position intraocular pressure (IOP) patterns of optic disc phenotypes (ODPs) in untreated normal-tension glaucoma (NTG) and the relationships between nocturnal IOP elevation and various clinical factors.DesignProspective, cross-sectional, observational study.MethodsEighty-two NTG patients with focal ischemic (FI) ODP and 82 age- and disease severity-matched NTG patients with myopic glaucomatous (MG) ODP were recruited prospectively over 3 years. The IOP was recorded 11 times over a 24-hour (h) period by a single ophthalmologist using a hand-held tonometer (TonoPen®XL). A cosinor model was used to describe the 24-h IOP rhythm. Associations between nocturnal IOP elevation and both ocular and demographic variables were evaluated using the generalized estimating equation (GEE).ResultsMean habitual-position IOP was significantly higher during nighttime than daytime in the FI group (16.44 vs. 14.23 mmHg, P < 0.001), but not in the MG group (15.91 vs. 15.70 mmHg, P = 0.82). The FI group also exhibited a significantly higher peak IOP during sleeping hours (P = 0.01) and lower trough IOP during the 24-h period than the MG group (P < 0.01). The MG group showed a significantly higher peak IOP during waking hours than the FI group (P < 0.01). Therefore, 24-h IOP fluctuation range was significantly higher in the FI group than the MG group (P = 0.013). In the FI group, peak habitual-position IOP and the highest frequency of IOP peaks occurred during sleeping hours (12 AM-6 AM). By contrast, IOP peaks in the MG group occurred during morning hours (8 AM-12 PM). The FI group showed an overall nocturnal acrophase in habitual-position IOP, with 45 patients (54.9%) having a nocturnal acrophase; 10 (12.2%), a diurnal acrophase; and 27 (32.9%), no evident acrophase. By contrast, the MG group showed no evident peak in habitual-position IOP, with 9 patients (10.9%) having a nocturnal acrophase; 43 (52.4%), a diurnal acrophase; and 30 (36.6%), no evident acrophase. In multivariate modeling using the GEE, ODP (P < 0.001) and spherical equivalent (SE, P = 0.001) were independently associated with nocturnal IOP elevation.ConclusionsBased on 24-h habitual-position IOP data, FI is associated with significant nocturnal IOP elevation, while no such nocturnal IOP elevation is observed in MG ODP. In untreated NTG, there are also significant differences in the 24-h IOP pattern between FI and MG ODPs.
| S-EPMC5154535 | biostudies-literature
Project description:In diabetes, retinal dysfunctions exist prior to clinically detectable vasculopathy, however the pathology behind these functional deficits is still not fully established. Previously, our group published a detailed study on the retinal histopathology of type 1 diabetic (T1D) rat model, where specific alterations were detected. Although the majority of human diabetic patients have type 2 diabetes (T2D), similar studies on T2D models are practically absent. To fill this gap, we examined Zucker Diabetic Fatty (ZDF) rats - a model for T2D - by immunohistochemistry at the age of 32 weeks. Glial reactivity was observed in all diabetic specimens, accompanied by an increase in the number of microglia cells. Prominent outer segment degeneration was detectable with changes in cone opsin expression pattern, without a decrease in the number of labelled elements. The immunoreactivity of AII amacrine cells was markedly decreased and changes were detectable in the number and staining of some other amacrine cell subtypes, while most other cells examined did not show any major alterations. Overall, the retinal histology of ZDF rats shows a surprising similarity to T1D rats indicating that despite the different evolution of the disease, the neuroretinal cells affected are the same in both subtypes of diabetes.
| S-EPMC5566374 | biostudies-literature
Project description:PurposeIntraocular pressure (IOP) fluctuation is considered as a risk factor for glaucoma progression. We investigated IOP values and IOP fluctuation before and after trabeculectomy (TE) with mitomycin C (MMC) measured by 48-hour diurnal-nocturnal-IOP-profiles (DNP).MethodsPre- and postoperative DNPs of 92 eyes undergoing primary TE with MMC were analysed. Each 48-hour IOP-profile involved 10 IOP measurements (8:00 a.m., 2:00 p.m., 6:00 p.m., and 9:00 p.m. in sitting and at 00:00 in supine position). The "preoperative DNP" was performed a few weeks before TE. The "postoperative DNP" was performed at least six months (range: 6 months-2 years) after TE. Mean IOP values and IOP fluctuations were calculated.ResultsAfter TE with MMC mean IOP was reduced from 16.94±3.83 to 11.26±3.77 mmHg at daytime and from 18.17±4.26 to 11.76±3.90 mmHg at night. At daytime mean IOP-fluctuation decreased from 8.61±4.19 to 4.92±2.52 mmHg, at night from 3.15±2.95 to 1.99±1.82 mmHg. Mean IOP was lower on the second day of the preoperative DNP. This effect was not present in the postoperative DNP. Preoperatively, IOP was controlled in all eyes with a mean of 3.22±0.94 antiglaucomatous agents. Postoperatively, IOP≤15 mmHg was achieved in 71.7%, IOP≤18 mmHg in 77.1% and a decrease in IOP of >30% in 47.8% without antiglaucomatous therapy. Postoperatively, pseudophakia was associated by a higher mean IOP-fluctuation compared to the phakic eyes.ConclusionsTE with MMC significantly reduces both mean IOP-values and IOP- fluctuations at day and night at least 6 months postoperatively. The effect of TE on the IOP fluctuation was less pronounced in pseudophakic eyes.
| S-EPMC5627910 | biostudies-literature
Project description:Diabetic retinopathy, a retinal vascular disease, is inhibited in animals treated with aminoguanidine, an inhibitor of inducible nitric-oxide synthase. This treatment also reduces retinal protein nitration, which is greater in diabetic rat retina than nondiabetic retina. As an approach to understanding the molecular mechanisms of diabetic retinopathy, we sought the identity of nitrotyrosine-containing proteins in retina from streptozotocin-induced diabetic rats and in a rat retinal Müller cell line grown in high glucose (25 mM). Anti-nitrotyrosine immunoprecipitation products from rat retina and Müller cells were analyzed by LC-MS/MS. Ten nitrated proteins in diabetic rat retina and three nitrated proteins in Müller cells grown in high glucose were identified; three additional nitrotyrosine-containing proteins were tentatively identified from diabetic retina. The identified nitrotyrosine-containing proteins participate in a variety of processes including glucose metabolism, signal transduction, and transcription/translation. Among the nitrated proteins were insulin-responsive glucose transporter type 4 (GLUT-4), which has been implicated previously in the pathogenesis of diabetes mellitus; exocyst complex component Exo70, which functions in insulin-stimulated glucose uptake of GLUT-4-containing vesicles; and fibroblast growth factor receptor 2, which influences retinal vascularization via fibroblast growth factor signaling. Nitration of tyrosine phosphorylation sites were identified in five proteins, including GLUT-4, exocyst complex component Exo70, protein-tyrosine phosphatase eta, sensory neuron synuclein, and inositol trisphosphate receptor 3. Quantitation of nitration and phosphorylation at common tyrosine modification sites in GLUT-4 and protein-tyrosine phosphatase eta from diabetic and nondiabetic animals suggests that nitration reduced tyrosine phosphorylation approximately 2X in these proteins from diabetic retina. The present results provide new insights regarding tyrosine nitration and its potential role in the molecular mechanisms of diabetic retinopathy.
| S-EPMC2401337 | biostudies-literature
Project description:Current therapies that target vascular endothelial growth factor (VEGF) have become a mainstream therapy for the management of diabetic macular oedema. The treatment involves monthly repeated intravitreal injections of VEGF inhibitors. VEGF is an important growth factor for many retinal cells, including different types of neurons. In this study, we investigated the adverse effect of multiple intravitreal anti-VEGF injections (200 ng/μl/eye anti-mouse VEGF164, once every 2 weeks totalling 5-6 injections) to retinal neurons in Ins2(Akita) diabetic mice. Funduscopic examination revealed the development of cotton wool spot-like lesions in anti-VEGF treated Ins2(Akita) mice after 5 injections. Histological investigation showed focal swellings of retinal nerve fibres with neurofilament disruption. Furthermore, anti-VEGF-treated Ins2(Akita) mice exhibited impaired electroretinographic responses, characterized by reduced scotopic a- and b-wave and oscillatory potentials. Immunofluorescent staining revealed impairment of photoreceptors, disruptions of synaptic structures and loss of amacrine and retinal ganglion cells in anti-VEGF treated Ins2(Akita) mice. Anti-VEGF-treated WT mice also presented mild amacrine and ganglion cell death, but no overt abnormalities in photoreceptors and synaptic structures. At the vascular level, exacerbated albumin leakage was observed in anti-VEGF injected diabetic mice. Our results suggest that sustained intraocular VEGF neutralization induces retinal neurodegeneration and vascular damage in the diabetic eye.
| S-EPMC4680939 | biostudies-literature
Project description:IntroductionWith the increasing use of intravitreal administration of corticosteroids in macular edema, steroid-induced intraocular pressure (IOP) rise is becoming an emergent issue. However, for patients in whom intravitreal steroids are indicated, there are no specific recommendations for IOP monitoring and management after intravitreal administration of corticosteroids.MethodAn expert panel of European ophthalmologists reviewed evidence on corticosteroid-induced IOP elevation. The objective of the panel was to propose an algorithm based on available literature and their own experience for the monitoring and management of corticosteroid-induced IOP elevation, with a focus on diabetic patients.ResultsData from trials including diabetic patients with a rise of IOP after intravitreal steroid administration indicate that IOP-lowering medical treatment is sufficient for a large majority of patients; only a small percentage underwent laser trabeculoplasty or filtering filtration surgery. A 2-step algorithm is proposed that is based on the basal value of IOP and evidence for glaucoma. The first step is a risk stratification before treatment. Patients normotensive at baseline (IOP ≤ 21 mmHg), do not require additional baseline diagnostic tests. However, patients with baseline ocular hypertension (OHT) (IOP > 21 mmHg) should undergo baseline imaging and visual field testing. The second step describes monitoring and treatment after steroid administration. During follow-up, patients developing OHT should have baseline and periodical imaging and visual field testing; IOP-lowering treatment is proposed only if IOP is >25 mmHg or if diagnostic tests suggest developing glaucoma.ConclusionThe management and follow-up of OHT following intravitreal corticosteroid injection is similar to that of primary OHT. If OHT develops, IOP is controlled in a large proportion of patients with standard IOP treatments. The present algorithm was developed to assist ophthalmologists with guiding principles in the management of corticosteroid-induced IOP elevation.FundingAlimera Sciences Limited.
| S-EPMC4909679 | biostudies-literature
Project description:PurposeTo investigate whether diurnal fluctuation in intraocular pressure (IOP) can influence the result of the correlations between IOP-related factors and progression of normal tension glaucoma (NTG).MethodsGlaucoma progression was defined as visual field (VF) progression and changes in the optic disc and/or retinal nerve fiber layer (RNFL). Two different methods were used to evaluate the impact of the diurnal fluctuation in IOP. 'Conventional method' used in previous studies included all IOP measurements during the follow up time. 'Time adjusted method' was used to adjust diurnal fluctuation in IOP with the preferred time. Mean IOP, long term IOP fluctuation and the difference between the lowest and highest IOP were calculated using both methods. Cox regression analyses were performed to evaluate the association between IOP-related factors and NTG progression.ResultsOne hundred and forty eyes of 140 patients with NTG were included in this study. 41% (58 of 140 eyes) of eyes underwent NTG progression. Long term IOP variation calculated by conventional method was not a significant risk factor for NTG progression (hazard ratio[HR], 0.311; 95% confidence interval[CI], 0.056-1.717; P = 0.180). Long term IOP variation calculated by time adjusted method, however, was related to progression, with an HR of 5.260 (95% CI,1.191-23.232; P = 0.029).ConclusionAlthough having the same IOP-related factors, if diurnal fluctuation is included, different results may be found on the relationship between IOP-related factors and NTG progression. Based on our results, diurnal fluctuation in IOP should be considered when IOP-related factors are studied in the future.
| S-EPMC5077094 | biostudies-literature
Project description:BACKGROUND AND PURPOSE:The kinin B1 receptor contributes to vascular inflammation and blood-retinal barrier breakdown in diabetic retinopathy (DR). We investigated the changes in expression, cellular localization and vascular inflammatory effect of B1 receptors in retina of streptozotocin diabetic rats. EXPERIMENTAL APPROACH:The distribution of B1 receptors on retinal cell types was investigated by immunocytochemistry. Effects of B1 receptor agonist, R-838, and antagonist, R-954, on retinal leukocyte adhesion, gene expression of kinin and VEGF systems, B1 receptor immunoreactivity, microgliosis and capillary leakage were measured. Effect of B1 receptor siRNA on gene expression was also assessed. KEY RESULTS:mRNA levels of the kinin and VEGF systems were significantly enhanced at 2 weeks in streptozotocin (STZ)-retina compared to control-retina and were further increased at 6 weeks. B1 receptor mRNA levels remained increased at 6 months. B1 receptor immunolabelling was detected in vascular layers of the retina, on glial and ganglion cells. Intravitreal R-838 amplified B1 and B2 receptor gene expression, B1 receptor levels (immunodetection), leukostasis and vascular permeability at 2 weeks in STZ-retina. Topical application (eye drops) of R-954 reversed these increases in B1 receptors, leukostasis and vascular permeability. Intravitreal B1 receptor siRNA inhibited gene expression of kinin and VEGF systems in STZ-retina. Microgliosis was unaffected by R-838 or R-954 in STZ-retina. CONCLUSION AND IMPLICATIONS:Our results support the detrimental role of B1 receptors on endothelial and glial cells in acute and advanced phases of DR. Topical application of the B1 receptor antagonist R-954 seems a feasible therapeutic approach for the treatment of DR.
| S-EPMC5825301 | biostudies-literature
Project description:Purpose:The purpose of this study was to test the hypothesis that the superficial, intermediate, and deep retinal vascular plexus show different responses to intraocular pressure (IOP) elevation. Methods:Anesthetized adult Long Evans rats (n = 14) were imaged using optical coherence tomography angiography (OCTA; Spectralis) at baseline (IOP 10 mm Hg) and in follow-up mode to examine the vasculature during IOP elevation (10 to 110 mm Hg, 10 mm Hg steps, each step 3 minutes). A 20° × 10° field was imaged. Vessel density within a 2D projection image was determined (%) for the superficial vascular complex (SVC), intermediate capillary plexus (ICP), and deep capillary plexus (DCP). Comparisons were made between layers using 2-way repeated measures ANOVA (layer versus IOP) following normalization to baseline (% relative to 10 mm Hg). Results:The three vascular layers responded differently to IOP elevation. For IOPs between 40 and 60 mm Hg, DCP and ICP capillaries were significantly more resistant to IOP elevation than those in the SVC. When IOP was elevated above 70 mm Hg, all layers showed reduced vessel density. IOP induced change in SVC vessel density closely followed reductions in thickness of the inner retinal layers (nerve fiber, ganglion cell, and inner plexiform layer). This close relationship between reductions in tissue thickness and vessel density was less apparent for the ICP and DCP. Conclusions:These data show that the intermediate and deep vascular plexus in the rat retina have a greater capacity for autoregulation against mild IOP elevation but are more affected at high IOP.
| S-EPMC7325622 | biostudies-literature
Project description:Hyperglycemia results in inhibition of cleavage of integrin-associated protein (IAP) thereby allowing it to bind to SHPS-1 which results in pathophysiologic changes in endothelial function. This study determined if an anti-rat IAP antibody directed against the SHPS-1 binding site which disrupts IAP/SHPS-1 association could inhibit these pathophysiologic changes. The anti-IAP antibody inhibited IGF-I-stimulated SHPS-1, p52Shc, MAP kinase phosphorylation, and proliferation in endothelial cells. To determine if it could reverse established pathophysiologic changes in vivo, this antibody or normal rat IgG F(ab)2 was injected intraperitoneally for 6 weeks into rats that had diabetes for 4 weeks. Optical coherence tomography (OCT) showed that retinal thickness increased at 4 weeks and this increase was maintained in rats treated with the control antibody for an additional 6 weeks. The increase was reversed by anti-IAP antibody treatment (84.6 ± 2.0 compared to 92.3 ± 2.5 μm, p < 0.01). This value was similar to nondiabetic animals (82.2 ± 1.6 μm, p, NS). The anti-IAP antibody also decreased retinal vascular permeability (0.62 ± 0.12 vs. 0.96 ± 0.25%/g/h, p < 0.001). To determine if it was effective after local injection, this antibody or control was administered via intravitreal injection. After 3 weeks, retinal thickness increased to 6.4 ± 2.8% in diabetic rats, and IAP antibody treatment prevented this increase (0.8 ± 2.5%, p < 0.01). It also prevented the increase of retinal vascular permeability (0.92 ± 0.62 vs. 1.63 ± 0.99%/g/h, p < 0.001). Biochemical analyses of retinal extracts showed that the anti-IAP antibody inhibited IAP/SHPS-1 association and SHPS-1 phosphorylation. This resulted in inhibition of AKT activation and VEGF synthesis in the retina: changes associated with increased vascular permeability. We conclude the anti-rat IAP antibody disrupts IAP/SHPS-1 association and attenuates aberrant IGF-I signaling thereby preventing or reversing the progression of retinal pathophysiological changes.
| S-EPMC6458945 | biostudies-literature