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Investigative Ophthalmology & Visual... Sep 2023Keratin 8/18 (KRT8/18), paired members of the intermediate filament family, have shown vital functions in regulating physiological activities more than supporting the...
PURPOSE
Keratin 8/18 (KRT8/18), paired members of the intermediate filament family, have shown vital functions in regulating physiological activities more than supporting the mechanic strength for cells and organelles. However, the KRT8/18 presence in retinal ganglion cells (RGCs) and functions on neuroprotection in a mouse model of acute ocular hypertension (AOH) are unknown and worthy of exploration.
METHODS
We identified the existence of KRT8/18 in normal human and mouse retinas and primary RGCs. KRT8/18 levels were detected after AOH modeling. The adeno-associated virus (AAV) system was intravitreally used for selective KRT8 knockdown in RGCs. The histological changes, the loss and dysfunction of RGCs, and the gliosis in retinas were detected. The markers of cell apoptosis and MAPK pathways were investigated.
RESULTS
KRT8/18 existed in all retinal layers and was highly expressed in RGCs, and they increased after AOH induction. The KRT8 knockdown in RGCs caused no histopathological changes and RGC loss in retinas without AOH modeling. However, after the KRT8 deficiency, AOH significantly promoted the loss of whole retina and inner retina thickness, the reduction, apoptosis, and dysfunction of RGCs, and the glial activation. Besides, downregulated Bcl-2 and upregulated cleaved-Caspase 3 were found in the AOH retinas with KRT8 knockdown, which may be caused by the increased phosphorylation level of MAPK pathways (JNK, p38, and ERK).
CONCLUSIONS
The KRT8 deficiency promoted RGC apoptosis and neurodegeneration by abnormal activation of MAPK pathways in AOH retinas. Targeting KRT8 may serve as a novel treatment for saving RCGs from glaucomatous injuries.
Topics: Animals; Humans; Mice; Apoptosis; Glaucoma; Ocular Hypertension; Retina; Retinal Ganglion Cells
PubMed: 37656477
DOI: 10.1167/iovs.64.12.1 -
Nepalese Journal of Ophthalmology : a... Jan 2022Ocular hypertension is a condition with elevated intraocular pressure that needs to be monitored closely to prevent glaucoma and other complications. The study aims to...
INTRODUCTION
Ocular hypertension is a condition with elevated intraocular pressure that needs to be monitored closely to prevent glaucoma and other complications. The study aims to find out the prevalence of ocular hypertension in patients aged more than 40 years.
MATERIALS AND METHODS
This is a hospital based cross-sectional study conducted in a community based tertiary hospital of Nepal.
RESULTS
Mean age of the patients was 47.53years. 62% of the patients were males and 38% were females. Mean intraocular pressure in the right eye was 15.8 mmHg and mean intraocular pressure in left eye was 16.2 mm Hg. Prevalence of ocular hypertension was 6%.
CONCLUSION
All patients more than 40 years of age should undergo detailed ocular examination for early detection and treatment of ocular hypertension.
Topics: Adult; Cross-Sectional Studies; Female; Glaucoma; Humans; Intraocular Pressure; Male; Middle Aged; Ocular Hypertension; Prevalence; Tonometry, Ocular
PubMed: 35996922
DOI: 10.3126/nepjoph.v14i1.29740 -
Scientific Reports Jun 2020Low ocular perfusion pressure (OPP) has been proposed as an important risk factor for glaucoma development and progression, but controversy still exists between studies.... (Meta-Analysis)
Meta-Analysis
Low ocular perfusion pressure (OPP) has been proposed as an important risk factor for glaucoma development and progression, but controversy still exists between studies. Therefore, we conducted a systematic review and meta-analysis to analyze the association between OPP and open-angle glaucoma (OAG). Studies were identified by searching PubMed and EMBASE databases. The pooled absolute and standardised mean difference in OPP between OAG patients and controls were evaluated using the random-effects model. Meta-regression analysis was conducted to investigate the factors associated with OPP difference between OAG patients and controls. A total of 43 studies were identified including 3,009 OAG patients, 369 patients with ocular hypertension, and 29,502 controls. The pooled absolute mean difference in OPP between OAG patients and controls was -2.52 mmHg (95% CI -4.06 to -0.98), meaning significantly lower OPP in OAG patients (P = 0.001). Subgroup analyses showed that OAG patients with baseline IOP > 21 mmHg (P = 0.019) and ocular hypertension patients also had significantly lower OPP than controls (P < 0.001), but such difference in OPP was not significant between OAG patients with baseline IOP of ≤21 mmHg and controls (P = 0.996). In conclusion, although no causal relationship was proven in the present study, our findings suggest that in patients with high baseline IOP, who already have a higher risk of glaucoma, low OPP might be another risk factor.
Topics: Glaucoma, Open-Angle; Humans; Ocular Hypertension; Ocular Hypotension; Risk Factors
PubMed: 32572072
DOI: 10.1038/s41598-020-66914-w -
Ophthalmic Research 2023The purpose of this study was to establish a novel and reversible experimental ocular hypertension primate model by blocking Schlemm's canal.
INTRODUCTION
The purpose of this study was to establish a novel and reversible experimental ocular hypertension primate model by blocking Schlemm's canal.
METHODS
A model was induced in adult cynomolgus monkeys (n = 4) by blocking Schlemm's canal with an inserted microcatheter (200 μm diameter); it was removed 6 weeks later from one monkey to reverse the elevated intraocular hypertension. All animals were monitored for 11 months; weekly measurements of intraocular pressure and biweekly examinations with spectral domain optical coherence tomography and disc photography were performed. Histopathology of the eye and retinal ganglion cell counts were completed at the end of the study.
RESULTS
The intraocular pressure of the blocked eyes was significantly higher than that of the contralateral eyes at 1 month after the blockage (p < 0.001); the mean intraocular pressure was similar to the contralateral eye from 1 week to 11 months after the microcatheter was removed in monkey A (p = 0.170). The mean intraocular pressure of the blocked eyes of the remaining monkeys was significantly higher than that of the contralateral eyes throughout the follow-up period (p < 0.001). The fundus imaging showed decreases in the retinal nerve fibre layer thickness, and localized defects were observed in two blocked eyes. A histological examination demonstrated that the number of retinal ganglion cells in the blocked eyes of monkeys A, B, and C was significantly decreased compared with the control.
CONCLUSION
Schlemm's canal blockage alone in the monkey model produces sustained elevation of intraocular pressure, which presents a novel animal model for studying the pathogenesis of glaucoma.
Topics: Animals; Schlemm's Canal; Sclera; Glaucoma; Ocular Hypertension; Intraocular Pressure; Primates; Haplorhini; Trabecular Meshwork
PubMed: 36380650
DOI: 10.1159/000527099 -
Scientific Reports Nov 2023Ocular hypertension during glaucoma can lead to hypoxia, activation of the HIF transcription factors, and a metabolic shift toward glycolysis. This study aims to test...
Ocular hypertension during glaucoma can lead to hypoxia, activation of the HIF transcription factors, and a metabolic shift toward glycolysis. This study aims to test whether chronic HIF activation and the attendant metabolic reprogramming can initiate glaucoma-associated pathology independently of ocular hypertension. HIF-1α stabilization was induced in mice for 2 and 4 weeks by inhibiting prolyl hydroxylases using the small molecule Roxadustat. HIF-1α stabilization and the expression of its downstream bioenergetic targets were investigated in the retina by immunofluorescence, capillary electrophoresis, and biochemical enzyme activity assays. Roxadustat dosing resulted in significant stabilization of HIF-1α in the retina by 4 weeks, and upregulation in glycolysis-associated proteins (GLUT3, PDK-1) and enzyme activity in both neurons and glia. Accordingly, succinate dehydrogenase, mitochondrial marker MTCO1, and citrate synthase activity were significantly decreased at 4 weeks, while mitophagy was significantly increased. TUNEL assay showed significant apoptosis of cells in the retina, and PERG amplitude was significantly decreased with 4 weeks of HIF-1α stabilization. A significant increase in AMPK activation and glial hypertrophy, concomitant with decreases in retinal ganglion cell function and inner retina cell death suggests that chronic HIF-1α stabilization alone is detrimental to retina metabolic homeostasis and cellular survival.
Topics: Animals; Mice; Apoptosis; Glaucoma; Hypoxia-Inducible Factor 1, alpha Subunit; Mitophagy; Ocular Hypertension; Respiration; Retina; Retinal Ganglion Cells
PubMed: 37996657
DOI: 10.1038/s41598-023-47942-8 -
Investigative Ophthalmology & Visual... May 2022To assess the changes in retinal morphology in a rat model of chronic glaucoma induced by ocular hypertension.
PURPOSE
To assess the changes in retinal morphology in a rat model of chronic glaucoma induced by ocular hypertension.
METHODS
Intraocular pressure (IOP) was surgically increased through weekly injections of sodium hyaluronate (HYA) in the anterior eye chamber of the left eye of male Wistar rats, whereas the right eyes were sham operated (salt solution). During the 10-week experimental period, IOP was measured weekly with a rebound tonometer. Retinal cryosections were prepared for histological/immunohistochemical analysis and morphometry.
RESULTS
IOP was higher in HYA-treated eyes than in sham-operated eyes along the 10-week period, which was significant from the fourth to the nineth week. Ocular hypertension in HYA-treated eyes was associated with morphologic and morphometric changes in bipolar cells, ON-OFF direction-selective ganglion cells, ON/OFF starburst amacrine cells, and inner plexiform layer sublamina.
CONCLUSIONS
Serial HYA treatment in the rat anterior eye chamber results in mild-to-moderate elevated and sustained IOP and ganglion cell death, which mimics most human open-angle glaucoma hallmarks. The reduced number of direction-selective ganglion cells and starburst amacrine cells accompanied by a deteriorated ON/OFF plexus in this glaucoma model could lend insight to the abnormalities in motion perception observed in patients with glaucoma.
Topics: Animals; Disease Models, Animal; Glaucoma; Glaucoma, Open-Angle; Humans; Hyaluronic Acid; Intraocular Pressure; Male; Ocular Hypertension; Rats; Rats, Wistar; Retinal Ganglion Cells
PubMed: 35503230
DOI: 10.1167/iovs.63.5.2 -
The British Journal of Ophthalmology Jun 2023To report the baseline intraocular pressure (IOP) characteristics and its diurnal fluctuation in the Laser in Glaucoma and Ocular Hypertension China cohort.
AIMS
To report the baseline intraocular pressure (IOP) characteristics and its diurnal fluctuation in the Laser in Glaucoma and Ocular Hypertension China cohort.
METHODS
622 primary open-angle glaucoma (POAG) patients and 149 ocular hypertension (OHT) patients were recruited at Zhongshan Ophthalmic Center from 2015 to 2019. Standardised ocular examinations were performed including IOP measurement using the Goldmann applanation tonometer. Daytime phasing IOP was recorded at 8:00, 10:00, 11:30, 14:30, 17:00 hour.
RESULTS
The mean baseline IOP was 20.2 mm Hg for POAG patients and 24.4 mm Hg for OHT. Multiple regression analysis revealed that thicker central corneal thickness (CCT) was correlated with higher IOP in both POAG and OHT. Male gender and younger age were correlated with higher IOP only for POAG. As for diurnal IOP fluctuation, mean IOP fluctuation was 3.4 mm Hg in POAG eyes and 4.4 mm Hg in OHT. The peak and trough IOP occurred at 8:00 and 14:30 hour in both POAG and OHT eyes.
CONCLUSIONS
Younger age, male gender and thicker CCT are correlated to higher IOP in POAG patients while only thicker CCT is related to higher IOP in OHT patients. Peak IOP appears mostly at early morning or late afternoon and trough value occurs mostly at early afternoon.
Topics: Humans; Male; Intraocular Pressure; Glaucoma, Open-Angle; Glaucoma; Ocular Hypertension; Tonometry, Ocular; Cornea
PubMed: 35086806
DOI: 10.1136/bjophthalmol-2021-320128 -
Journal Francais D'ophtalmologie Oct 2021Dysthyroidism, especially Graves' disease, causes potentially severe orbital disease. This is frequently accompanied by ocular hypertension stemming from multiple... (Review)
Review
Dysthyroidism, especially Graves' disease, causes potentially severe orbital disease. This is frequently accompanied by ocular hypertension stemming from multiple pathophysiological mechanisms. Adaptations in the technique of intraocular pressure measurement must occur, using portable equipment if necessary. Glaucomatous optic neuropathy secondary to dysthyroid orbitopathy is rare, and screening for signs of compressive optic neuropathy is essential in the case of visual field loss. In cases of secondary glaucomatous optic neuropathy, treatment of the intraocular pressure is based mainly on systemic corticosteroid therapy and topical medications as necessary.
Topics: Glaucoma; Graves Ophthalmopathy; Humans; Intraocular Pressure; Ocular Hypertension; Optic Nerve Diseases
PubMed: 34303550
DOI: 10.1016/j.jfo.2021.01.026 -
Current Eye Research Feb 2020: This study is aimed to investigate the effects of periocular steroids induction on intraocular pressure (IOP), retinal ganglion cells (RGCs) and trabecular meshwork...
: This study is aimed to investigate the effects of periocular steroids induction on intraocular pressure (IOP), retinal ganglion cells (RGCs) and trabecular meshwork (TM) ultrastructure in glucocorticoid-induced ocular hypertension mice model.: Dexamethasone-21-acetate (Dex-Ace) was administered through periocular conjunctival fornix injection every 3 days in C57BL/6J mice. Intraocular pressure was measured weekly by rebound tonometry. RGCs were examined with immunofluorescent staining of BRN3a at week 1, 4, and 8. TM morphology was visualized with electron microscopy. Autophagy was evaluated with immunoblotting in TM tissues.: Dex-Ace rapidly and significantly induced IOP, which peaked at week 4. The absolute increase in IOP in the Dex-Ace-treated mice was 8.1 ± 1.4 mmHg, a 60% induction ( < .0001) compared with that in the vehicle-treated mice. The IOP sustained a higher level in the Dex-Ace group from week 4 to week 8. Dex-Ace treatment decreased the number of RGCs in a time-dependent manner, suggesting that high IOP resulted in optic neuropathy. In addition, Dex-Ace thickened trabecular beams and decreased intertrabecular spaces, with marked accumulation of fibrillar and amorphous granular extracellular material. Moreover, Dex-Ace induced swollen and elongated mitochondria in TM cells. The average mitochondria area was 0.090 ± 0.044 µm in the vehicle-treated mice, and increased to 0.161 ± 0.094 µm ( < .0001), 0.121 ± 0.029 µm ( = .0223) and 0.171 ± 0.076 µm ( < .0001) in the Dex-Ace-treated mice at weeks 1, 4 and 8, respectively. Autophagy was also increased by Dex-Ace treatment, indicating by the upregulation of LC3-I, LC3-II and beclin-1, and downregulation of p62.: Dex-Ace administration decreased RGCs and changed TM ultrastructure, mimicking hallmarks of human glucocorticoid-induced glaucoma (GIG). In addition, mitochondria and autophagy dysfunction suggested abnormal energy metabolism in TM cells, which warranted further study to fully elucidate the pathogenesis of GIG.
Topics: Animals; Autophagy; Dexamethasone; Disease Models, Animal; Female; Fluorescent Antibody Technique, Indirect; Glaucoma; Glucocorticoids; Immunoblotting; Intraocular Pressure; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Mitochondria; Mitochondrial Diseases; Ocular Hypertension; Retinal Ganglion Cells; Tonometry, Ocular; Trabecular Meshwork; Transcription Factor Brn-3A
PubMed: 31425668
DOI: 10.1080/02713683.2019.1657462 -
Biomedicine & Pharmacotherapy =... Sep 2023Reactive oxygen species (ROS) overproduction plays an essential role in the etiology of ischemic/hypoxic retinopathy caused by acute glaucoma. NADPH oxidase (NOX) 4 was...
Inhibition of NOX4 with GLX351322 alleviates acute ocular hypertension-induced retinal inflammation and injury by suppressing ROS mediated redox-sensitive factors activation.
Reactive oxygen species (ROS) overproduction plays an essential role in the etiology of ischemic/hypoxic retinopathy caused by acute glaucoma. NADPH oxidase (NOX) 4 was discovered as one of the main sources of ROS in glaucoma. However, the role and potential mechanisms of NOX4 in acute glaucoma have not been fully elucidated. Therefore, the current study aims to investigate the NOX4 inhibitor GLX351322 that targets NOX4 inhibition in acute ocular hypertension (AOH)-induced retinal ischemia/hypoxia injury in mice. Herein, NOX4 was highly expressed in AOH retinas, particularly the retinal ganglion cell layer (GCL). Importantly, the NOX4 inhibitor GLX351322 reduced ROS overproduction, inhibited inflammatory factor release, suppressed glial cell activation and hyperplasia, inhibited leukocyte infiltration, reduced retinal cell senescence and apoptosis in damaged areas, reduced retinal degeneration and improved retinal function. This neuroprotective effect is at least partially associated with mediated redox-sensitive factor (HIF-1α, NF-κB, and MAPKs) pathways by NOX4-derived ROS overproduction. These results suggest that inhibition of NOX4 with GLX351322 attenuated AOH-induced retinal inflammation, cellular senescence, and apoptosis by inhibiting the activation of the redox-sensitive factor pathway mediated by ROS overproduction, thereby protecting retinal structure and function. Targeted inhibition of NOX4 is expected to be a new idea in the treatment of acute glaucoma.
Topics: Animals; Mice; Glaucoma; Inflammation; NADPH Oxidase 4; NADPH Oxidases; Ocular Hypertension; Oxidation-Reduction; Reactive Oxygen Species; Retinal Diseases; Piperazines; Thiophenes
PubMed: 37399715
DOI: 10.1016/j.biopha.2023.115052