Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure.
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ABSTRACT:
SUBMITTER: Wang WH
PROVIDER: S-EPMC2242621 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing murine Angptl7 levels via injection into mouse eyes increases the IOP. We also show that acute Angptl7 silencing in adult mice lowers the IOP (~2-4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma.
| S-EPMC9529959 | biostudies-literature
Project description:PurposeTo describe two cases of peripapillary retinal schisis in patients with glaucoma without evidence of optic nerve pits, pseudopits, or X-linked retinoschisis.DesignTwo observational case reports and literature review.MethodsImaging of the peripapillary nerve fiber layer and schisis cavities was completed in two patients, and one patient was followed over time.ResultsThe first patient, diagnosed with narrow angle glaucoma, was noted to have peripapillary schisis in the right eye with matching changes on visual field and optical coherence tomographic (OCT) results. Follow-up examination revealed that the schisis disappeared in the right eye while appearing in the left. The findings were verified with high-speed ultra-high-resolution OCT performed in both eyes. The second case involved a patient with anatomically narrow angles, high intraocular pressure (IOP), and peripapillary schisis extending into the macula.ConclusionsPeripapillary retinoschisis may represent a unique sequelae of intraocular fluctuations in patients with uncontrolled glaucoma. Further studies are needed to better understand this disease process.
| S-EPMC1941763 | biostudies-literature
Project description:PurposeThe A3 adenosine receptor (A3AR) is a known therapeutic target for glaucoma treatment. In this study, we developed HL3501 and examined its selectivity profile and in vitro and in vivo effects.MethodsFor the rabbit model, intraocular pressure (IOP) was increased by laser photocoagulation of the trabecular meshwork (TM). The rabbits were then topically treated with HL3501, latanoprost, timolol, or vehicle for 3 weeks. For the mouse model, HL3501, latanoprost, or vehicle was administered following induced IOP elevation by dexamethasone (Dex). The IOP of all rabbits and mice was measured. Electroretinography was performed on both eyes of dark-adapted anesthetized mice on days 0 and 21. The mice's eyes were enucleated at the end of the treatment for immunofluorescence staining.ResultsHL3501 was highly specific to the A3AR and inhibitory of A3AR function. In the rabbit glaucoma model, HL3501 and latanoprost significantly decreased the IOP. In the Dex-treated mouse model, HL3501 and latanoprost significantly decreased the IOP and increased the b-wave amplitude as compared with the vehicle treatment. HL3501 and latanoprost also inhibited fibronectin and α-smooth muscle actin expression induced by Dex treatment.ConclusionsHL3501 had effects similar to those of latanoprost in reducing ocular hypertension in animal models. HL3501 could be used as a novel approach to treat glaucoma.Translational relevanceHL3501 is a novel preclinical compound targeting the A3 adenosine receptor, which may also be a new treatment option to fill the unmet needs of many glaucoma patients.
| S-EPMC8883152 | biostudies-literature
Project description:Secreted frizzled related proteins (Sfrps) are extracellular attenuators of Wnt signaling that play important roles in both embryogenesis and oncogenesis. Although Sfrps are generally thought to bind and sequester Wnts away from active receptor complexes, very little is known about the specificity of Sfrp family members for various Wnts. In the developing chick neural tube, sfrp-1, 2, and 3 transcripts are expressed in and adjacent to the dorsal neural tube, where Wnt-1 and Wnt-3a are expressed. To better define the possible roles of Sfrp-1, 2, and 3 in the neural tube, we first tested the ability of purified Sfrps to inhibit Wnt-3a-induced accumulation of beta-catenin in L cells. We find that both Sfrp-1 and Sfrp-2 can inhibit Wnt-3a activity while Sfrp-3 cannot. To determine where Sfrp-1 and Sfrp-2 impinge on the Wnt signaling pathway, we tested the ability of these Sfrps to inhibit Wnt signaling induced by the addition of LiCl, an inhibitor of GSK-3. Sfrp-1 and Sfrp-2 are unable to inhibit the accumulation of beta-catenin in LiCl-treated cells, suggesting that the ability of Sfrps to inhibit the accumulation of beta-catenin is GSK-3 dependent. We have further shown that Sfrp-2 inhibits the ability of ectopic Wnt-3a to stimulate proliferation in the developing chick neural tube. These results provide the framework for understanding how Sfrps function to regulate Wnt-3a activity in developing embryos and in cancer.
| S-EPMC2566934 | biostudies-literature
Project description:ImportanceThe ability of patients to measure their own intraocular pressure (IOP) would allow more frequent measurements and better appreciation of peak IOP and IOP fluctuation.ObjectiveTo examine whether patients with glaucoma can perform self-tonometry using a rebound tonometer and examine patient acceptability.Design, setting, and participantsAn observational study in which IOP was assessed using Goldmann applanation tonometry and a rebound tonometer. Consecutive patients were provided with a patient information sheet and those consenting to take part in the study received standardized self-tonometry training and were then instructed to measure their own IOP under observation. This study was conducted at a glaucoma clinic at a university hospital from March 1, 2016, to December 30, 2016, and included both eyes of 100 patients with glaucoma or ocular hypertension.Main outcomes and measuresThe percentage of patients who could successfully perform self-tonometry. Complete success was defined by a good technique and an IOP reading within 5 mm Hg of that obtained by a clinician using the same device. A 3-item questionnaire was used to examine perceptions of self-tonometry among patients.ResultsAmong the 100 patients, the mean (SD) age was 67.5 (10.9) years (53% female). A total 73 of 100 patients (73%) met the complete success criteria. An additional 6 patients could use the device but had IOP readings greater than 5 mm Hg different from those obtained by the clinician. On average, IOP by the rebound tonometer was 2.66 mm Hg lower than Goldmann applanation tonometry (95% limits of agreement, -3.48 to 8.80 mm Hg). The IOPs with the rebound tonometer were similar whether obtained by self-tonometry or investigator, with excellent reproducibility with an intraclass correlation coefficient of 0.903 (95% CI, 0.867-0.928). A total of 56 of 79 successful or partially successful patients (71%) felt self-tonometry was easy, with 73 of 79 (92%) reporting self-tonometry to be comfortable, and a similar number happy to perform self-tonometry in the future.Conclusions and relevanceMost patients could perform self-tonometry and the method was acceptable to patients. Self-tonometry has the potential to improve patient engagement, while also providing a more complete picture of IOP changes over time.
| S-EPMC5710491 | biostudies-literature
Project description:PurposeThe human CAV1-CAV2 locus has been associated with susceptibility to primary open-angle glaucoma in four studies of Caucasian, Chinese, and Pakistani populations, although not in several other studies of non-Korean populations. In this study with Korean participants, the CAV1-CAV2 locus was investigated for associations with susceptibility to primary open-angle glaucoma accompanied by elevated intraocular pressure (IOP), namely, high-tension glaucoma (HTG), as well as with IOP elevation, which is a strong risk factor for glaucoma.MethodsTwo single nucleotide polymorphisms (SNPs) were genotyped in 1,161 Korean participants including 229 patients with HTG and 932 healthy controls and statistically examined for association with HTG susceptibility and IOP. One SNP was rs4236601 G>A, which had been reported in the original study, and the other SNP was rs17588172 T>G, which was perfectly correlated (r2=1) with another reported SNP rs1052990. Expression quantitative trait loci (eQTL) analysis was performed using GENe Expression VARiation (Genevar) data.ResultsBoth SNPs were associated with HTG susceptibility, but the rs4236601 association disappeared when adjusted for the rs17588172 genotype and not vice versa. The minor allele G of rs17588172 was associated significantly with 1.5-fold increased susceptibility to HTG (p=0.0069) and marginally with IOP elevation (p=0.043) versus the major allele T. This minor allele was also associated with decreased CAV1 and CAV2 mRNA in skin and adipose according to the Genevar eQTL analysis.ConclusionsThe minor allele G of rs17588172 in the CAV1-CAV2 locus is associated with decreased expression of CAV1 and CAV2 in some tissues, marginally with IOP elevation, and consequently with increased susceptibility to HTG.
| S-EPMC4431411 | biostudies-literature
Project description:The alternative mechanical theory of glaucoma, in which an increased pressure difference across the lamina cribrosa (difference between intraocular and intracranial pressure; IOP and ICP), rather than solely an elevated IOP, leads to structural and functional vision loss, is still controversial. If the theory is true, a drug that simultaneously lowers both the IOP and ICP may be ineffective. The aim of this study was to determine how acetazolamide (AAZ; a drug prescribed in glaucoma that aims to lower the IOP) affects both IOP and ICP in glaucoma patients and to compare the magnitude and time course of the induced pressure changes with those of healthy subjects not taking AAZ. IOP and noninvasive ICP (measured through emissions from the ear) were measured in 20 glaucoma patients taking 125 mg of AAZ twice daily. Measurements were taken for 30 minutes before taking the drug and for 2 hours post-ingestion. Comparisons were made with 13 age-similar controls. After 12 hours with no anti-glaucoma medication, AAZ did not further reduce IOP in glaucoma patients compared to controls (P = 0.58) but did reduce ICP compared to controls (P = 0.035), by approximately 4 mmHg. Our findings suggest that there are periods during the day when the pressure difference across the lamina cribrosa is larger in case of AAZ use. Future studies should focus on improving the noninvasive ICP testing, different doses and dosing schedules of AAZ, and the time course of IOP in glaucoma patients not taking AAZ.
| S-EPMC7302490 | biostudies-literature
Project description:Minimally invasive glaucoma surgeries (MIGS) offer an effective way to lower intraocular pressure without inducing extensive trauma to the anterior segment. In order to predict their efficacy, an analytical model of the conventional aqueous humor outflow pathway is developed using a resistor network. The model describes outflow through the normal eye and allows for the effects of geometric changes in the outflow pathway as IOP changes. By selectively removing these resistors, the model can be used to examine and predict the outcomes of several surgical procedures currently used to treat glaucoma. Treatments examined include traditional trabeculectomy, several ab interno methods for trabeculotomy and trabeculectomy, as well as recently developed trabecular stents that bypass the trabecular meshwork and dilate Schlemm canal. The model's predictions for the efficacy of these procedures generally matched well with the efficacy determined in experimental studies, although it tended to somewhat overestimate the efficacy of these procedures. Matching the model to experimental data indicated that a partial trabeculotomy substantially increases flow to collector channels within that region and approximately 1.5 clock hours past the ends of the trabeculotomized region. Similarly, trabecular bypass stents substantially increase flow to collector channels up to 1.5 clock hours past the open ends of the stent. The resistor model we have developed can be used to predict the efficacy of a variety of MIGS procedures. Circumferential flow in Schlemm canal extends the efficacy of MIGS, but this effect is limited to a few clock hours.
| S-EPMC8595518 | biostudies-literature
Project description:Glaucoma is a group of eye conditions that damage the optic nerve, the health of which is vital for vision. The key risk factor for the development and progression of this disease is increased intraocular pressure (IOP). Implantable glaucoma drainage devices have been developed to divert aqueous humor from the glaucomatous eye as a means of reducing IOP. The artificial drainage pathway created by these devices drives the fluid into a filtering bleb. The long-term success of filtration surgery is dictated by the proper functioning of the bleb and overlying Tenon's and conjunctival tissue. To better understand the influence of the health condition of these tissues on IOP, we have developed a mathematical model of fluid production in the eye, its removal from the anterior chamber by a particular glaucoma implant-the PRESERFLO® MicroShunt-, drainage into the bleb and absorption by the subconjunctival vasculature. The mathematical model was numerically solved by commercial FEM package COMSOL. Our numerical results of IOP for different postoperative conditions are consistent with the available evidence on IOP outcomes after the implantation of this device. To obtain insight into the adjustments in the implant's hydrodynamic resistance that are required for IOP control when hypotony or bleb scarring due to tissue fibrosis take place, we have simulated the flow through a microshunt with an adjustable lumen diameter. Our findings show that increasing the hydrodynamic resistance of the microshunt by reducing the lumen diameter, can effectively help to prevent hypotony. However, decreasing the hydrodynamic resistance of the implant will not sufficiently decrease the IOP to acceptable levels when the bleb is encapsulated due to tissue fibrosis. Therefore, to effectively reduce IOP, the adjustable glaucoma implant should be combined with a means of reducing fibrosis. The results reported herein may provide guidelines to support the design of future glaucoma implants with adjustable hydrodynamic resistances.
| S-EPMC9439203 | biostudies-literature
Project description:To present a method to analyze circadian intraocular pressure (IOP) patterns in glaucoma patients and suspects undergoing repeated continuous 24-hour IOP monitoring.Forty patients with established (n = 19) or suspected glaucoma (n = 21) underwent ambulatory 24-hour IOP monitoring on two sessions 1 week apart using a contact lens sensor (CLS). The CLS provides its output in arbitrary units (a.u.). A modified cosinor rhythmometry method was adapted to the CLS output to analyze 24-hour IOP patterns and their reproducibility. Nonparametric tests were used to study differences between sessions 1 and 2 (S1 and S2). Patients pursued their routine daily activities and their sleep was uncontrolled. CLS data were used to assess sleep times.Complete 24-hour data from both sessions were available for 35 patients. Mean (SD) age of the patients was 55.8 ± 15.5 years. The correlation of the cosinor fitting and measured CLS values was r = 0.38 (Spearman r; P < 0.001) for S1, r = 0.50 (P < 0.001) for S2, whereas the correlation between S1 and S2 cosinor fittings was r = 0.76 (P < 0.001). Repeated nocturnal acrophase was seen in 62.9% of patients; 17.1% of patients had no repeatable acrophase. The average amplitude of the 24-hour curve was 143.6 ± 108.1 a.u. (S1) and 130.8 ± 68.2 a.u. (S2) (P = 0.936).Adapting the cosinor method to CLS data is a useful way for modeling the rhythmic nature of 24-hour IOP patterns and evaluating their reproducibility. Repeatable nocturnal acrophase was seen in 62.9% of patients. (ClinicalTrials.gov number, NCT01319617.).
| S-EPMC3522433 | biostudies-literature