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Changes of Ocular Dimensions as a Marker of Disease Progression in a Murine Model of Pigmentary Glaucoma

ABSTRACT: Purpose The elevation of intraocular pressure (IOP), a major risk factor in glaucoma, is an important parameter tracked in experimental models of this disease. However, IOP measurement in laboratory rodents is challenging and may not correlate with some key pathological events that occur in the development of glaucoma. The aims of this study were to quantify changes in ocular morphology in DBA/2J mice that develop spontaneous, age-dependent, pigmentary glaucoma and to check the possible correlation of these parameters with IOP. Method Eye morphology was evaluated with MRI in DBA/2J, DBA/2J-Gpnmb+/SjJ, and C57BL/6J female mice ages 3, 6, 9, 12, and 15 months. The animals were anesthetized with isoflurane. A planar receive-only surface coil (inner diameter = 10 mm) was placed over each animal’s left eye and the image was acquired with a 7T small animal-dedicated magnetic resonance tomograph and T2-weighted TurboRARE sequence. Ocular dimensions were manually quantitated using OsiriX software. IOP was measured with rebound tonometry. Results In the control animals, no age-related changes in the ocular morphology were noted. Since 6 months of age, the anterior chamber deepening and elongation of the eyeballs of DBA/2J mice was detectable. We found a significant, positive correlation between IOP and axial length, anterior chamber area, or anterior chamber width in C57BL/6J mice but not in DBA/2J mice. However, after excluding the measurements performed in the oldest DBA/2J mice (i.e. analyzing only the animals ages 3 to 12 months), we demonstrated a significant positive correlation between IOP and anterior chamber width. Conclusion High-resolution magnetic resonance imaging of the eye area in mice enables reproducible and consistent measures of key dimensions of the eyeball. We observed age-dependent alterations in the eye morphology of DBA/2J mice that mostly affected the anterior chamber. We also demonstrated a correlation between some of the ocular dimensions and the IOP of C57Bl/6J mice and DBA/2J mice with moderately advanced glaucomatous pathology.

SUBMITTER: Fiedorowicz M

PROVIDER: S-EPMC7500411 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:PurposeGlaucoma is a group of heterogeneous optic neuropathies characterized by the progressive degeneration of retinal ganglion cells. However, the underlying mechanisms have not been understood completely. We aimed to elucidate the genetic network associated with the development of pigmentary glaucoma with DBA/2J (D2) mouse model of glaucoma and corresponding genetic control D2-Gpnmb (D2G) mice carrying the wild type (WT) Gpnmb allele.MethodsRetinas isolated from 13 D2 and 12 D2G mice were subdivided into 2 age groups: pre-onset (1-6 months: samples were collected at approximately 1-2, 2-4, and 5-6 months) and post-onset (7-15 months: samples were collected at approximately 7-9, 10-12, and 13-15 months) glaucoma were compared. Differential gene expression (DEG) analysis and gene-set enrichment analyses were performed. To identify micro-RNAs (miRNAs) that target Gpnmb, miRNA expression levels were correlated with time point matched mRNA expression levels. A weighted gene co-expression network analysis (WGCNA) was performed using the reference BXD mouse population. Quantitative real-time PCR (qRT-PCR) was used to validate Gpnmb and miRNA expression levels.ResultsA total of 314 and 86 DEGs were identified in the pre-onset and post-onset glaucoma groups, respectively. DEGs in the pre-onset glaucoma group were associated with the crystallin gene family, whereas those in the post-onset group were related to innate immune system response. Of 1329 miRNAs predicted to target Gpnmb, 3 miRNAs (miR-125a-3p, miR-3076-5p, and miR-214-5p) were selected. A total of 47 genes demonstrated overlapping with the identified DEGs between D2 and D2G, segregated into their time-relevant stages. Gpnmb was significantly downregulated, whereas 2 out of 3 miRNAs were significantly upregulated (P < 0.05) in D2 mice at both 3-and 10-month time points.ConclusionsThese findings suggest distinct gene-sets involved in pre-and post-glaucoma in the D2 mouse. We identified three miRNAs regulating Gpnmb in the development of murine pigmentary glaucoma.

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Changes of Ocular Dimensions as a Marker of Disease Progression in a Murine Model of Pigmentary Glaucoma

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