Glaucoma News: Study Reveals That MicroRNA-93 Is A Key Player In Glaucoma Pathogenesis!

Glaucoma News: Glaucoma, a leading cause of blindness worldwide, remains a challenging disease to treat effectively. The hallmark of glaucoma is the apoptosis of retinal ganglion cells (RGCs), ultimately leading to glaucomatous optic neuropathy. Elevated intraocular pressure (IOP) is the primary risk factor for the development and progression of this condition. Current treatments focus on reducing IOP through pharmacological or surgical interventions, but these approaches do not always prevent the ongoing degeneration of RGCs and axons.


 
There is an urgent need for innovative therapies that can protect these vital cells. MicroRNAs (miRNAs) have emerged as potential regulators of glaucoma pathogenesis, offering new avenues for research into its diagnosis and treatment. This Glaucoma News report explores the study by researchers from Nanfang Hospital, Affiliated Hospital of Southwest Medical University, Luzhou- China on the role of microRNA-93 (miR-93) in promoting the development of glaucoma and the underlying molecular mechanisms.
 
MicroRNAs: Key Regulators in Glaucoma Pathogenesis
MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a critical role in post-transcriptional gene regulation. They have been implicated in numerous physiological and pathological processes, including cell proliferation, apoptosis, differentiation, and organogenesis. In recent years, miRNAs have gained significant attention in the study of glaucoma, offering a promising avenue for understanding its pathogenesis and identifying potential therapeutic targets.
 
Previous research demonstrated that miR-93 promotes apoptosis in glaucomatous trabecular meshwork (TM) cells. Inhibition of miR-93 led to increased TM cell viability, suggesting that miR-93 may be a potential target for glaucoma therapy.
https://www.spandidos-publications.com/mmr/14/6/5746
 
However, the effect of miR-93 on RGC apoptosis and its role in animal models of glaucoma remained unexplored, making it essential to investigate the impact of miR-93 on RGCs and its contribution to glaucoma development.
 
MiR-93 Promotes RGC Apoptosis
Ischemic-hypoxic injury is a leading cause of damage to the visual nervous system. To investigate the effect of miR-93 on retinal ganglion cells, the researchers induced RGC apoptosis using oxygen-glucose deprivation and reperfusion (OGD/R). They transfected miR-93 mimics and inhibitors into OGD/R-induced RGCs to assess the impact. Results showed that miR-93 mimics significantly decreased RGC viability while promoting apoptosis. In contrast, miR-93 inhibitors increased RGC viability and reduced apoptosis, suggesting that miR-93 plays a role in promoting RGC apoptosis.
 
MiR-93 Exacerbates Retinal Tissue Damage
The study extended its focus to an acute glaucoma mouse model induced by high IOP. Animals in this model were divided into three groups: a vehicle group, a miR-93 mimics group, and a miR-93 inhibitor group, with healthy mice serving as a normal control. Hematoxylin and Eosin (H&E) staining was e mployed to assess histopathological changes in retinal tissue, including cell counts in the ganglion cell layer and the thickness of different layers. The findings revealed that miR-93 mimics significantly exacerbated retinal tissue damage, decreasing the number of ganglion cell layer (GCL) cells and the thickness of various tissue layers.
 
MiR-93 Impacts IOP Levels
Interestingly, the study found that miR-93 mimics significantly increased IOP in mice with acute glaucoma, while miR-93 inhibitors reversed these changes. This suggests that miR-93 has a direct influence on IOP levels in glaucoma, further supporting its role in the disease's pathogenesis.
 
MiR-93 Regulates ECM and MMP-Related Proteins
Extracellular matrix (ECM) and matrix metalloproteinases (MMPs) are crucial factors in glaucoma development. An imbalance between ECM deposition and MMP activity can lead to increased resistance in aqueous outflow channels, elevated IOP, and ultimately glaucoma. The researchers investigated the effect of miR-93 on these factors.
 
In RGCs subjected to OGD/R induction, miR-93 mimics significantly upregulated the expression of ECM-related proteins and downregulated MMPs. Inhibition of miR-93 reversed these changes, indicating that miR-93 impacts the balance between ECM and MMP-related proteins. In acute glaucoma mice, miR-93 mimics increased IOP levels, concomitant with upregulated ECM-related protein expression and downregulated MMP-related protein expression. Inhibition of miR-93 had the opposite effect, decreasing IOP and rebalancing ECM and MMP-related proteins.
 
Activation of the Rho/ROCK Signaling Pathway by miR-93
The Rho/ROCK signaling pathway has been implicated in glaucoma pathogenesis, offering potential targets for its treatment. Rho is a member of the small GTPase superfamily, playing a crucial role in various cellular processes, including cytoskeletal adjustments, cell contraction, nerve regeneration, and apoptosis regulation.
 
Western blot analysis revealed that miR-93 mimics significantly activated the Rho/ROCK signaling pathway in RGCs and upregulated α-SMA protein expression. This activation was also observed in retinal tissue of mice with acute glaucoma. Conversely, inhibition of miR-93 reversed the expression levels of α-SMA and Rho/ROCK signaling pathway-related proteins in both RGCs and retinal tissue.
 
Study Implications
Research on miRNAs in ocular tissues has revealed the complex and highly tissue-specific nature of these molecules. The expression patterns of miRNAs in the eye vary significantly across different tissues, suggesting unique roles for miRNAs in ocular development, homeostasis, and disease. Moreover, miRNAs have been implicated in the regulation of aqueous humor secretion, IOP maintenance, trabecular meshwork remodeling, and other processes central to glaucoma pathogenesis.
 
Studies have shown that miR-93 is associated with diabetic retinopathy (DR) and primary open-angle glaucoma (POAG). Elevated plasma levels of miR-93 have been linked to a high risk of type 2 diabetic retinopathy, and increased miR-93 expression has been observed in patients with POAG. Inhibition of miR-93 has been shown to promote the viability of trabecular meshwork cells and inhibit apoptosis. Despite these findings, the specific mechanisms by which miR-93 promotes apoptosis in RGCs and its interaction with glaucoma development remain to be fully elucidated.
 
Conclusion
This study sheds light on the role of miR-93 in the pathogenesis of glaucoma. MiR-93 promotes RGC apoptosis, exacerbates retinal tissue damage, influences IOP levels, and disrupts the balance between ECM and MMP-related proteins. Furthermore, miR-93 activates the Rho/ROCK signaling pathway, a key player in glaucoma pathogenesis.
 
As a crucial player in the regulation of glaucoma, miR-93 holds promise as a potential therapeutic target for the disease. However, the exact targets of miR-93 remain to be identified, and further research is required to elucidate potential adverse effects associated with manipulating miR-93 expression. Future investigations should aim to unravel the intricate mechanisms through which miR-93 influences glaucoma, ultimately providing novel strategies for its diagnosis and treatment.
 
In conclusion, miR-93 represents a significant advance in our understanding of the molecular mechanisms underlying glaucoma pathogenesis, offering promising prospects for advanced therapies and diagnostic markers for this challenging eye disease.
 
The study findings were published in the peer reviewed journal: Heliyon.
https://www.cell.com/heliyon/fulltext/S2405-8440(23)09220-4
 
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