MicroRNA Let-7f Identified As A Key Player In Dry Age-Related Macular Degeneration

Ophthalmology Updates: Researchers at Université de Montréal have uncovered a significant connection between the microRNA Let-7f and the progression of dry age-related macular degeneration (AMD). This study covered in this Ophthalmology Updates report, delves into how Let-7f induces senescence and oxidative stress in retinal pigment epithelial (RPE) cells, potentially leading to this common and debilitating eye condition.


MicroRNA Let-7f Identified As A Key Player In Dry Age-Related Macular Degeneration

Understanding the Role of RPE Cells
The retinal pigment epithelium (RPE) is a layer of cells situated at the outermost part of the retina. These cells are vital for maintaining vision. They perform multiple functions, including forming the blood-retinal barrier, playing a role in the visual cycle, absorbing excess light, and supporting photoreceptor cells. RPE cells are responsible for the phagocytosis of photoreceptor tips, crucial for the survival and functionality of photoreceptors.
 
The Impact of Aging and Oxidative Stress
RPE cells need to meet high energy demands to function properly, making them vulnerable to oxidative stress. The body's defense mechanisms typically counterbalance the excessive production of reactive oxygen species (ROS). However, as we age, this defense weakens, leading to RPE cell dysfunction and eventual degeneration. This situation worsens when coupled with other stressors like smoking, obesity, and genetic predisposition, potentially resulting in various eye diseases, including AMD.
 
AMD is a leading cause of blindness in developed countries, especially among the elderly. It manifests in two forms: wet AMD, characterized by the rapid growth of abnormal blood vessels causing quick vision loss, and dry AMD, which is more common and involves the accumulation of lipid deposits called drusen. These deposits lead to the gradual atrophy of the RPE layer.
 
What is MicroRNA Let-7f?
MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in regulating gene expression post-transcriptionally. The Let-7 family of miRNAs, including Let-7f, was one of the first to be discovered. This family consists of 12 members (let-7a-1, 7a-2, 7a-3, 7b, 7c, 7d, 7e, 7f-1, 7f-2, 7g, 7i, and mir-98) and is highly conserved across species.
 
In humans, the Let-7 family has well-established roles in cellular differentiation, cell cycle regulation, and tumor suppression. These miRNAs are also implicated in regulating aging, oxidative stress, and senescence in various cell types, including those related to ocular tissues. Recent studies have identified several Let-7 family members, including Let-7f, among the most abundant miRNAs in extracellular vesicles released by photo-oxidative damaged retinas.
 
The Study: Let-7f and Oxidative Stress
The study aimed to understand the role of Let-7f in RPE cell dysfunction and degeneration by investigating its effects on senescence and oxidative stress. Researchers explored whether inhibiting Let-7f could protect RPE cells from oxidative damage induced by sodium iodate (SI).
 
The research demonstrated that Let-7f expression and oxidative stress in RPE cells are reciprocally regulated. Overexpression of Let-7f in ARPE-19 cells increased ROS production and induced senescence. Conversely, inhibiting Let-7f protected RPE cells from the harmful effects of SI. Additionally, Let-7f overexpression impaired RPE cell functions like migration and phagocytosis of photoreceptor outer segments.
 
In Vivo Confirmation
The study's in vitro findings were confirmed in vivo using C57BL/6 mice. Intravitreal injections of SI and Let-7f antagomir provided strong evidence that Let-7f contributes to RPE cell dysfunction through oxidative stress and senescence. This research suggests that Let-7f plays a significant role in the pathogenesis of dry AMD.
 
The Mechanism of Action
MicroRNAs (miRNAs) like Let-7f are small non-coding RNAs that regulate gene expression post-transcriptionally. The Let-7 family, consisting of 12 members, is conserved across species and is known for roles in cellular differentiation, cell cycle regulation, and tumor suppression. They also regulate aging, oxidative stress, and senescence in various cells, including those related to the eye.

Previous studies have shown that Let-7 family miRNAs are highly expressed in extracellular vesicles released by photo-oxidative damaged retinas. Despite substantial evidence linking Let-7 miRNAs to age-related retinal disorders, their roles in RPE cells remained largely unexplored until this study.
 
Results and Implications
-Upregulation and Induction of Oxidative Stress: The study found that Let-7f expression is upregulated in response to oxidative stress in RPE cells treated with SI and hydrogen peroxide (H2O2). This upregulation was also observed in vivo in mice injected with SI, indicating a localized response in the RPE.
 
-Promotion of Cellular Dysfunction: Overexpression of Let-7f in ARPE-19 cells increased intracellular and mitochondrial ROS production, impairing the cells' phagocytic activity, migration, proliferation, and viability. These findings suggest that Let-7f overexpression promotes cellular dysfunction through oxidative stress.
Induction of Senescence: The research showed that Let-7f overexpression induces senescence in RPE cells. This was evidenced by a decrease in Ki67-positive cells (indicating cell cycle arrest) and an increase in senescence-associated β-galactosidase activity. Additionally, protein levels of senescence markers p16INK4a and p21Waf/Cip1 were significantly elevated.
 
-Protection through Inhibition: Inhibition of Let-7f protected ARPE-19 cells from SI-induced oxidative injury. This protective effect was observed in reduced ROS production, improved cell viability, and decreased senescence. In vivo, Let-7f inhibition significantly reduced the extent of RPE cell damage caused by SI.
 
Discussion and Future Directions
This study highlights the potential of Let-7f as a therapeutic target for AMD. By regulating oxidative stress and senescence, Let-7f plays a crucial role in RPE cell dysfunction and degeneration. The findings suggest that targeting Let-7f could lead to novel treatments for dry AMD, a condition currently without effective therapeutic options beyond slowing disease progression.
 
Future research should focus on further elucidating the mechanisms by which Let-7f influences oxidative stress and senescence in RPE cells. Understanding these pathways could pave the way for the development of targeted therapies aimed at preventing or slowing the progression of dry AMD.
 
Conclusion
The Université de Montréal study provides compelling evidence that Let-7f is a key player in the degeneration and dysfunction of RPE cells through the induction of oxidative stress and senescence. These findings offer new insights into the pathogenesis of dry AMD and open the door to potential new treatments for this prevalent and debilitating eye disease.
 
The study findings were published in the peer reviewed journal: Antioxidants.
https://www.mdpi.com/2076-3921/13/6/646
 
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