A recent study conducted at Zhejiang University in China has revealed important insights into the role of Keratin 8 (KRT8) in preserving retinal ganglion cells (RGCs) under conditions of high intraocular pressure (IOP). Glaucoma, a leading cause of irreversible blindness worldwide, is characterized by the gradual loss of vision, often due to the damage and loss of RGCs. Understanding the mechanisms involved in preserving these cells could lead to new therapeutic strategies for glaucoma patients.
The study found that KRT8, a type II keratin, is expressed in RGCs, with significantly higher expression compared to other retinal layers. Additionally, the expression of KRT8 increased following the induction of acute ocular hypertension (AOH) in mouse retinas. To investigate the role of KRT8 in RGCs, the researchers used an adeno-associated virus (AAV) system to selectively knock down KRT8 in these cells. Under normal conditions, the knockdown of KRT8 had no noticeable effect on the retinal structure, thickness, RGC counts, or ultrastructural features.
However, when AOH was induced after KRT8 knockdown, there was a more severe reduction in retinal thickness and inner retinal layers, as well as an exacerbation of ultrastructural changes and loss of RGCs. Visual function, as measured by electroretinography, was also significantly impaired in the KRT8 knockdown group. These findings suggest that KRT8 plays a crucial role in preserving RGCs under conditions of high IOP.
Further investigation into the mechanisms underlying the aggravated RGC damage in the KRT8 knockdown group revealed that the aberrant activation of mitogen-activated protein kinase (MAPK) pathways, specifically JNK and p38, contributed to RGC apoptosis. Interestingly, KRT8 knockdown also led to a decreased level of phosphorylated ERK, which could potentially activate the NF-κB signaling pathway and increase gliosis, contributing to retinal neuroinflammation.
In conclusion, this study highlights the critical role of KRT8 in preserving RGCs under high IOP conditions. The deficiency of KRT8 leads to the abnormal activation of MAPK pathways, resulting in RGC apoptosis. These findings provide valuable insights into the regulatory mechanisms underlying glaucoma and open up new possibilities for therapeutic approaches. Preserving KRT8 in RGCs could potentially lead to innovative treatments that protect these cells and mitigate the impact of glaucoma.