Targeting tRNA-Derived Non-Coding RNA Alleviates Diabetes-Induced Visual Impairment through Protecting Retinal...

Area of Science:

• Ophthalmology
• Molecular Biology
• Endocrinology

Background:

• Diabetes mellitus is a leading cause of vision loss, primarily through diabetic retinopathy.
• Diabetic retinopathy is characterized by neurovascular unit dysfunction, including retinal vasculopathy and neuropathy.
• The exact mechanisms driving diabetic retinopathy and effective therapeutic targets remain elusive.

Purpose of the Study:

• To investigate the role of tRNA-derived stress-induced RNAs in diabetic retinopathy.
• To elucidate the function of 5'tiRNA-His-GTG in retinal neurovascular dysfunction.
• To identify novel therapeutic strategies for diabetic retinopathy.

Main Methods:

• In vitro studies on Müller glia, endothelial cells, and retinal ganglion cells (RGCs).
• In vivo studies using animal models to assess retinal vascular function, neurodegeneration, and visual behavior.
• Analysis of arachidonic acid (AA) metabolism and the Cytochrome P450 (CYPs) pathway.

Main Results:

• Up-regulation of 5'tiRNA-His-GTG was observed in response to diabetic stress.
• 5'tiRNA-His-GTG directly impacts Müller glia and indirectly affects RGC survival and endothelial cells.
• Downregulation of 5'tiRNA-His-GTG improved retinal vascular function, reduced neurodegeneration, and enhanced visual behaviors in vivo.
• The 5'tiRNA-His-GTG-CYP2E1-19(S)-HETE signaling axis was identified as a key mediator of retinal neurovascular dysfunction.

Conclusions:

• 5'tiRNA-His-GTG is a critical regulator of diabetic retinal neurovascular dysfunction.
• Targeting 5'tiRNA-His-GTG and its associated signaling pathway offers a promising therapeutic approach for diabetic retinopathy.
• Modulating this pathway may provide new interventions for diabetic vasculopathy and neuropathy.