tiRNA-Val promotes angiogenesis via Sirt1–Hif-1α axis in mice with diabetic retinopathy

Abstract

Background Diabetic retinopathy (DR) is a specific microvascular complication arising from diabetes, and its pathogenesis is not completely understood. tRNA-derived stress-induced RNAs (tiRNAs), a new type of small noncoding RNA generated by specific cleavage of tRNAs, has become a promising target for several diseases. However, the regulatory function of tiRNAs in DR and its detailed mechanism remain unknown. Results Here, we analyzed the tiRNA profiles of normal and DR retinal tissues. The expression level of tiRNA-Val was significantly upregulated in DR retinal tissues. Consistently, tiRNA-Val was upregulated in human retinal microvascular endothelial cells (HRMECs) under high glucose conditions. The overexpression of tiRNA-Val enhanced cell proliferation and inhibited cell apoptosis in HRMECs, but the knockdown of tiRNA-Val decreased cell proliferation and promoted cell apoptosis. Mechanistically, tiRNA-Val, derived from mature tRNA-Val with Ang cleavage, decreased Sirt1 expression level by interacting with sirt1 3'UTR, leading to the accumulation of Hif-1α, a key target for DR. In addition, subretinal injection of adeno-associated virus to knock down tiRNA-Val in DR mice ameliorated the symptoms of DR. Conclusion tiRNA-Val enhance cell proliferation and inhibited cell apoptosis via Sirt1/Hif-1α pathway in HRMECs of DR retinal tissues.

Signature of circulating small non-coding RNAs during early fracture healing in mice

“…Val-AAC-5′end and Val-CAC-5′end tiRNAs were also highly expressed in callus tissue and upregulated by 1.5 to 1.9 log2FC during fracture healing in comparison to the control diaphyseal bone ( Bourgery et al, 2021 ). Functions of tiRNA-Val family members associate, e.g., with angiogenesis and, in the mouse retinal tissue with diabetic retinopathy 5′end tiRNA-Val was demonstrated to directly target the 3′UTR of Sirt1 and repress its expression ( Xu et al, 2022 ). This finding is interesting as angiogenesis is a crucial process also during fracture healing ( Einhorn and Gerstenfeld, 2015 ; Gerstenfeld et al, 2003 ).…”

Scatter Irradiation of Rat Brain Triggers Sex- and Brain Region-Specific Changes in the Expression of Non-Coding RNA Fragments

“…Many tiRNAs and tRFs are differentially expressed in response to stress, with most data coming from the realm of cancer biology [ 60 ]. tiRNAs and tRFs are also found to be differentially expressed in other diseases/conditions, including diabetic retinopathy [ 61 ], endometriosis [ 25 ], spinal cord injury [ 62 ], and many more. Some are involved in multiple pathologies—5′tiRNA-His-GTG was shown to respond to tissue hypoxia and may be involved in malignancy [ 29 ].…”