Hyperglycemia-regulated tRNA-derived fragment tRF-3001a propels neurovascular dysfunction in diabetic mice

Jun-Ya Zhu; Wen Yao; Xi-Sen Ni; Mu-Di Yao; Wen Bai; Tian-Jing Yang; Zi-Ran Zhang; Xiu-Miao Li; Qin Jiang; Biao Yan

doi:10.1016/j.xcrm.2023.101209

Hyperglycemia-regulated tRNA-derived fragment tRF-3001a propels neurovascular dysfunction in diabetic mice

Cell Rep Med. 2023 Oct 17;4(10):101209. doi: 10.1016/j.xcrm.2023.101209. Epub 2023 Sep 26.

Authors

Jun-Ya Zhu¹, Wen Yao², Xi-Sen Ni², Mu-Di Yao³, Wen Bai², Tian-Jing Yang², Zi-Ran Zhang², Xiu-Miao Li⁴, Qin Jiang⁵, Biao Yan⁶

Affiliations

¹ Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200030, China; Department of Ophthalmology and Optometry, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210000, China.
² Department of Ophthalmology and Optometry, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210000, China.
³ Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200030, China.
⁴ Department of Ophthalmology and Optometry, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210000, China; Department of Ophthalmology and Optometry, The Affiliated Eye Hospital, Nanjing Medical University, Nanjing 210000, China.
⁵ Department of Ophthalmology and Optometry, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing 210000, China; Department of Ophthalmology and Optometry, The Affiliated Eye Hospital, Nanjing Medical University, Nanjing 210000, China. Electronic address: jiangqin710@126.com.
⁶ Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200030, China; National Health Commission Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, Shanghai 200030, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200030, China. Electronic address: biao.yan@fdeent.org.

Abstract

Neurovascular dysfunction is a preclinical manifestation of diabetic complications, including diabetic retinopathy (DR). Herein, we report that a transfer RNA-derived RNA fragment, tRF-3001a, is significantly upregulated under diabetic conditions. tRF-3001a downregulation inhibits Müller cell activation, suppresses endothelial angiogenic effects, and protects against high-glucose-induced retinal ganglion cell injury in vitro. Furthermore, tRF-3001a downregulation alleviates retinal vascular dysfunction, inhibits retinal reactive gliosis, facilitates retinal ganglion cell survival, and preserves visual function and visually guided behaviors in STZ-induced diabetic mice and db/db diabetic mice. Mechanistically, tRF-3001a regulates neurovascular dysfunction in a microRNA-like mechanism by targeting GSK3B. Clinically, tRF-3001a is upregulated in aqueous humor (AH) samples of DR patients. tRF-3001a downregulation inhibits DR-induced human retinal vascular endothelial cell and Müller cell dysfunction in vitro and DR-induced retinal neurovascular dysfunction in C57BL/6J mice. Thus, targeting tRF-3001a-mediated signaling is a promising strategy for the concurrent treatment of vasculopathy and neuropathy in diabetes mellitus.

Keywords: diabetic retinopathy; neuropathy; neurovascular dysfunction; transfer RNA-derived RNA fragment; vasculopathy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus, Experimental* / complications
Diabetic Retinopathy* / drug therapy
Diabetic Retinopathy* / etiology
Humans
Hyperglycemia* / complications
Mice
Mice, Inbred C57BL
Retina