Circular Noncoding RNA HIPK3 Mediates Retinal Vascular Dysfunction in Diabetes Mellitus
Kun Shan1, Chang Liu1, Bai-Hui Liu1
1From Eye Institute, Eye and ENT Hospital, Shanghai Medical College, Fudan University, China (K.S., C.L., X.L., S.-J.Z., J.-J.W., S.-H.Z., J.-H.W., C.Z., B.Y.); Fourth School of Clinical Medicine, Nanjing Medical University, China (C.L.); Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China (B.-H.L., R.D.); Department of Ophthalmology, First Affiliated Hospital of Nanjing Medical University, China (X.C.); Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, China (Y.-Y.Z.); Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, China (B.L.); and Shanghai Key Laboratory of Visual Impairment and Restoration, China (C.Z., B.Y.).
Circular RNA circHIPK3 is upregulated in diabetes, promoting retinal vascular dysfunction by inhibiting miR-30a. Targeting circHIPK3 may offer a new treatment for diabetic retinopathy.
Area of Science:
- Molecular Biology
- Ophthalmology
- Endocrinology
Background:
- Diabetic retinopathy is a leading cause of vision loss, driven by vascular complications.
- Circular RNAs (circRNAs) are regulators of gene expression with emerging roles in disease.
- The specific role of circRNAs in diabetic retinal vascular dysfunction remains unclear.
Purpose of the Study:
- To investigate the role of circular RNA HIPK3 (circHIPK3) in diabetic retinopathy.
- To elucidate the molecular mechanisms underlying circHIPK3's function in retinal vascular cells.
Main Methods:
- Quantitative PCR, Sanger sequencing, and Northern blots to assess circHIPK3 expression.
- In vitro assays (MTT, EdU, Transwell, Matrigel) to evaluate retinal endothelial cell function.
- In vivo studies including retinal trypsin digestion and vascular permeability assays to assess retinal vascular health.
- Bioinformatics, luciferase assays, and RNA pull-down assays to determine the molecular mechanism.
Main Results:
- circHIPK3 expression is significantly increased in diabetic retinas and endothelial cells.
- circHIPK3 manipulation affects endothelial cell viability, proliferation, migration, and tube formation.
- circHIPK3 silencing ameliorates in vivo retinal vascular dysfunction, reducing leakage and inflammation.
- circHIPK3 functions as a miR-30a-3p sponge, upregulating VEGF-C, FZD4, and WNT2.
Conclusions:
- circHIPK3 exacerbates diabetic retinopathy by sponging miR-30a, promoting endothelial proliferation and vascular dysfunction.
- circHIPK3 represents a potential therapeutic target for managing diabetic proliferative retinopathy.
