Research Paper Volume 13, Issue 6 pp 8643—8664

Follistatin-like protein 1 functions as a potential target of gene therapy in proliferative diabetic retinopathy

Rui Niu1, *,#, , Ze-Tong Nie1, *,#, , Lin Liu1, , Yu-Wen Chang2, , Jian-Qun Shen2, , Qiong Chen1, , Li-Jie Dong1, , Bo-Jie Hu1, ,

  • 1 Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
  • 2 Hetian District People's Hospital, Xinjiang, China
* Equal contribution
# Co-first author

Received: May 21, 2020       Accepted: December 3, 2020       Published: March 10, 2021
How to Cite

Copyright: © 2021 Niu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


The degree of retinal fibrosis increased in proliferative diabetic retinopathy (PDR) patients after administration of anti-Vascular endothelial growth factor (VEGF) injections. Previous studies showed that the balance between connective tissue growth factor (CTGF) and VEGF plays an important role. Therefore, in a high-glucose state, an anti-VEGF and CTGFshRNA dual-target model was used to simulate clinical dual-target treatment in PDR patients, and RNA sequencing (RNA-Seq) technology was used for whole transcriptome sequencing. A hypoxia model was constructed to verify the sequencing results at the cellular level, and the vitreous humor and proliferative membranes were collected from patients for verification. All sequencing results included Follistatin-like protein 1 (FSTL1) and extracellular matrix (ECM) receptor pathway, indicated that anti-VEGF therapy may upregulate FSTL1 expression, while dual-target treatment downregulated FSTL1. Thus, we further studied the function of FSTL1 on the expression of VEGF and ECM factors by both overexpressing and silencing FSTL1. In conclusion, our results suggested that FSTL1 may be involved in the pathogenesis of PDR and is related to fibrosis caused by the anti-VEGF treatment, thus providing a potential target for gene therapy in PDR.


PDR: proliferative diabetic retinopathy; DR: diabetic retinopathy; RNA: Ribonucleic Acid; RNA-Seq: RNA sequencing; DEGs: differentially expressed genes; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; DM: Diabetes mellitus; ELISA: enzyme-linked immunosorbent assays; RT-PCR: real-time quantitative PCR; ECM: extracellular matrix; VEGF: Vascular endothelial growth factor; CTGF: connective tissue growth factor; FSTL1: follistatin-like protein 1; TGFβ1: Transforming growth factor - beta 1; FN: fibronectin; COL1: collagen 1; α-SMA: α-smooth muscle actin; RF-6A: rhesus choroid-retinal endothelial cells; HRCEC: human retinal cortical epithelial cell; HUVEC: human umbilical vein endothelial cell.