let-7 Contributes to Diabetic Retinopathy but Represses Pathological Ocular Angiogenesis

Qinbo Zhou; Robert J A Frost; Chastain Anderson; Fangkun Zhao; Jing Ma; Bo Yu; Shusheng Wang

doi:10.1128/MCB.00001-17

let-7 Contributes to Diabetic Retinopathy but Represses Pathological Ocular Angiogenesis

Mol Cell Biol. 2017 Jul 28;37(16):e00001-17. doi: 10.1128/MCB.00001-17. Print 2017 Aug 15.

Authors

Qinbo Zhou¹, Robert J A Frost², Chastain Anderson¹, Fangkun Zhao^{1

3}, Jing Ma¹, Bo Yu¹, Shusheng Wang^{4

5}

Affiliations

¹ Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA.
² Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
³ Department of Ophthalmology, Fourth Affiliated Hospital of China Medical University, Eye Hospital of China Medical University, Key Lens Research Laboratory of Liaoning Province, Shenyang, China.
⁴ Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA swang1@tulane.edu.
⁵ Department of Ophthalmology, Tulane University, New Orleans, Louisiana, USA.

Abstract

The in vivo function of microRNAs (miRs) in diabetic retinopathy (DR) and age-related macular degeneration (AMD) remains unclear. We report here that let-7 family members are expressed in retinal and choroidal endothelial cells (ECs). In ECs, overexpression of let-7 by adenovirus represses EC proliferation, migration, and networking in vitro, whereas inhibition of the let-7 family with a locked nucleic acid (LNA)-anti-miR has the opposite effect. Mechanistically, silencing of the let-7 target HMGA2 gene mimics the phenotype of let-7 overexpression in ECs. let-7 transgenic (let-7-Tg) mice show features of nonproliferative DR, including tortuous retinal vessels and defective pericyte coverage. However, these mice develop significantly less choroidal neovascularization (CNV) compared to wild-type controls after laser injury. Consistently, silencing of let-7 in the eye increased laser-induced CNV in wild-type mice. Together, our data establish a causative role of let-7 in nonproliferative diabetic retinopathy and a repressive function of let-7 in pathological angiogenesis, suggesting distinct implications of let-7 in the pathogenesis of DR and AMD.

Keywords: AMD; angiogenesis; choroidal; diabetic retinopathy; endothelial cells; let-7; neovascularization.

Abstract

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