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Diabetologia. 2016 Mar;59(3):644-54. doi: 10.1007/s00125-015-3832-0. Epub 2015 Dec 19.

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway.

Author information

1
Department of Ophthalmology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Haining Road 100, Shanghai, 200080, People's Republic of China.
2
Department of Ophthalmology, Lishui City Center Hospital, Lishui, People's Republic of China.
3
Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Yishan Road 301, Shanghai, 200233, People's Republic of China. chenhb@sjtu.edu.cn.
4
Department of Ophthalmology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Haining Road 100, Shanghai, 200080, People's Republic of China. zzheng88@sjtu.edu.cn.

Abstract

AIMS/HYPOTHESIS:

The mechanisms underlying the cellular metabolic memory induced by high glucose remain unclear. Here, we sought to determine the effects of microRNAs (miRNAs) on metabolic memory in diabetic retinopathy.

METHODS:

The miRNA microarray was used to examine human retinal endothelial cells (HRECs) following exposure to normal glucose (N) or high glucose (H) for 1 week or transient H for 2 days followed by N for another 5 days (H→N). Levels of sirtuin 1 (SIRT1) and acetylated-nuclear factor κB (Ac-NF-κB) were examined following transfection with miR-23b-3p inhibitor or with SIRT1 small interfering (si)RNA in the H→N group, and the apoptotic HRECs were determined by flow cytometry. Retinal tissues from diabetic rats were similarly studied following intravitreal injection of miR-23b-3p inhibitor. Chromatin immunoprecipitation (ChIP) analysis was performed to detect binding of NF-κB p65 to the potential binding site of the miR-23b-27b-24-1 gene promoter in HRECs.

RESULTS:

High glucose increased miR-23b-3p expression, even after the return to normal glucose. Luciferase assays identified SIRT1 as a target mRNA of miR-23b-3p. Reduced miR-23b-3p expression inhibited Ac-NF-κB expression by rescuing SIRT1 expression and also relieved the effect of metabolic memory induced by high glucose in HRECs. The results were confirmed in the retina using a diabetic rat model of metabolic memory. High glucose facilitated the recruitment of NF-κB p65 and promoted transcription of the miR-23b-27b-24-1 gene, which can be suppressed by decreasing miR-23b-3p expression.

CONCLUSIONS/INTERPRETATION:

These studies identify a novel mechanism whereby miR-23b-3p regulates high-glucose-induced cellular metabolic memory in diabetic retinopathy through a SIRT1-dependent signalling pathway.

KEYWORDS:

Diabetic retinopathy; Metabolic memory; NF-κB; SIRT1; miR-23b-3p

PMID:
26687158
DOI:
10.1007/s00125-015-3832-0
[Indexed for MEDLINE]

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