Metformin suppresses retinal angiogenesis and inflammation in vitro and in vivo.

Jing Han,Xiuli Liu,Xiaoxi Qiao,Fu-Shin Yu,Haijing Sun,Hua Gao,Tongrong Zhou,Paul Edwards,Yue Li,Jing Chen

doi:10.1371/journal.pone.0193031

Abstract

The oral anti-diabetic drug metformin has been found to reduce cardiovascular complications independent of glycemic control in diabetic patients. However, its role in diabetic retinal microvascular complications is not clear. This study is to investigate the effects of metformin on retinal vascular endothelium and its possible mechanisms, regarding two major pathogenic features of diabetic retinopathy: angiogenesis and inflammation. In human retinal vascular endothelial cell culture, metformin inhibited various steps of angiogenesis including endothelial cell proliferation, migration, and tube formation in a dose-dependent manner. Its anti-angiogenic activity was confirmed in vivo that metformin significantly reduced spontaneous intraretinal neovascularization in a very-low-density lipoprotein receptor knockout mutant mouse (p<0.05). Several inflammatory molecules upregulated by tumor necrosis factor-α in human retinal vascular endothelial cells were markedly reduced by metformin, including nuclear factor kappa B p65 (NFκB p65), intercellular adhesion molecule-1 (ICAM-1), monocyte chemotactic protein-1 (MCP-1), and interleukin-8 (IL-8). Further, metformin significantly decreased retinal leukocyte adhesion (p<0.05) in streptozotocin-induced diabetic mice. Activation of AMP-activated protein kinase was found to play a partial role in the suppression of ICAM-1 and MCP-1 by metformin, but not in those of NFκB p65 and IL-8. Our findings support the notion that metformin has considerable anti-angiogenic and anti-inflammatory effects on retinal vasculature. Metformin could be potentially used for the purpose of treating diabetic retinopathy in addition to blood glucose control in diabetic patients.

Highlights

Diabetic retinopathy (DR) is the leading cause of irreversible visual impairment and blindness at working age populations in the United States[1]
We have found that 2.5 ng/mL of tumor necrosis factor-α (TNFα) dramatically elevated the expression of NFκB p65, ICAM-1 and production of monocyte chemotactic protein-1 (MCP-1), IL-8 by human retinal vascular endothelial cells (hRVECs) (Fig 3A–3C)
Compound C partially reversed the inhibition effect of metformin on MCP-1 concentration (Fig 5E; 50%; p < 0.05 versus metformin plus TNFα group). These results indicate that AMPK signaling pathway is involved in the regulation of ICAM-1 and MCP-1 by metformin in hRVECs, but not in that of NFκB and IL-8

Summary

Introduction

Diabetic retinopathy (DR) is the leading cause of irreversible visual impairment and blindness at working age populations in the United States[1]. Clinical and basic research has revealed a complex pathogenesis of DR, including inflammation, angiogenesis, non-enzymatic glycosylation, redox injuries, and genetic predisposition factors [2]. Current treatments of DR include panretinal photocoagulation, and intravitreal injection of anti-vascular endothelial growth factor agents and corticosteroids [5]. These treatments were able to retard severe DR progression in a subset of diabetic patients [6]. And effective interventions that treat the initiative pathogenic changes of DR would be required to improve vision outcomes in diabetic patients

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Conclusion