High glucose-induced hyperosmolarity contributes to COX-2 expression and angiogenesis: implications for diabetic retinopathy

Rosalinda Madonna,Raffaele De Caterina,Yong-Jian Geng,Francesca Vera Renna,Pamela Confalone,Gaia Giovannelli

doi:10.1186/s12933-016-0342-4

Abstract

BackgroundWe tested the hypothesis that glucose-induced hyperosmolarity, occurring in diabetic hyperglycemia, promotes retinal angiogenesis, and that interference with osmolarity signaling ameliorates excessive angiogenesis and retinopathy in vitro and in vivo.Methods and ResultsWe incubated human aortic (HAECs) and dermal microvascular endothelial cells (HMVECs) with glucose or mannitol for 24 h and tested them for protein levels and in vitro angiogenesis. We used the Ins2 Akita mice as a model of type 1 diabetes to test the in vivo relevance of in vitro observations. Compared to incubations with normal (5 mmol/L) glucose concentrations, cells exposed to both high glucose and high mannitol (at 30.5 or 50.5 mmol/L) increased expression of the water channel aquaporin-1 (AQP1) and cyclooxygenase (COX)-2. This was preceded by increased activity of the osmolarity-sensitive transcription factor Tonicity enhancer binding protein (TonEBP), and enhanced endothelial migration and tubulization in Matrigel, reverted by treatment with AQP1 and TonEBP siRNA. Retinas of Ins2 Akita mice showed increased levels of AQP1 and COX-2, as well as angiogenesis, all reverted by AQP1 siRNA intravitreal injections.ConclusionsGlucose-related hyperosmolarity seems to be able to promote angiogenesis and retinopathy through activation of TonEBP and possibly increasing expression of AQP1 and COX-2. Osmolarity signaling may be a target for therapy.

Highlights

We tested the hypothesis that glucose-induced hyperosmolarity, occurring in diabetic hyperglycemia, promotes retinal angiogenesis, and that interference with osmolarity signaling ameliorates excessive angiogenesis and retinopathy in vitro and in vivo
AQP1 mediates high glucose‐induced COX‐2 expression in endothelial cells Since AQP1 regulates responses to hyperosmolarity in endothelial cells [28], we tested whether AQP1 is involved in hyperosmolarity-induced COX-2 expression
COX-2 expression in high glucose- and high mannitol-treated cells was substantially suppressed after transfection with small interfering RNA (siRNA) against AQP1 (Fig. 2c–d)

Summary

Introduction

We tested the hypothesis that glucose-induced hyperosmolarity, occurring in diabetic hyperglycemia, promotes retinal angiogenesis, and that interference with osmolarity signaling ameliorates excessive angiogenesis and retinopathy in vitro and in vivo. Hyperglycemia can cause diabetic micro- [1] and macrovascular complications [2] by triggering oxidative stress [3, 4], forming advanced glycation end products (AGEs) [4, 5], increasing the flux of glucose to sorbitol through the polyol and hexosamine pathways [3], activating. Hyperglycemia has been reported to increase the endothelial expression of the proinflammatory proteins intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1, and to decrease production of nitric oxide, all through activation of the water channel protein aquaporin (AQP)1 [11]. COX-2 is expressed in human monocytes and macrophages, as well as human endothelial cells [22] exposed to high glucose [7]

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Conclusion