Hyperosmolar stress induces TonEBP activation in human retinal pigmented epithelial cells

Abstract

AbstractPurpose Macular edema, a frequently encountered complication of diabetic retinopathy (DR), results from alterations of the blood retinal barrier (BRB) and leads to modifications of the retinal pigmented epithelium (RPE) functions. Osmolar changes of the surrounding medium could be responsible for some modifications of the RPE functions leading to a disturbance of the retinal homeostasis.Methods To study the modification and stability of the key hyperosmolar response factor Tonicity Enhancer Binding Protein’s (TonEBP) expression in ARPE‐19 cells, derived from human RPE, were submitted to hyperosmolar stress of increasing concentration and for various times.Results In response to hyperosmolar stimulation of ARPE‐19 cells, a dose‐dependent increase in TonEBP mRNA and protein levels, as well as TonEBP nuclear translocation, were observed. Moreover, the mRNA levels of Aldose Reductase (AR) and Sodium‐dependent Taurine Transporter (TauT), two TonEBP target genes required for increasing the intracellular ionic force, increased in a delayed manner following hyperosmolar stimulation. Additionally, SB203580, a p38 protein kinase inhibitor, but not its inactive analogue SB202474, inhibited TonEBP nuclear translocation in ARPE‐19 cells submitted to hyperosmolar stimulation.Conclusion In ARPE‐19 cells submitted to hyperosmolar stress, TonEBP expression is induced, and its nuclear translocation stimulated through a mechanism involving p38 protein kinase activation. It is likely that TonEBP nuclear translocation mediates the increase of AR and TauT expression induced by hyperosmolar stress and plays a role in RPE cells osmoadaptation.