Recent studies revealed that
Tonicity-responsive enhancer binding protein (TonEBP) directly regulates the transcription of
aldose reductase (AR), which catalyzes the first step of the
polyol pathway of
glucose metabolism. Activation of
protein kinase C δ (PKCδ) is dependent on AR and it has been linked to
diabetic complications. However, whether TonEBP affects expressions of AR and PKCδ in
diabetic retinopathy was not clearly shown. In this study, we used TonEBP heterozygote mice to study the role of TonEBP in
streptozotocin (STZ)-induced
diabetic retinopathy. We performed immunofluorescence staining and found that
retinal expressions of AR and PKCδ were significantly reduced in the heterozygotes compared to wild type littermates, particularly in
ganglion cell layer. To examine further the effect of TonEBP reduction in
retinal tissues, we performed
intravitreal injection of TonEBP
siRNA and confirmed the decrease in AR and PKCδ levels. In addition, we found that a proapoptotic factor, Bax level was reduced and a survival factor, Bcl2 level was increased after injection of TonEBP
siRNA, indicating that TonEBP mediates apoptotic cell death. In parallel, TonEBP
siRNA was applied to the in vitro human
retinal pigment epithelial (ARPE-19) cells cultured in high
glucose media. We have consistently found the decrease in AR and PKCδ levels and changes in apoptotic factors for survival. Together, these results clearly demonstrated that
hyperglycemia-induced TonEBP plays a crucial role in increasing AR and PKCδ levels and leading to apoptotic death. Our findings suggest that TonEBP reduction is an effective therapeutic strategy for
diabetic retinopathy.