Tonicity-responsive enhancer binding protein regulates the expression of aldose reductase and protein kinase C δ in a mouse model of diabetic retinopathy.

Abstract

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.

• Authors: Jeongsook Park, Hwajin Kim, So Yun Park, Sun Woo Lim, Yoon Sook Kim, Dong Hoon Lee, Gu Seob Roh, Hyun Joon Kim, Sang Soo Kang, Gyeong Jae Cho, Bo-Young Jeong, H Moo Kwon, Wan Sung Choi
• Journal: Experimental eye research (Exp Eye Res) Vol. 122 Pg. 13-9 (May 2014) ISSN: 1096-0007 [Electronic] England
• PMID: 24631337 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Bax protein, mouse
• NFATC Transcription Factors
• Nfat5 protein, mouse
• Proto-Oncogene Proteins c-bcl-2
• RNA, Small Interfering
• Transcription Factors
• bcl-2-Associated X Protein
• Bcl2 protein, mouse
• Aldehyde Reductase
• protein kinase C gamma
• Protein Kinase C

Topics

• Aldehyde Reductase (metabolism)
• Animals
• Apoptosis
• Blotting, Western
• Cells, Cultured
• Diabetes Mellitus, Experimental (enzymology)
• Diabetic Retinopathy (enzymology, pathology, prevention & control)
• Disease Models, Animal
• Fluorescent Antibody Technique, Indirect
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• NFATC Transcription Factors (physiology)
• Protein Kinase C (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA, Small Interfering (genetics)
• Retina (enzymology)
• Retinal Ganglion Cells (enzymology)
• Transcription Factors (physiology)
• bcl-2-Associated X Protein (metabolism)