title: 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.affiliation: Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea; Department of Food & Nutrition, College of Natural Sciences, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Jeongsook
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Hwajin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: So Yun
authors.initials: SY
authors.lastname: Park
authors.affiliation: Transplant Research Center, The of Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Sun Woo
authors.initials: SW
authors.lastname: Lim
authors.affiliation: Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Yoon Sook
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Gu Seob
authors.initials: GS
authors.lastname: Roh
authors.affiliation: Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Hyun Joon
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kang
authors.affiliation: Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Gyeong Jae
authors.initials: GJ
authors.lastname: Cho
authors.affiliation: Department of Food & Nutrition, College of Natural Sciences, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Bo-Young
authors.initials: BY
authors.lastname: Jeong
authors.affiliation: School of Nano-Biotechnology and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
authors.forename: H Moo
authors.initials: HM
authors.lastname: Kwon
authors.affiliation: Department of Anatomy and Neurobiology, Institute of Health Science, Medical Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea. Electronic address: choiws@gnu.ac.kr.
authors.forename: Wan Sung
authors.initials: WS
authors.lastname: Choi
mesh_terms: D000449:Aldehyde Reductase / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology; D003930:Diabetic Retinopathy / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012160:Retina / Q000201:enzymology; D012165:Retinal Ganglion Cells / Q000201:enzymology; D014157:Transcription Factors / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494827:Bax protein, mouse; D050778:NFATC Transcription Factors; C492200:Nfat5 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse; D000449:Aldehyde Reductase; C087857:protein kinase C gamma; D011493:Protein Kinase C
keywords: TonEBP; aldose reductase; diabetic retinopathy; hyperglycemia; protein kinase C