O-GlcNAc Modification Is a Promising Therapeutic Target for Diabetic Retinopathy.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Diabetic Retinopathy*/metabolism ; Diabetic Retinopathy*/drug therapy ; Diabetic Retinopathy*/pathology ; Acetylglucosamine*/metabolism ; N-Acetylglucosaminyltransferases*/metabolism ; N-Acetylglucosaminyltransferases*/antagonists & inhibitors ; Diabetes Mellitus, Experimental*/metabolism ; Diabetes Mellitus, Experimental*/drug therapy ; AMP-Activated Protein Kinases*/metabolism; Animals ; Mice ; Humans ; Male ; Apoptosis/drug effects ; Metformin/pharmacology ; beta-N-Acetylhexosaminidases/metabolism ; beta-N-Acetylhexosaminidases/antagonists & inhibitors ; Retina/metabolism ; Retina/pathology ; Retina/drug effects ; Mice, Inbred C57BL ; Cell Line

Diabetic retinopathy (DR) is a very serious diabetes complication. Changes in the O-linked N-acetylglucosamine (O-GlcNAc) modification are associated with many diseases. However, its role in DR is not fully understood. In this research, we explored the effect of O-GlcNAc modification regulation by activating AMP-activated protein kinase (AMPK) in DR, providing some evidence for clinical DR treatment in the future. Bioinformatics was used to make predictions from the database, which were validated using the serum samples of diabetic patients. As an in vivo model, diabetic mice were induced using streptozotocin (STZ) injection with/without an AMPK agonist (metformin) or an AMPK inhibitor (compound C) treatment. Electroretinogram (ERG) and H&E staining were used to evaluate the retinal functional and morphological changes. In vitro, 661 w cells were exposed to high-glucose conditions, with or without metformin treatment. Apoptosis was evaluated using TUNEL staining. The protein expression was detected using Western blot and immunofluorescence staining. The angiogenesis ability was detected using a tube formation assay. The levels of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) in the serum changed in the DR patients in the clinic. In the diabetic mice, the ERG wave amplitude and retinal thickness decreased. In vitro, the apoptotic cell percentage and Bax expression were increased, and Bcl2 expression was decreased in the 661 w cells under high-glucose conditions. The O-GlcNAc modification was increased in DR. In addition, the expression of GFAT/TXNIP O-GlcNAc was also increased in the 661 w cells after the high-glucose treatment. Additionally, the Co-immunoprecipitation(CO-IP) results show that TXNIP interacted with the O-GlcNAc modification. However, AMPK activation ameliorated this effect. We also found that silencing the AMPKα1 subunit reversed this process. In addition, the conditioned medium of the 661 w cells may have affected the tube formation in vitro. Taken together, O-GlcNAc modification was increased in DR with photoreceptor cell degeneration and neovascularization; however, it was reversed after activating AMPK. The underlying mechanism is linked to the GFAT/TXNIP-O-GlcNAc modification signaling axis. Therefore, the AMPKα1 subunit plays a vital role in the process.

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LJKQZ20222389 Liaoning Provincial Education Department; 2020-BS-189 Natural Science Foundation of Liaoning Province

Keywords: AMPK; O-GlcNAc modification; apoptosis; diabetic retinopathy; photoreceptor

V956696549 (Acetylglucosamine)
EC 2.4.1.- (N-Acetylglucosaminyltransferases)
EC 2.7.11.31 (AMP-Activated Protein Kinases)
9100L32L2N (Metformin)
EC 3.2.1.52 (beta-N-Acetylhexosaminidases)
EC 2.4.1.- (O-GlcNAc transferase)
EC 3.2.1.50 (hexosaminidase C)

Date Created: 20240619 Date Completed: 20240619 Latest Revision: 20240708

20250114

PMC11173153

10.3390/ijms25116286

38892474