Redoxisome and diabetic retinopathy: Pathophysiology and therapeutic interventions. (August 2022)

• Record Type: Journal Article
• Authors: Sharma, Isha; Yadav, Karan Singh; Mugale, Madhav Nilakanth
• Is Part Of: Pharmacological research. Volume 182(2022)
• Publication Date: 2022-08
• Subjects: GLUT Glucose transporter -- DHAP dihydroxyacetone phosphate -- GA-3 PGlyceraldehyde-3-phosphate -- AGE Advanced glycation end-product -- RAGE Receptor for AGEs -- Gln Glutamine -- Glu Glutamate -- GlcN-6-P Glucosamine-6-phosphate -- GNA-1 Glucosamine-6-phosphate-N- acetyl transferase -- PGM-3 Phosphoglucomutase -- GlcNAc-6-P N-acetylglucosamine-6-phosphate -- UAP-1-UDP-N Acetylglucosamine Pyrophosphorylase 1 -- PPi pyrophosphate -- UTP Uracil triphosphate -- NADPH nicotinamide adenine dinucleotide phosphate -- NADH nicotinamide adenine dinucleotide -- GSH Reduced glutathione -- GSSG Oxidized glutathione -- PPARα/γ Peroxisome proliferator-activated receptors -- SDH succinate dehydrogenase -- DAG Diacylglycerol -- PK-C Protein kinase-C -- ACE Angiotensin-converting enzyme -- ANG angiotensin -- AT-1 Angiotensin receptor-1 -- AP-1 Activator protein-1 -- Col Collagenase -- VCAM Vascular cell adhesion protein 1 -- ICAM-1 Intercellular Adhesion Molecule-1 -- FXII Factor XII -- PPK pre-plasma kallikrein -- PK Plasma kallikrein -- HK high molecular weight Kininogen -- BK bradykinin -- B2R BK receptor 2 -- B1R BK receptor 1 -- eNOS Endothelial nitric oxide synthase -- PLA2 Phospholipase A-2 -- iNOS nitric oxide synthase -- DABK des-Arg9-bradykinin -- LRG-1 Leucine rich α2 glycoprotein -- Alk-1 Activin receptor-like kinase-1 -- TRX thioredoxin -- TXNIP Thioredoxin interacting protein -- BIP Binding immunoglobulin protein -- ChREBP Carbohydrate response element binding protein -- ATF-5 Activating Transcription Factor 5 -- ER-UPR Endoplasmic reticulum- unfolded protein response -- PERK Protein kinase R-like endoplasmic reticulum kinase -- IRE-1α Inositol-requiring transmembrane kinase/endoribonuclease 1α -- eIF-2α eukaryotic initiation factor-2 alpha -- VDAC Voltage dependent anion channels -- IP3R inositol 1, 4, 5-trisphosphate (IP3) receptors -- NLRP3 (NOD)-like receptor pyrin domain containing protein-3 -- Cyt c cytochrome c -- ASK-1 Apoptosis signal-regulating kinase 1 -- Fis-1 Mitochondrial fission 1 protein -- SNO-Drp1 S-nitrosylation-Dynamin-related protein 1 -- ASC apoptosis-associated speck-like protein containing a caspase recruitment domain -- NEK NimA related kinase -- PIP3 Phosphatidylinositol (3, 4, 5)-trisphosphate -- PIP2 Phosphatidylinositol 4, 5-bisphosphate, -- PDGF Platelet-derived growth factor -- PTEN Phosphatase and tensin homolog, -- PI3K Phosphoinositide 3-kinases -- TSC Tuberous sclerosis proteins -- Ub ubiquitin -- Redd 1 regulated in development and DNA damage responses 1 -- ATG4B Autophagy Related 4B Cysteine Peptidase -- BNip BCL2/adenovirus E1B 19 kd-interacting protein -- BCl2 B-cell lymphoma 2 -- OPTN Optineurin -- NDP52 Nuclear dot protein 52 kDa -- PINK PTEN-induced kinase 1 -- HAT histone acetyl transferase -- H3K9Ac acetylation of 9th lysine of histone 3 -- SAM-S adenosylmethionine -- lncRNA long non coding RNA -- NPDR Non-Proliferative diabetic retinopathy -- PDR Proliferative diabetic retinopathy -- CircRNA Circular RNA -- METRN Meteorin -- miR micro-RNA -- SD rat Sprague Dawley -- ARPE-19 Adult retinal pigment epithelial cell line-19 -- TNF-α Tumour necrosis factor alpha -- IL interleukin -- Cox cyclooxygenase -- TGF-α tumour growth factor alpha -- MMP Matrix metalloproteinase -- VEGF vascular endothelial growth factor -- FZD4 Frizzled -- Wnt Wingless/Integrated -- ANRIL Antisense Non-coding RNA in the INK4 Locus -- MIAT Myocardial infarction associated transcript -- MALAT1 metastasis associated lung adenocarcinoma transcript 1, -- MEG3 Maternally expressed gene 3 -- PiRNA P-element Induced WImpy testis (Piwi) interacting RNA -- MCP Monocyte chemoattractant protein-1 -- αSMA α smooth muscle actin -- EGFR Epidermal growth factor receptor -- FGF-7 fibroblast growth factor -- IRF3 interferon regulatory factor-3 -- HMGB-1 high mobility group box protein 1 -- IV intravitreal -- OS ocular suspension -- CCR3 C-C chemokine receptor-3 -- HDAC Histone deacetylase -- DNMT DNA methyl transferase; Diabetic retinopathy -- Epigenetic modifications -- Inflammasome -- Redox homeostasis -- Redoxisome; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106292
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Diabetic retinopathy (DR) is a chronic microvascular complication of diabetes mellitus (DM). It is a worldwide growing epidemic disease considered to be the leading cause of vision-loss and blindness in people with DM. Redox reactions occurring at the extra- and intracellular levels are essential for the maintenance of cellular homeostasis. Dysregulation of redox homeostasis are implicated in the onset and development of DR. Thioredoxin1 (TRX1) and Thioredoxin2 (TRX2) are cytoplasmic and mitochondrially localized antioxidant proteins ubiquitously expressed in various cells and control cellular reactive oxygen species (ROS) by reducing the disulfides into thiol groups. Thioredoxin-interacting protein (TXNIP) binds to TRX system and inhibits the active reduced form of TRX through disulfide exchange reaction. Recent studies indicate the association of TRX/TXNIP with redox signal transduction pathways including activation of Nod-like receptor pyrin domain containing protein-3 (NLRP3) inflammasome, apoptosis, autophagy/mitophagy, epigenetic modifications in a redox-dependent manner. Thus, it is important to gain a more in-depth understanding about the cellular and molecular mechanisms that links redoxisome and ER/Mitochondrial dysfunction to drive the progression of DR. The purpose of this review is to provide a mechanistic understanding of the complex molecular mechanisms and pathophysiological roles associated with redoxisome, the TRX/TXNIP redox signaling complex under oxidative stress in the development of DR. Also, the molecular targets of FDA approved drugs and clinical trials in addition to effective antioxidant strategies for the treatment of diabetic retinopathy are reviewed. Graphical Abstract: ga1 Highlights: Hyperglycemia mediated oxidative stress promotes redoxisome activation in the retina. Disruption of the cellular homeostasis by redoxisomal signaling complex contributes to the pathogenesis of diabetic retinopathy. TXNIP activates NLRP3 inflammasome which promotes retinal apoptosis and inflammation. TXNIP/NLRP3 under oxidative stress triggers signaling cascades associated with ER stress and mitochondrial dysfunction in retina. TXNIP plays an essential role in epigenetic alterations associated with retinopathy. TXNIP can be a potential therapeutic target for the management of diabetic retinopathy.