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Pathogenetic Mechanisms in Diabetic Retinopathy: From Molecules to Cells to Tissues

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Mechanisms of Vascular Defects in Diabetes Mellitus

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 17))

Abstract

Diabetic retinopathy is a debilitating ocular condition that occurs as a chronic microvascular complication of diabetes. The presence of distinct clinical features categorizes diabetic retinopathy into different severity stages (mild to very severe), where vision loss is eminent in the advanced stages of diabetic retinopathy. Further, each stage of diabetic retinopathy is associated with unique pathological features at the cellular level such as basement membrane thickening, pericyte and endothelial cell dysfunction/loss, breakdown of the blood-retinal barrier, retinal capillary non-perfusion, and retinal neovascularization. These cellular alterations are the end products of various biochemical and molecular pathway abnormalities: polyol pathway, protein kinase C activation, hexosamine pathway, advanced glycation end-products formation, retinal renin-angiotensin system, and neural-and-immuno-inflammatory mechanisms. Although there are several metabolic pathway alterations in a hyperglycemic environment, the heightened production of reactive oxygen species may interconnect the foregoing pathways. Nevertheless, recent advances in genetic technology have identified that a significant number of epigenetic alterations participate in the development and progression of diabetic retinopathy: DNA methylation, histone modifications, and non-coding RNAs. This chapter will first provide the reader with sufficient background on the clinical and pathological features of diabetic retinopathy and then provide significant insight into the current known pathogenic mechanisms implicated in the progression of diabetic retinopathy.

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Abbreviations

α-MSH:

Alpha-melanocyte-stimulating hormone

ACE:

Angiotensin-converting enzyme

AGE:

Advanced glycation end-product

ANRIL:

Antisense non-coding RNA in the INK4 locus

AP-1:

Activator protein-1

Ang-2:

Angiopoietin-2

ATP:

Adenosine triphosphate

BRB:

Blood-retinal barrier

BM:

Basement membrane

–CH3 :

Methyl group

CH3CO:

Acetyl group

CNP:

Capillary non-perfusion

COX-2:

Cyclooxygenase-2

DAG:

Diacylglycerol

DCCT-EDIC:

Diabetes Control and Complications-Epidemiology of Diabetes Interventions and Complications Trial

DGCR8:

DiGeorge syndrome critical region 8

Dll4:

Delta-like ligand 4

DM:

Diabetes mellitus

DME:

Diabetic macular edema

DMNTs-:

DNA methyltransferases

DNA:

Deoxyribonucleic acid

DR:

Diabetic retinopathy

EndMT:

Endothelial-to-mesenchymal transition

eNOS:

Endothelial nitric oxide synthase

ET-1:

Endothelin-1

ETC:

Electron transport chain

EZH2:

Enhancer of zeste homolog 2

FADH2 :

Fully reduced form of flavin adenine dinucleotide

FasL:

Fas Ligand

FN:

Fibronectin

FOXO1:

Forkhead box protein O1

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GFAT:

Glutamine:fructose-6-phosphate amidotransferase

HATs:

Histone acetyltransferases

HDACs:

Histone deacetylases

HDMCs:

Histone demethylases

HIF-1α:

Hypoxia-inducible factor-1α

HMGB1:

High-mobility group box-1

HMTs:

Histone methyltransferases

HSP:

Hexosamine pathway

IL-6:

Interleukin-6

IL-1β:

Interleukin-1β

iNOS:

Inducible nitric oxide synthase

JAK-STAT:

Janus kinase/signal transducers and activators of transcription

LSD1:

Lysine-specific demethylase 1

MALAT1:

Metastasis-associated lung adenocarcinoma transcript 1

MCP-1:

Monocyte chemoattractant protein-1

MIF:

Macrophage migration inhibitory factor

NPDR:

Non-proliferative diabetic retinopathy

PEDF:

Pigment epithelium derived factor

PDR:

Proliferative diabetic retinopathy

PDGF-BB-PDGFRß-:

platelet-derived growth factor-BB-platelet-derived growth factor receptor subunit B pathway

PDGF-BB:

platelet-derived growth factor-BB

PI3K:

Phosphatidylinositol-3 kinase

MAPK:

Mitogen-activated protein kinase

miRNAs:

micro RNAs

MMP-9:

Matrix metalloproteinase-9

mRNA:

messenger RNA

NADH:

Reduced form of nicotinamide adenine dinucleotide

NAPDH:

Reduced form of nicotinamide adenine dinucleotide phosphate

NAD+ :

Oxidized form of nicotinamide adenine dinucleotide

ncRNAs:

Non-coding RNAs

sncRNAs:

Small non-coding RNAs

lncRNAs:

Long non-coding RNAs

NF-κB:

Nuclear factor-kappa B

NO:

Nitric oxide

NV:

Neovascularization

PAI-1:

Plasminogen activator inhibitor-1

PARP:

Poly (ADP-ribose) polymerase

PGE2:

Prostaglandin E2

PKC:

Protein kinase C

PLGF:

Placental growth factor

PRC2:

Polycomb repressive complex 2

RAGE:

Receptor for AGEs

RAS:

Renin-angiotensin system

RISC:

RNA-induced silencing complex

RNA:

Ribonucleic acid

RNA pol II:

RNA polymerase II

ROS:

Reactive oxygen species

SAA3:

Serum amyloid antigen three

SDF-1:

Stromal derived growth factor

SHP-1:

Src homology-2-domain-containing phosphatase-1

SIRT1:

Sirtuin (silent mating type information regulation 2 homolog) 1

SOD2:

Manganese superoxide dismutase gene

TCA:

Tricarboxylic acid

TET:

Ten-eleven translocase

TGF-β1:

Transforming growth factor-beta1

TNF-α:

Tumor necrosis factor- alpha

UKPDS:

United Kingdom Prospective Diabetes Study

VEGF:

Vascular endothelial growth factor

VHL:

von Hippel-Lindau

VIP:

Vasoactive intestinal peptide

3′ UTR:

3′ untranslated regions

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Acknowledgements

The research presented in this chapter was supported by the Canadian Diabetes Association and the Heart and Stroke Foundation of Ontario. The authors would also like to acknowledge Shali Chen, Biao Feng, Andrew Gordon, and Anu Thomas, in the Chakrabarti lab for their ongoing support in the advancement of diabetic research.

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  1. Department of Pathology and Laboratory Medicine, Western University, Schulich School of Medicine & Dentistry, LHSC/SJHC, 339 Windermere Rd, N6A 5A5, London, ON, Canada

    Saumik Biswas & Subrata Chakrabarti MBBS, PhD, FRCP(C)

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  1. Saumik Biswas
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  2. Subrata Chakrabarti MBBS, PhD, FRCP(C)
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Correspondence to Subrata Chakrabarti MBBS, PhD, FRCP(C) .

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  1. Division of Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India

    C.C. Kartha

  2. Division of Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India

    Surya Ramachandran

  3. Translational Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India

    Radhakrishna M. Pillai

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Biswas, S., Chakrabarti, S. (2017). Pathogenetic Mechanisms in Diabetic Retinopathy: From Molecules to Cells to Tissues. In: Kartha, C., Ramachandran, S., Pillai, R. (eds) Mechanisms of Vascular Defects in Diabetes Mellitus. Advances in Biochemistry in Health and Disease, vol 17. Springer, Cham. https://doi.org/10.1007/978-3-319-60324-7_9

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