Diabetes Metab J.  2018 Oct;42(5):364-376. 10.4093/dmj.2018.0182.

Pathophysiology of Diabetic Retinopathy: The Old and the New

Affiliations
  • 1Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
  • 2Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.
  • 3Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. uemura@med.nagoya-cu.ac.jp
  • 4Department of Ophthalmology, Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, MD, USA.

Abstract

Vision loss in diabetic retinopathy (DR) is ascribed primarily to retinal vascular abnormalities"”including hyperpermeability, hypoperfusion, and neoangiogenesis"”that eventually lead to anatomical and functional alterations in retinal neurons and glial cells. Recent advances in retinal imaging systems using optical coherence tomography technologies and pharmacological treatments using anti-vascular endothelial growth factor drugs and corticosteroids have revolutionized the clinical management of DR. However, the cellular and molecular mechanisms underlying the pathophysiology of DR are not fully determined, largely because hyperglycemic animal models only reproduce limited aspects of subclinical and early DR. Conversely, non-diabetic mouse models that represent the hallmark vascular disorders in DR, such as pericyte deficiency and retinal ischemia, have provided clues toward an understanding of the sequential events that are responsible for vision-impairing conditions. In this review, we summarize the clinical manifestations and treatment modalities of DR, discuss current and emerging concepts with regard to the pathophysiology of DR, and introduce perspectives on the development of new drugs, emphasizing the breakdown of the blood-retina barrier and retinal neovascularization.

Keyword

Angiopoietins; Blood-retina barrier; Diabetic retinopathy; Endothelial cells; Macular edema; Pericytes; Retinal neovascularization; Vascular endothelial growth factors

MeSH Terms

Adrenal Cortex Hormones
Angiopoietins
Animals
Diabetic Retinopathy*
Endothelial Cells
Endothelial Growth Factors
Ischemia
Macular Edema
Mice
Models, Animal
Neuroglia
Pericytes
Retinal Neovascularization
Retinal Neurons
Retinaldehyde
Tomography, Optical Coherence
Vascular Endothelial Growth Factors
Adrenal Cortex Hormones
Angiopoietins
Endothelial Growth Factors
Retinaldehyde
Vascular Endothelial Growth Factors

Figure

  • Fig. 1 Clinical features of diabetic retinopathy (DR). (A) Pseudo-colored fundus (left) and fluorescein angiography (right) images from ultra-widefield ophthalmoscopy. Note the elevated leakage of fluorescein dye in the macular area in non-proliferative DR (NPDR) and from aberrant neovascularization (NV) in proliferative DR (PDR). Dark areas in fluorescein angiography represent vascular non-perfusion (NP). (B) Cross-sectional macular images from optical coherence tomography (OCT). Note the recurrence of diabetic macular edema (DME) at 3 months after intravitreal anti-vascular endothelial growth factor injection. (C) Superficial and deep retinal vessel images from OCT angiography. Note the microaneurysms and enlargement of the foveal avascular zone in NPDR. HE, hard exudate; VH, vitreous hemorrhage.

  • Fig. 2 Schematic of key cellular and molecular events in the progression of diabetic retinopathy. Hyperglycemia initiates oxidative stress, epigenetic modifications, and inflammation in vascular endothelial cells (ECs). Neuroglial degeneration precedes microvascular changes. Pericyte loss from vessel walls sensitizes ECs to microenvironmental stimuli. Infiltrating macrophages secrete vascular endothelial growth factor (VEGF) A and placental growth factor (PlGF). A positive feedback loop between angiopoietin-2 (Ang2) and a forkhead box transcription factor, forkhead Box O1 (FOXO1), in ECs further destabilizes vessel integrity. These events form a cycle of vessel damage, leading to the breakdown of the blood-retina barrier. Retinal hypoxia resulting from vessel occlusion induces extra-retinal neoangiogenesis accompanied by fibrovascular membrane formation. Throughout these processes, signal transduction via the mitogen-activated protein kinase (MAPK) and the phosphatidyl inositol 3-kinase (PI3K)/Akt pathways downstream of VEGF receptor (VEGFR) 2 in ECs is pivotal in retinal angiogenesis and vascular leakage. Tie2, tyrosine kinase with immunoglobulin-like loops and epidermal growth factor homology domains 2.


Cited by  1 articles

Dipeptidyl Peptidase-4 Inhibitors versus Other Antidiabetic Drugs Added to Metformin Monotherapy in Diabetic Retinopathy Progression: A Real World-Based Cohort Study
Yoo-Ri Chung, Kyoung Hwa Ha, Hyeon Chang Kim, Sang Jun Park, Kihwang Lee, Dae Jung Kim
Diabetes Metab J. 2019;43(5):640-648.    doi: 10.4093/dmj.2018.0137.


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