Diabetes-Enhanced Tumor Necrosis Factor-α Production Promotes Apoptosis and the Loss of Retinal Microvascular Cells in Type 1 and Type 2 Models of Diabetic Retinopathy

Abstract

Retinal microvascular cell loss plays a critical role in the pathogenesis of diabetic retinopathy. To examine this further, type 1 streptozotocin-induced diabetic rats and type 2 Zucker diabetic fatty rats were treated by intravitreal injection of the tumor necrosis factorspecific inhibitor pegsunercept, and the impact was measured by analysis of retinal trypsin digests. For type 2 diabetic rats, the number of endothelial cells and pericytes positive for diabetes-enhanced activated caspase-3 decreased by 81% and 86%, respectively, when treated with pegsunercept (P < 0.05). Similarly, the number of diabetes-enhanced terminal deoxynucleotidyl transferase-mediated dUTP nickend labeling-positive endothelial cells and pericytes decreased by 81% and 67% respectively when treated with pegsunercept (P < 0.05). Diabetes-increased activated caspase-3-and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive microvascular cell numbers were both reduced by 81% and 80%, respectively, in pegsunercept-treated type 1 diabetic rats (P < 0.05). Inhibition of tumor necrosis factor reduced type 1 diabetes-enhanced pericyte ghost formation by 87% and the number of type 2 diabetes-enhanced pericyte ghosts by 62% (P < 0.05). Similarly, increased acellular capillary formation caused by type 1 and type 2 diabetes was reduced by 68% and 67%, respectively, when treated with pegsunercept (P < 0.05). These results demonstrate a previously unrecognized role of tumor necrosis factor-␣ in promoting the early pathogenesis of diabetic retinopathy leading to loss of retinal microvascular cells and demonstrate the potential therapeutic benefit of modulating its activity.

Mechanistic Insights into Pathological Changes in the Diabetic Retina

“…inflammation-mediated events in DR. 36,37 Such events may lead to retinal vascular cells and tight junctions becoming compromised, 38,39 which can lead to vascular leakage. Inflammatory molecules, such as tumor necrosis factor-a, IL-1b, IL-6, IL-8, intracellular adhesion molecule-1, vascular cell adhesion molecule 1, integrin b-2 (CD-18), and monocyte chemoattractant protein-1, play pivotal roles in the pathogenesis of DR lesions.…”

Diabetic microangiopathy: Pathogenetic insights and novel therapeutic approaches

“…The loss of pericytes activates a disordered capillarization, represented by acellular capillaries and microaneurysms, which are responsible for areas of underperfusion of the depending tissues [48]. Mechanisms underlying pericyte apoptosis include the formation of AGEs and the tumor necrosis factor (TNF)-α-dependent activation of the Forkhead box O1 (FOXO1) transcription factor [49][50][51]. Pericytes from healthy subjects contribute to reparative angiogenesis through paracrine mechanisms and the physical interaction with resident ECs, involving angiopoietin 1, platelet-derived growth factor (PDGF)-BB and cAMP-responsive element binding (CREB)/miR-132 [52].…”

Diabetes mellitus and apoptosis: inflammatory cells

“…This endothelial cell dysfunction arises as a result of impaired NO bioavailability, oxidative stress and increased polyol pathway activation and AGE formation, which in combination lead to activation of intracellular signalling pathways involving PKC, PKB, and MAPK, finally culminating in induction of the pro-inflammatory transcription factors such as NFjB and AP-1 [174]. TNF-a has also recently been implicated in the loss of retinal microvascular cells that occurs early in the pathogenesis of DR [175]. This study demonstrated that intravitreal injection of the TNF-specific inhibitor pegsunercept reduced the number of apoptotic endothelial cells, pericytes and microvascular cells in models of both T1DM (STZ rats) and T2DM (Zucker diabetic fatty rats).…”