Insulin-Like Growth Factor-I Plays a Pathogenetic Role in Diabetic Retinopathy

Abstract

Although the molecular pathophysiology of diabetic retinopathy, the current leading cause of blindness in Western societies, 1 is not fully elucidated, studies have documented a pivotal role for leukocyte adherence within the retinal vasculature. The adhesion of leukocytes to the retinal endothelium is a process that depends on ␤ 2 integrin-intercellular adhesion molecule (ICAM)-1 interactions and leads to breakdown of the blood-retinal barrier. 2 These data, in combination with our previous findings that aggressive anti-inflammatory therapy suppressed leukocyte adhesion and blood retinal breakdown in a relevant animal model, 3 support the hypothesis that a chronic subclinical inflammation may underlie much of the vascular pathology of diabetic retinopathy. 4 These vascular pathological findings are orchestrated by vascular endothelial growth factor (VEGF), a factor that potently promotes the growth and maintenance of endothelial cells and the formation of new vessels, and is implicated in both background and proliferative diabetic retinopathy. 5-11 Intraocular VEGF levels are increased in diabetic patients with blood-retinal barrier breakdown and neovascularization, 5,10,12,13 whereas the specific inhibition of VEGF prevents these complications in animal models. 7,11,14 Therefore, regulation of VEGF expression could conceivably be both a mediator for converging local and systemic stimuli modulating vessel pathophysiology, as well as a target for therapeutic intervention. Within a constellation of known modulators of VEGF expression that can possibly function at the transcriptional [through AP-1, AP-2, steroid hormone receptors, p53, and nuclear factor (NF-B)] or posttranscriptional level, [15][16][17][18] hypoxia is the most potent inducer of VEGF transcription in vivo; its effects are mainly mediated by the helix-loop helix (bHLH)-PAS transcription factor HIF-1␣, which heterodimerizes with the bHLH-PAS protein ARNT or HIF-1␤, 19 -22 and binds to consensus and ancillary hypoxia-response elements (HREs) in the VEGF promoter. 21,[23][24][25]

Placental growth factor-1 and epithelial haemato–retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy

“…1d). Exposure of human RPE cells to hypoxic conditions or insulin upregulates PLGF-1 and increases permeability of RPE monolayers Because hypoxia and IGF-1 induce the production of angiogenic and permeating factors [19], we investigated the upregulation of PLGF-1 production and its influence on RPE cell permeability after exposure of RPE cells to hypoxia and insulin.…”

“…Interestingly, not only hypoxia but also insulin directly induced a transitory upregulation of PLGF-1 associated with an increased permeability of RPE cells in vitro. It has been reported that PLGF-1 plays a role in the pathogenesis of diabetic retinopathy through increased levels of VEGF and activation of protein kinase B, c-Jun =-terminal kinase, hypoxia-inducible factor 1 alpha, nuclear factor .B and activator protein 1 in the retina [19].…”

Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes

“…9. Inappropriate regulation of nuclear factor kappa B (NF-κB) DNA binding has been observed in the retina in diabetes [17,[48][49][50], resulting in increased transcription of NF-κB-regulated gene products, including iNOS [51]. Inhibition of inflammatory pathways via inhibition of PARP [17], NF-κB [51], cyclooxygenase [52], intercellular adhesion molecule-1 [16] and now also of iNOS inhibits the diabetes-induced degeneration of retinal capillaries in experimental diabetic animals.…”

The purpose of the HIF-1/PHD feedback loop: To limit mTOR-induced HIF-1α

“…46,[48][49][50][51][52][53][54][55] Insulin, growth factors and nutrients such as glucose activate the mTOR (Target of Rapamycin) pathway. [56][57][58][59][60][61][62][63] Importantly, cellular senescence is mTOR-dependent, [64][65][66][67][68][69] and rapamycin suppresses the senescent phenotype. [70][71][72] It was suggested that mTOR activation links the senescent phenotype to age-related diseases.…”