Imbalance between pro‐apoptotic and pro‐survival factors in human retinal pericytes in diabetic‐like conditions

Abstract

Purpose Loss of pericytes is one the key events in the pathogenesis of diabetic retinopathy. We have previously demonstrated that human retinal pericytes (HRP) are more vulnerable to intermittent than stable high glucose concentrations, with an increase in apoptosis. Our aim was to explore the expression of molecules involved in pro‐apoptotic and survival pathways in pericytes cultured in stable/intermittent high glucose and/or hypoxia, to clarify the mechanisms of action of these diabetic‐like stressing stimuli. Methods Human retinal pericytes (HRP) were exposed intermittently at 48‐hr intervals to high/physiological glucose for 8 days (intHG) and/or hypoxia over the last 48 hr. Control cells were kept in stable physiological and high glucose. Cell proliferation and apoptosis were assessed. The expression of pro‐apoptotic and pro‐survival molecules was evaluated by Western blotting. Caspase‐8 translocation from the cytoplasm into the nucleus was checked by Western blotting of nuclear versus cytoplasmic fractions and immunofluorescence. Results Hypoxia, alone and combined with intHG, increased HRP apoptosis and decreased proliferation. Pro‐apoptotic molecules increased in HRP cultured in these conditions, while some survival markers decreased. Conversely, in stable HG, pro‐apoptotic molecules were stable or even decreased, and survival factors increased. Translocation of caspase‐8 from cytoplasm into nucleus indicates a primary role for this molecule in inducing apoptosis. Conclusion Diabetic‐like conditions are able to stimulate pericyte apoptosis through activation of pro‐apoptotic molecules, leading to an imbalance between pro‐apoptotic and survival signalling pathways, with caspase‐8 playing a pivotal role. Our identification of such intermediates could help finding new therapeutic approaches for the prevention of diabetic retinopathy.

Diabetes Alone Does Not Impair Recovery From Uneventful Cataract Surgery

“…22 Further, activation of pro-apoptotic pathways, angiopoietin-2 signaling, and consecutive vasoregression evidenced by pericyte loss have been identified as early pathologic features of diabetic posterior segment complications and blood-retinal barrier breakdown. [23][24][25][26] High HbA1c levels, a sign of poor glycemic control, correlated with systemic and intravitreal levels of VEGF-A. 6,27,28 Moreover, high levels of VEGF in the aqueous humor were to be a risk factor for macular edema after cataract surgery on diabetic patients with nonproliferative retinopathy.…”

Poor glycemic control as a risk factor for pseudophakic cystoid macular edema in patients with diabetes

“…Glycemic oscillations postprandial (after mealtime) and during fasting might activate oxidative stress, systemic proinflammatory, and proapoptotic signaling pathways and promote microvascular endothelial dysfunction and pericyte dropout. 17,18 Patients with type 1 diabetes have a higher glycemic variability than patients with type 2 diabetes, regardless of overall glycemic control. 19 Given that glucose fluctuation might differ between insulin-dependent and non-dependent diabetic patients, and glycemic variability might promote inflammation and vascular complications, patients with type 1 or type 2 diabetes with insulin dependence seem to be at greater risk for pseudophakic CME.…”

Homonoia riparia and its major component, myricitrin, inhibit high glucose-induced apoptosis of human retinal pericytes

“…The results of the present study showed that HG-induced apoptosis in HRPs involved ERK-Sp1 signaling and ROS. The loss of retinal cells, including retinal pericytes, in individuals with hyperglycemia is important for the pathogenesis of visual system changes in DR. 9 , 22 According to previous studies, HG increases the intracellular nitric oxide and superoxide levels, resulting in endothelial cell and mitochondrial dysfunction, which eventually leads to apoptosis. 22 , 23 , 24 Some mechanistic studies have shown that antiapoptotic effect of retinal pericytes is mediated via the inhibition of nicotinamide adenine dinucleotide phosphate oxidase activation, glyceraldehyde 3-phosphate dehydrogenase activity, and ROS generation.…”

“… 2 According to several reports, exposure of pericytes to high glucose (HG) levels reduced their proliferation and induced apoptosis. 2 , 6 , 7 , 8 , 9 Hyperglycemia is known to increase the generation of reactive oxygen species (ROS), especially in retinal vessels. 10 , 11 , 12 , 13 Accordingly, diabetes-related dysfunction of the retinal vasculature may be ameliorated by blocking the generation of ROS.…”