Starvation to Glucose Reprograms Development of Neurovascular Unit in Embryonic Retinal Cells

Abstract

Perinatal exposure to starvation is a risk factor for development of severe retinopathy in adult patients with diabetes. However, the underlying mechanisms are not completely understood. In the present study, we shed light on molecular consequences of exposure to short-time glucose starvation on the transcriptome profile of mouse embryonic retinal cells. We found a profound downregulation of genes regulating development of retinal neurons, which was accompanied by reduced expression of genes encoding for glycolytic enzymes and glutamatergic signaling. At the same time, glial and vascular markers were upregulated, mimicking the diabetes-associated increase of angiogenesis—a hallmark of pathogenic features in diabetic retinopathy. Energy deprivation as a consequence of starvation to glucose seems to be compensated by upregulation of genes involved in fatty acid elongation. Results from the present study demonstrate that short-term glucose deprivation during early fetal life differentially alters expression of metabolism- and function-related genes and could have detrimental and lasting effects on gene expression in the retinal neurons, glial cells, and vascular elements and thus potentially disrupting gene regulatory networks essential for the formation of the retinal neurovascular unit. Abnormal developmental programming during retinogenesis may serve as a trigger of reactive gliosis, accelerated neurodegeneration, and increased vascularization, which may promote development of severe retinopathy in patients with diabetes later in life.

Genetics of diabetes-associated microvascular complications

“…Although hyperglycaemia is a strong driver of complication development, accumulating evidence suggests that other factors either act in synergy with hyperglycaemia or counteract it in a way that protects some individuals [ 93 ]. We demonstrated that intrauterine programming during early fetal developmental may play an important role in the development of proliferative diabetic retinopathy by making vessels and nerves more vulnerable and, thereby, susceptible to the damaging effects of chronically elevated glucose levels [ 68 , 89 , 90 ]. However, the relative contribution of low insulin or high glucose levels to neuron damage and related risks of retinopathy and neuropathy still needs to be determined.…”

“…In support of the fetal programming hypothesis in the predisposition to vascular complications of diabetes, we have recently reported a disproportionally elevated risk for proliferative diabetic retinopathy in individuals with type 2 diabetes: in two independent populations (from Ukraine and Hong Kong), we found that the incidence of proliferative diabetic retinopathy was disproportionately higher in individuals who experienced perinatal exposure to famine [ 89 ]. Furthermore, our experimental data on starved-for-glucose embryonic retinal cells allowed us to generate a hypothesis of irreversible and detrimental reprogramming of formation of the entire neurovascular unit during retinal development after early-life exposure to glucose starvation [ 90 ]. Specifically, using transcriptomic analysis, we found a profound decrease in the expression of neuronal markers, while genes encoding for vascular markers were upregulated, similar to the diabetes-associated increase in angiogenesis in diabetic retinopathy [ 90 ].…”

“…Furthermore, our experimental data on starved-for-glucose embryonic retinal cells allowed us to generate a hypothesis of irreversible and detrimental reprogramming of formation of the entire neurovascular unit during retinal development after early-life exposure to glucose starvation [ 90 ]. Specifically, using transcriptomic analysis, we found a profound decrease in the expression of neuronal markers, while genes encoding for vascular markers were upregulated, similar to the diabetes-associated increase in angiogenesis in diabetic retinopathy [ 90 ].…”

Neuronal Dysfunction Is Linked to the Famine-Associated Risk of Proliferative Retinopathy in Patients With Type 2 Diabetes

“…In the present study, the immunostaining experiments displayed some isolated immunopositive profile of ADRA2A , PCSK9 and PROX 1 not colocalizing with beta3 tubulin. Notably, our recently published data on the global mRNA sequencing analyses from the same cellular model indicated that starvation for glucose caused marked transcriptomics changes in various retinal markers including vascular markers and allowed us to generate hypothesis of potential detrimental reprogramming of the entire neurovascular unit ( Özgümüs et al, 2021 ).…”