Metabolic memory in mitochondrial oxidative damage triggers diabetic retinopathy

Abstract

BackgroundDiabetic retinopathy (DR) is a microvascular complication induced by high blood glucose. This study was conducted to investigate the effect of metabolic memory on mitochondrial oxidative damage-induced DR.MethodsRat retinal endothelial cells (rRECs) were isolated from SD rats and treated with high glucose (20 mM) for various times and then cultured in normal glucose (5.6 mM) medium for 2 days. The cells were assayed for the expression of respiratory chain complexes cytochrome c oxidase subunit 1 (CO1) and NADPH-1 using RT-PCR, mitochondrial membrane potentials and reactive oxygen species (ROS) production using flow cytometry and apoptosis using Annexin V/PI flow cytometry.ResultsrRECs displayed like short spindles after cultured for 9–10 days and reached 100% confluency. Compared with the control grown in normal glucose (5.6 mM) medium, rRECs exposed to high glucose medium for 3, 12 and 24 h had significantly increased mRNA levels of CO1 and NAPDH-1 even after being shifted back to normal glucose medium. They also had lower mitochondrial membrane potential (89.13% vs 78.21%, p < 0.05), cytochrome C level (1 in control vs 0.25 after 24 h exposure to high glucose, p < 0.05 and higher ROS production (2.77% in control vs 9.00% after 12 h exposure to high glucose, p < 0.05) and apoptosis (7.15% in control vs and 29.91% after 24 h exposure to high glucose, p < 0.05).ConclusionIt is likely that mitochondrial oxidative damage triggers metabolic memory via ROS overproduction, leading to diabetic retinopathy.

<p>mRNAs expression profiles of high glucose-induced memory in human umbilical vein endothelial cells</p>

“…A growing body of experimental evidence supports the concept that the risk for diabetes complications may be linked to oxidative stress, non-enzymatic glycation of proteins, epigenetic changes, and chronic inflammation, laying the foundation for the MM theory 30. Nigris et al reported that dipeptidyl peptidase-4 (DPP-4) induced oxidative stress in the HUVECs and MM in retinal endothelial cells,31,32,33 which could be reduced by the inhibitor teneligliptin32,33 We analyzed the protein-coding mRNA expression profile by high throughput RNA-seq in HUVECs from the LG, HG, and MM groups. HGMMGs were identified, including 516 up-HGMMGs and 210 down-HGMMGs.…”

Heme Synthesis Inhibition Blocks Angiogenesis via Mitochondrial Dysfunction

“…The mitochondrial ETC is a major source of ROS induced by vascular endothelial growth factor (VEGF) in hyperglycemic and hypoxic cellular environments ( Cheng et al., 2011 ; Pearlstein et al., 2002 ; Wang et al., 2018 ). In PDR, increased mitochondrial ROS and impaired Ca 2+ signaling can cause an increase in oxidative stress ( Kowluru and Mishra, 2015 ; Pangare and Makino, 2012 ; Tang et al., 2014 ; Wang et al., 2018 ). Complex III of the ETC was recently shown to be important for umbilical vein EC respiration and thus proliferation during angiogenesis ( Diebold et al., 2019 ).…”

Heme synthesis inhibition blocks angiogenesis via mitochondrial dysfunction

“…The mitochondrial electron transport chain (ETC) is a major source of ROS induced by vascular endothelial growth factor (VEGF) in hyperglycemic and hypoxic cellular environments (Cheng et al, 2011;Pearlstein et al, 2002;Wang et al, 2018). In PDR, increased mitochondrial ROS and impaired Ca 2+ signaling can cause an increase in oxidative stress (Kowluru and Mishra, 2015;Pangare and Makino, 2012;Tang et al, 2014;Wang et al, 2018). Complex III of the ETC was recently shown to be important for umbilical vein EC respiration and thus proliferation during angiogenesis (Diebold et al, 2019).…”