Focusing on Sodium Glucose Cotransporter-2 and the Sympathetic Nervous System: Potential Impact in Diabetic Retinopathy
Table 1
Proposed mechanisms involved in the pathogenesis of DR. Prolonged exposure to hyperglycemia leads to the activation of a number of interconnecting biochemical pathways that contribute to the pathogenesis of DR.
Pathway
Mechanism
Reference
Activation of protein kinase C (PKC)
(i) Hyperglycemia increases the synthesis of diacylglycerol (DAG). (ii) Several PKC isoforms (such as PKC-β, α, and δ) are activated. (iii) Phosphorylation of substrate proteins mediated via PKC promotes changes in retinal blood flow, increased vascular permeability, endothelial cell dysfunction, and altered growth factor signaling. (iv) Retinal ischemia and neovascularization result.
(i) Metabolizes excess glucose to sorbitol and then fructose during hyperglycemia. (ii) Intracellular accumulation of sorbitol leads to osmotic stress in retinal cells including ganglion cells, Muller glia, vascular endothelial cells, and pericytes. (iii) Pathophysiological consequences include thickening of capillary basement membrane, pericyte loss, formation of acellular capillaries, microaneurysms, hemorrhages, glial cell activation, and apoptosis.
(i) Hyperglycemia increases the formation of AGEs. (ii) Production of AGEs damages target cells via three mechanisms: (1) Changed extracellular matrix brings about abnormal interactions with matrix receptor proteins and surrounding matrix components. (2) AGE-modified intracellular proteins have altered functions. (3) AGE-modified plasma proteins bind to the receptor for advanced glycation end products (RAGE) on endothelial cells, leading to the production of reactive oxygen species.
(i) During hyperglycemia, ~3% of glucose is processed through the hexosamine pathway. (ii) Fructose-6-phosphate is converted to glucosamine-6-phosphate. (iii) Subsequently, glucosamine-6-phosphate is metabolized to UDP-GluNAc (uridine diphosphate N-acetyl glucosamine). (iv) UDP-GluNAc attaches to serine and threonine residues of transcription factors.
