Figure 1 displays an illustration of the key molecular pathways involved in the development and progression of Diabetic Retinopathy coinciding with the stages of disease progression and corresponding clinical symptoms. Hyperglycemia causes oxidative stress, inflammation, Protien Kinase C (PKC) activation, the formation of Advanced Glycation End products (AGEs), and the activation of the polyol pathway. These effects in turn lead to neural and vascular damage leading to Diabetic Retinopathy and vision loss. Diabetic Retinopathy progression is shown in purple boxes with corresponding clinical symptoms aligned in grey boxes 11 .
Increased oxidative stress:
Oxygen metabolism is essential for sustaining life, and normal cellular function works on a fine balance between the formation and elimination of reactive oxygen species (ROS). Oxidative stress, is an adverse consequence of excessive production of ROS and the suppression of ROS removal by antioxidant defence system, is implicated in diabetic retinopathy. The exact mechanism of its development remains elusive.
The polyol pathway becomes activated when intracellular levels of glucose are high. The polyol pathway is a 2-step pathway which converts glucose initially to sorbitol via the action of the enzyme Aldose Reductase (AR); sorbitol is then metabolized to fructose by an enzyme sorbitol dehydrogenase. Sorbitol is hydrophilic (loves water based environments) and accumulates intracellularly with osmotic consequences (damaging). The fructose generated leads to the formation of damaging advanced glycation end products (AGEs). AR uses a molecule called NADPH to work, this reduction in NADPH by AR may reduce the capability of cells to respond to oxidative stress. Thus, activation of the polyol pathway, by altering intracellular tonicity, generating AGEs precursors, and exposing cells to oxidative stress, can initiate and multiply several mechanisms of cellular damage. (12)
Protein Kinase C activation:
Hyperglycaemia increases the activation of protein kinase C (PKC). In diabetic retinopathy, PKC mediates changes in endothelial (blood vessel) permeability, blood flow, and both the formation and response to angiogenic growth factors (molecules which promote the growth of blood vessels), all contributing to retinal leakage, ischaemia (not enough oxygen supply), and neovascularisation (growth of new vessels). PKC activation also contributes to loss of pericytes, an early feature of diabetic retinopathy.
Accumulation of Advanced Glycation End products (AGEs):
As mentioned about, another pathway provoked by hyperglycemia involves the formulation of Advanced Glycation End products (AGEs) and activation of receptors for AGEs (RAGE). AGEs alter proteins on cells and binding to receptors on cells causing a cascade of events which lead to the breakdown of the blood vessel wall resulting in leaky blood vessels. The effects of AGEs include loss of pericyte cells (the cells on the outer wall of the blood vessel), endothelial dysfunction (incorrect functioning of the cells on the inner wall of the blood vessel) and vascular inflammation, increasing levels of proangiogenic factors which result in the formation of new, poor quality, fragile, leaky blood vessels.