**6. AGEs and diabetic complications**

Hyperglycaemia in diabetes mellitus affects many organ systems, including the eyes, kidneys, heart, and peripheral and autonomic nervous systems. They can be broadly divided into microangiopathy, which occurs mainly in the capillaries, and macroangiopathy, which occurs in relatively large blood vessels. Three major complications, i.e., diabetic retinopathy, diabetic nephropathy, and DN, are microangiopathies that occur in patients with diabetes [95]. In contrast, arteriosclerotic diseases, which cause vascular diseases, such as myocardial infarction and cerebral infarction, are considered as macroangiopathies. AGEs are the leading causes of complications caused by microangiopathy and macroangiopathy [96–98].

Diabetic retinopathy causes bleeding and ischaemia in capillaries due to the hyperglycaemic environment, and progression results in bleeding or retinal detachment inside the vitreous body. AGEs are associated with the presence and progression of diabetic retinopathy [99]. Diabetic keratopathy, in which the corneal epithelium is exfoliated due to aggregation of AGEs-ised proteins, is thought to be related to AGE formation via laminin, which is found in the basement membrane

of the corneal epithelium [100]. In human RAGE transgenic mice induced by streptozotocin as an experimental model of diabetes, the blood-retinal barrier was disrupted, and leukostasis was increased [101]. However, systemic administration of sRAGE intraperitoneally suppressed collapse of the blood-retinal barrier and leukostasis [101]. Administration of soluble RAGE, which comprises the extracellular domain of RAGE, enhances AGEs in the blood and blocks the interaction with cell membrane RAGE. As a result, pathological conditions related to diabetic retinopathy, such as increased retinal vascular permeability and adhesion of leukocytes to retinal blood vessels, can be suppressed [101, 102]. Thus, AGE/RAGE signalling plays important roles in the development of diabetic retinopathy.

The kidney is an organ that filters waste products in the blood to produce urine and is formed by the renal glomerulus, which is similar to a mass of capillaries. In patients with diabetes, renal dysfunction can also occur. Chronic kidney disease occurs in approximately 20–40% of patients with diabetes [103]. If renal failure occurs, artificial haemodialysis is required. Diabetic nephropathy is the most common cause of dialysis. In diabetic nephropathy, accumulation of AGEs has been reported in various cells, such as the glomerular basement membrane, mesangium, podocytes, tubular cells, and endothelial cells [104]. In addition, several studies have suggested that RAGE expression is increased in patients with diabetic nephropathy [104, 105]. Administration of AGEs to nondiabetic rats induces proteinuria and degenerative changes in the renal tissue, highlighting the important roles of AGEs in the development of diabetic nephropathy [106]. CML in patients with type 1 diabetes was found to correlate with the severity of nephropathy [107]. Moreover, the levels of CML- and hydroimidazolone-AGEs in the serum of patients with type 2 diabetes are significantly increased [108]. CML-human serum protein levels are higher in patients with proteinuria, and increased levels of circulating AGE peptides are correlated with the severity of renal dysfunction [109]. Studies in RAGE transgenic mice revealed the development of advanced diabetic nephropathy features, such as renal hypertrophy, glomerular hypertrophy, mesangial enlargement, glomerulosclerosis, and proteinuria [110]. In OVE26 mice, a diabetic mouse model that exhibits progressive glomerular sclerosis and decreased renal function, RAGE deficiency alleviates histological and morphological changes and albuminuria associated with diabetic nephropathy and does not result in decreased renal function [111]. Thus, these findings support that RAGE is involved in the development of diabetic nephropathy and as a target molecule in for treating this disease.

DN is a peripheral nerve disorder caused by prolonged hyperglycaemia in diabetes, resulting in numbness, pain, and hypoesthesia of the limbs. In the nervous tissue, hyperglycaemia increases non-insulin-dependent glucose uptake. Excess glucose is thought to cause sorbitol accumulation via the polyol pathway and microangiopathy, which nourishes the nerves. Accumulation of AGEs is observed in perineurial cells, nerve axons, and Schwann cells in the peripheral nerves of patients with diabetes [112]. In Schwann cells, neurofilaments and tubulin, which are important for axonal transport, are converted to AGEs [113]. Overexpression of AGEs and RAGE in the nerves of patients with diabetes activates NF-κB; these changes correlate with hypoesthesia [114]. Therefore, antiglycation agents, such as aminoguanidine, have been promoted as treatments for DN [115]. However, aminoguanidine was shown to have various side effects in a clinical trial of patients with DN, and thus its development was discontinued. Recently, the anti-inflammatory cytokine interleukin-10 has attracted attention because of ability to suppress AGEinduced apoptosis in Schwann cells by reducing oxidative stress through inhibition of NF-κB activation [116]. Thus, the potential use of interleukin-10 for treating DN is also being discussed.

*Advanced Glycation End Products and Oxidative Stress in a Hyperglycaemic Environment DOI: http://dx.doi.org/10.5772/intechopen.97234*
