RAGE, adipose derived estrogens and dietary AGEs; interactions in obesity induced kidney disease

Abstract

Obesity is now commonly seen worldwide and across all age groups. Obesity is the result of excessive nutrient intake often from sources which are highly processed which have a high energy-to-nutrient ratio. These dietary excuses are then compounded by decreased physical activity levels. Whilst these aetiological influences are thought to be easily modifiable, the reality is that individuals are becoming increasingly over-weight and obesity related diseases are posing more problems than ever before. Obesity has many metabolic consequences including, insulin resistance and predisposition for the development of chronic diseases such as cancers, autoimmune diseases, and type 2 diabetes (T2D). Diabetes then incurs further vascular complications in organs that have intricate microvascular networks such as those within, neurons, eyes and kidneys, leading to gangrenous limbs and amputations, cataracts and blindness, renal failure. Of course the ultimate complication of diabetes is early death, normally as a result of cardiac disease and heart failure. Receptor for advanced glycation end products (RAGE) and its modulation of downstream pathways are recognised pathological contributors to the vascular complications of diabetes including renal disease. There is increasing evidence that obesity is an independent risk factor for kidney disease, in particular in the context of type 2 diabetes. However, the mechanisms by which obesity contributes to kidney disease remain to be determined. Estradiol (17-β-estradiol) has been shown to confer protection against renal and cardiovascular disease when it is the major biologically active estrogen. In obesity, white adipose tissue deposits secrete another estrogen isoform called estrone, which alters the balance of estrogens. Imbalances in estradiol to estrone are the development of obesity related diseases. At the time of beginning this thesis, there were no drugs available for the specific treatment of obesity related renal diseases. Some treatments are borrowed from type 2 diabetes and chronic kidney disease and have modest effects on excretion of albumin or target blood pressure lowering pathways. Others directly target obesity, leading to weight loss although these are often temporary. Therefore this thesis examines the development of obesity related renal disease. I have examined the role of excessive adipose tissue deposition and the ability of estrogens to modulate the receptor for advanced glycation end products (RAGE), to discover potential therapeutic targets to control the growing problem of obesity related kidney disease.