Development of a pre-clinical model of adenine diet induced chronic kidney disease in exercise resistant rats

Abstract

Chronic kidney disease (CKD) has been increasingly recognized as a public health problem. Hyperglycaemia, inflammation, oxidative stress, and angiotensin signaling are molecular events that could play a mechanistic role in the development and progression of CKD. Whereas aerobic endurance training can prevent or minimize CKD complications, poor levels of physical activity and exercise intolerance are highly prevalent across the CKD trajectory. Recent evidence demonstrated that improvement of exercise capacity in response to aerobic training was blunted by hyperglycaemia, which was associated with extracellular matrix (ECM) accumulation. Rat models generated by selective breeding for low (LRT) or high (HRT) response to aerobic training can be used to understand the exercise-disease linkage and exercise resistance phenomenon. Moreover, rats treated with adenine diet produced several characteristics of human CKD and progressive kidney damage. By using specific experimental models, we will investigate key biological pathways involved in the exercise resistance (LRT vs. HRT models) and directly test the hypothesis that exercise resistance has profound impact on ECM accumulation, inflammatory response, and oxidative damage in CKD. Furthermore, the mechanisms behind the changes in ECM homeostasis would involve the activation intracellular kinases. Therefore, our purpose is to uncover novel molecular links between exercise resistance and CKD responses by investigating the glucose homeostasis, inflammatory response, oxidative stress, angiotensin signaling and ECM remodeling. (AU)