Mechanisms of proximal tubular cell injury in diabetes :role of AMPK and the Cytochromes P450 enzymes

Abstract

347 million people worldwide suffer from Diabetes, and the prevalence of raised fasting blood glucose levels is increasing vastly by the year, and especially in the Middle East region. Worldwide, more than 3 million people die each year as a consequence of diabetes-related complications. Diabetes is a chronic metabolic disease that involves impaired blood glucose homeostasis. The elevated levels of blood glucose result in several complications among which diabetic nephropathy stands as one of the most serious. Diabetic nephropathy causes functional and histological changes to renal cells. Studies have shown a relation between certain metabolic pathways and the development of nephropathy. Oxidative stress was also linked and was shown to play a major pathological role in its development, and is manifested by the increased production of reactive oxygen species (ROS).Studies show that high glucose decreases the phosphorylation of AMP-activated protein kinase (AMPK), which is a serine-threonine kinase that acts as an energy sensor regulated by glucose. The activation of AMPK requires its phosphorylation, and its deactivation was shown to cause a cascade of events that eventually leads to the increase in the production of ROS, mainly the increased expression of NOX4 – a ROS generating NADPH oxidase.It has also been shown that HG leads to an increase in the expression of Cytochrome P450 (CYP 450), and specifically the 4A subfamily of the enzyme. This up-regulation leads to increased ROS production in the kidneys, mediated by the increased production of 20-HETE.We hypothesize that the common resulting increased production of ROS due to deactivation of AMPK and increased expression of CYP 450 underlies a relationship between these two enzymes. Our research aims to reveal this cross-talk, and further elucidate the signaling pathway involving them.In order to achieve this aim, we conducted in-vivo setting experiments, where diabetes was induced in male Sprague-Dawley rats, and different groups were treated with diff