Role of advanced glycation end products (AGEs) and their receptor (RAGE) in the pathogenesis of diabetic microangiopathy.
ABSTRACT Diabetic vascular complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Chronic hyperglycemia is essentially involved in the pathogenesis of diabetic micro- and macrovascular complications via various metabolic derangements. In this review, we discuss the molecular mechanisms of diabetic retinopathy and nephropathy, especially focusing on advanced glycation end products (AGEs) and their receptor (RAGE) system. Several types of AGE inhibitors and their therapeutic implications in diseases, including diabetic microangiopathy, will be discussed in the next review article.
SourceAvailable from: Pedro Enrique Miguel Soca[Show abstract] [Hide abstract]
ABSTRACT: RESUMEN Las complicaciones vasculares de la diabetes mellitus están representadas por la macroangiopatía y la microangiopatía. La última afecta los pequeños vasos de la retina, los riñones y los nervios periféricos y causa severos daños a los pacientes afectados. En esta revisión se tratan los mecanismos básicos implicados en la microangiopatía, que comprenden la activación de la proteín quinasa C, la formación de los productos finales de la glicosilación avanzada, la reducción de aldosas y el estrés oxidativo. El conocimiento de estos procesos es importante para el diseño de nuevos fármacos que logren prevenir o retrasar el desarrollo de estas complicaciones. ABSTRACT The vascular complications of the diabetes mellitus are represented by macroangiopathy and microangiopathy. The latest affecting the small vessels of the retina, the kidneys, and periferal nerves, causing severe damage of affected patients. In this bibliographical revision, the basic mechanisms implicated in diabetic microangiopathy are treated as examples of the protein kinase C activation, advanced glycation end products, the reduction of aldoses and oxidative stress. It is important for the design of new drugs.
[Show abstract] [Hide abstract]
ABSTRACT: Chronic kidney disease (CKD) has been shown to be associated with high oxidative stress and cardiovascular disease. In this chapter our focus will be on the role of advanced glycation end products (AGE) and their receptor, RAGE in CKD progression and their role on cardiovascular complications. We provide a succinct, yet comprehensive summary of the current knowledge, the challenges and the future therapeutic avenues that are stemming out from novel recent findings. We first briefly review glycation and AGE formation and the role of the kidney in their metabolism. Next, we focus on the RAGE, its signaling and role in oxidative stress. We address the possible role of soluble RAGEs as decoys and the controversy regarding this issue. We then provide the latest information on the specific role of both AGE and RAGE in inflammation and perpetuation of kidney damage in diabetes and in CKD without diabetes, which is the main purpose of the review. Finally, we offer an update on new avenues to target the AGE-RAGE axis in CKD.Advances in Experimental Medicine and Biology 01/2014; 824:191-208. DOI:10.1007/978-3-319-07320-0_14 · 2.01 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease around the world. It includes a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis (NASH) and can lead to fibrosis, cirrhosis, liver failure, and/or hepatocellular carcinoma. NAFLD is also associated with other medical conditions such as obesity, diabetes mellitus (DM), metabolic syndrome, hypertension, insulin resistance, hyperlipidemia, and cardiovascular disease (CVD). In diabetes, chronic hyperglycemia contributes to the development of both macro- and microvascular conditions through a variety of metabolic pathways. Thus, it can cause a variety of metabolic and hemodynamic conditions, including upregulated advanced glycation end-products (AGEs) synthesis. In our previous study, the most abundant type of toxic AGEs (TAGE); i.e., glyceraldehyde-derived AGEs, were found to make a significant contribution to the pathogenesis of DM-induced angiopathy. Furthermore, accumulating evidence suggests that the binding of TAGE with their receptor (RAGE) induces oxidative damage, promotes inflammation, and causes changes in intracellular signaling and the expression levels of certain genes in various cell populations including hepatocytes and hepatic stellate cells. All of these effects could facilitate the pathogenesis of hypertension, cancer, diabetic vascular complications, CVD, dementia, and NASH. Thus, inhibiting TAGE synthesis, preventing TAGE from binding to RAGE, and downregulating RAGE expression and/or the expression of associated effector molecules all have potential as therapeutic strategies against NASH. Here, we examine the contributions of RAGE and TAGE to various conditions and novel treatments that target them in order to prevent the development and/or progression of NASH.