The effects of chronic administration of albumin modified by advanced glycation (AGE) on renal tissue: characterization of the inflammatory, antioxidant and epigenetic profile

Abstract

Diabetes mellitus (DM) is the major cause of chronic kidney disease in the world and glomerular dysfunction is the most common etiologic factor for kidney function loss. Hyperglycemia participates in the development of diabetic nephropathy (DN), among other pathways, through the increased production of advanced glycation end products (AGEs). However only a few studies have evaluated the effects of AGEs in the absence of hyperglycemia and this is an important aspect, since exogenous AGEs also exert deleterious effects. AGEs not excreted by the kidneys are distributed in the tissues, remain biologically active and can cause local inflammation, oxidative stress and stimulate other systems, such as the renin-angiotensin system (RAS). Thus, the main hypothesis of this study is that AGEs contribute to DN regardless of hyperglycemia, by changing the expression of pro-fibrotic, pro-inflammatory, and anti-oxidant genes, stimulating the RAS and inducing epigenetic alterations. The second hypothesis is that treatment with the antioxidant N-acetylcysteine (NAC) could prevent the effects of AGEs. The aims of this study are: 1) to evaluate in vivo the effects of chronic treatment with glycated albumin and the possible therapeutic action of NAC on renal function and morphology, induction of oxidative stress, expression of genes involved in this process and epigenetic mechanisms; 2) to evaluate in vitro, in kidney cells (podocytes and mesangial cells), the effects of glycated albumin and the possible therapeutic effects of NAC on the expression of pro and anti-oxidant genes, secretion of cytokines / growth factors, induction of oxidative stress and the involvement of epigenetic mechanisms; 3) to study in vitro, in podocytes, the effect of glycated albumin and the possible therapeutic effects of NAC on the expression of proteins involved in cell adhesion and cytoskeleton arrangement. The results of this study will be important to understand the molecular mechanisms through which AGEs can affect renal physiology and represents an important strategy in the search for future preventive and / or therapeutic approaches to correct the kidney injury, especially on mesangial cells and podocytes. (AU)