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Effect of dietary antioxidants on Advanced Glycation End Products (AGEs) related complications during diabetic nephropathy in rats.

Mallikarjun, B. Chougala (2013) Effect of dietary antioxidants on Advanced Glycation End Products (AGEs) related complications during diabetic nephropathy in rats. PhD thesis, University of Mysore.

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The impact of diabetes mellitus on global health care and economy are enormous. Diabetes is main epidemic of this century, whose incidence has increased by 50% over the past 10 years. Diabetes is clinically characterized by hyperglycemia. Persistent hyperglycemia and oxidative stress accelerate formation of Advanced Glycation End products (AGEs). The AGEs are a varied group of compounds that are formed by non-enzymatic glycation of sugars with free amino groups on proteins. In diabetes, not only do long lived proteins become heavily modified, but short lived proteins are also altered by AGEs. Hyperglycaemia causes increased production of free radicals via the processes of autoxidation of glucose and non-enzymatic protein glycation. AGEs related diseases have reached epidemic proportions and one of its ominous complications is diabetic nephropathy. Diabetic nephropathy develops in approximately 40% of patients with diabetes mellitus. Several studies have shown that AGEs are one of the important factors in the pathogenesis of nephropathy. Accumulation of AGEs is related to severity of diabetic nephropathy. AGEs lead to kidney damage through several mechanisms that include alterations in the structure and function of proteins, as well as cellular injury. Direct cross-linking of slow turnover proteins in extracellular matrix (ECM) results in multiple abnormalities: disrupted matrix protein structure and function, aberrant cell– matrix interactions that contribute to changes in cellular adhesion, altered cell growth and loss of epithelial phenotype and inhibition of interactions required for selfassembly of type IV collagen and laminin. Exposition to AGEs-cross linked proteins results in increased oxidative stress in rat mesangial cells and an increase in protein kinase C activity. Increase in circulating AGE-peptides in diabetics correlates well with severity of renal function impairment. It is important to understand the iii relationship of AGEs to their receptors, because AGEs elicit their receptor mediated effects via their engagement with various receptors. The receptors of AGEs are important modulators of their deleterious effects. Receptor for Advanced Glycation End products (RAGE) and other receptors appear to activate stress response leading to inflammation and cellular dysfunction. The complexities of this system are still not fully understood. Hyperglycemia is implicated in accelerated vascular damage associated with diabetes, which manifests as nephropathy due to microvascular complications. Vascular dysfunction, including basement membrane thickening, increased vascular permeability and prothrombotic state and decreased blood flow, are ubiquitous traits of microvascular disease of nephron. AGEs play an important role in causing these abnormalities and the attendant microvascular diseases. Mechanisms leading to such complications are however not fully understood. There is some evidence that AGEs modification of the vasogenic growth factors, within the context of hyperglycemia, impairs their angiogenic potential both in vitro and in vivo. However, the role of AGEs in angiogenesis remains somewhat controversial, with several studies reporting that these adducts can promote aspects of the angiogenic process in vitro, including stimulation of endothelial cell proliferation and tube formation, perhaps through the induction of the angiogenic vascular endothelial growth factor (VEGF). Among various factors, angiogenesis, associated factors such as VEGF are known to be involved in the development of diabetic nephropathy. Different approaches may be used to counter AGEs accumulation and its deleterious effects. The first approach is to reduce formation of AGEs. Compounds like aminoguanidine and ALT-946 are shown to block specific steps during AGEs formation. The Second approach is to iv increase breakdown of already formed AGEs. The third approach is to prevent deleterious effects of AGEs. However, the exact sequence of events from exposure to high glucose concentrations to development of renal damage remains equivocal. The study aims at determining formation of AGEs during diabetes and their role in complications of diabetic nephropathy with respect to changes in extracellular matrix components. The role of extracellular matrix during diabetic nephropathy is well established and the study aims at examining changes in extracellular matrix components such as heparan sulfate, laminin and type IV collagen during diabetes and their amelioration by dietary treatment. Diet is now well established to be one of the means in the management of diabetes only next to insulin and drugs. In this direction dietary antioxidants such as curcumin and quercetin are receiving increasing attention.

Item Type: Thesis (PhD)
Uncontrolled Keywords: diabetes mellitus, Advanced Glycation End products, Diabetic nephropathy, dietary antioxidants
Subjects: 600 Technology > 01 Medical sciences > 04 Diabetes Mellitus
600 Technology > 08 Food technology > 32 Antioxidants
Divisions: Dept. of Biochemistry
Depositing User: Food Sci. & Technol. Information Services
Date Deposited: 19 Mar 2015 10:35
Last Modified: 19 Mar 2015 10:35
URI: http://ir.cftri.com/id/eprint/11759

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