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

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Title Effect of dietary antioxidants on Advanced Glycation
End Products (AGEs) related complications during
diabetic nephropathy in rats.
 
Creator Mallikarjun, B. Chougala
 
Subject 04 Diabetes Mellitus
32 Antioxidants
 
Description 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
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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
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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.
 
Contributor Salimath, P. V.
 
Date 2013
 
Type Thesis
NonPeerReviewed
 
Format application/pdf
 
Language en
 
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Identifier http://ir.cftri.com/11759/1/Mallikarjun%20B%20Chougala%20Ph.D.%20Thesis.pdf
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.