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16
VOLUME 9 NUMBER 1 • MARCH 2012
RESEARCH ARTICLE
SA JOURNAL OF DIABETES & VASCULAR DISEASE
Correspondence to: MA Zaki
Chemical Pathology Department, Medical Research Institute, Alexandria
University, Egypt
Tel: +203 428-2331
Fax: +203 428-3719
e-mail: moyassar@gmail.com, moyassar.zaki@alex-mri.edu.eg
KM Ahmed
Cardiology and Angiology Unit, Internal Medicine Department, Medical
Research Institute Teaching Hospital, Alexandria University, Egypt
S Afr J Diabetes Vasc Dis
2012;
9
: 15–20
Impact of vascular complications on serum levels of soluble
RAGE and TNF-
α
in females with type 2 diabetes
Abstract
Background:
Binding of advanced glycation end products
(AGEs) to AGE receptors (RAGE), and endothelial dysfunction
resulting from oxidative stress and pro-inflammatory
cytokines, such as tumour necrosis factor (TNF-
α
), contribute
to the pathogenesis of diabetic vascular complications.
A soluble form of RAGE (sRAGE) acts as a decoy receptor
in an attempt to decrease cellular binding of AGEs. We
aimed to measure sRAGE, TNF-
α
and the products of lipid
peroxidation (thiobarbituric acid-reactive substances: TBARS)
in females with type 2 diabetes with and without vascular
complications.
Methods:
Forty-five females with type 2 diabetes (30 with
vascular and 15 without vascular complications) were
compared to 15 healthy control females. Serum sRAGE and
TNF-
α
weremeasuredwith enzyme immunoassays specific for
each, while plasma TBARS was determined colorimetrically.
Results:
Diabetic females with vascular complications had
higher mean serum value of both sRAGE and TNF-
α
, as well
as a higher plasma TBARS mean value, compared to the other
two groups. The mean sRAGE value was higher in those with
both micro- and macrovascular complications compared to
those without vascular complications. Serum sRAGE values
correlated with duration of diabetes in the whole patient
group.
Conclusion:
A high plasma sRAGE value in the diabetics
with vascular complications implicates a possible role of
vascular insult in triggering sRAGE production in a trial to
overcome AGEs toxicity. The use of RAGE as a potential
therapeutic means could benefit the diabetic patients with
vascular complications, particularly those presenting with
microvascular complications.
Keywords:
solubleRAGE, tumor necrosis factor-
α
, lipidperoxidation
products, type 2 diabetes vascular complications
Submitted 18/6/2011, accepted 1/2/2012
MA ZAKI, KM AHMED
Diabetes mellitus, particularly type 2 diabetes, is increasing at an
alarming rate.
1
Its macro-
and microvascular complications are
the main causes of morbidity and mortality
in diabetics.
2
Several
mechanisms are proposed for explaining the link between chronic
hyperglycaemia and both the onset and progression of diabetic
vascular complications, including the non-enzymatic glycation of
proteins and lipids, with the resultant formation of irreversible
advanced glycation end products (AGEs).
3
The AGEs exert their effects on cellular function through
interaction with receptors associated with increased oxidative stress,
growth, and inflammatory effects, known as receptors for AGE
(RAGE).
4
Other receptors involved in AGE detoxification include
macrophage scavenger receptors class A, type-II (MSR-AII) and
class B type-I (MSR-BI),
5
AGE receptor-1 [AGE-R1, oligosaccharide
transferase-48 (OST-48)], AGE receptor-2 (AGE-R2, 80K-H
phosphoprotein) and AGE receptor-3 (AGE-R3, galectin-3).
6,7
The RAGE is a signal-transducing receptor for AGEs that
mediates diverse cellular responses. Engagement of RAGE amplifies
the development of complications, particularly in a ligand-enriched
environment.
8,9
Being a member of the immunoglobulin superfamily,
RAGE is a multi-ligand receptor, expressed by a variety of cell types
including endothelial cells, smooth muscle cells, lymphocytes,
monocytes and neurons.
8,9
Since RAGE recognises tertiary structures
rather than amino acid sequences, RAGE has the ability to engage
classes of molecules rather than individual ligands.
In diabetic blood vessels, an up-regulation of RAGE and its ligands,
particularly AGEs and S100/calgranulins occurs.
10
One of the best-
documented consequences of RAGE activation is the generation
of reactive oxygen species (ROS). Increased ROS is also associated
with the formation of AGEs. At sites of vascular inflammation there
would be an expectation of increased ROS formation, which would
be further enhanced by the activation of RAGE.
11
A 50-KDa soluble formof RAGE (sRAGE) exists in circulating blood
and extracellular fluids, resulting from either alternative splicing
of RAGE mRNA, called endogenous secretory RAGE (esRAGE),
or neprilysin-mediated proteolytic cleavage of membrane-bound
RAGE, called cleaved RAGE (cRAGE).
12,13
Whatever its source,
sRAGE exerts cytoprotective properties against the action of AGEs
by acting as a decoy receptor that binds ligands, thus preventing
them from reaching the cell surface of RAGE and exerting their
effects.
14
The hyperglycaemia-induced oxidative stress and pro-
inflammatory cytokines, such as tumour necrosis factor (TNF-
α
),
have a share in the endothelial dysfunction seen in diabetic vascular
complications.
15
In addition, both AGEs and TNF-
α
were shown to
enhance RAGE expression in human vascular endothelial cells via
activation of the p65/p50 complex of nuclear factor kappa-B.
16
Our study aimed to measure serum sRAGE and TNF-
α
as well as
plasma lipid peroxidation products (TBARS) in females with type 2
diabetes presenting with vascular complications, and to correlate
them with type of vascular complications.