الفهرس 
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Abstract
Diabetes mellitus (DM) is one of the most common chronic diseases
associated with high morbidity and mortality, International Diabetes Federation
(IDF) reported that about 424.9 million adults globally had diabetes in 2017 and
this is expected to rise to 628.6 million by 2045 (IDF, 2018).
Type 2 diabetes mellitus (T2DM) is rapidly rising in Egypt where its
prevalence was tripled in the last 2 decades to reach around 15.6% of all adults
above 20 years. DM often leads to multi-systems complications including
nephropathy, cardiomyopathy, retinopathy, neuropathy and others. Diabetic
nephropathy (DN) is a major microvascular complication of diabetes (Alnaggar
et al., 2019).
It has been estimated that more than 40% of people with diabetes will
develop DN, including a significant number who will develop end stage renal
disease (ESRD) requiring renal replacement therapies (Gheith et al., 2016).
The precise cause of DN is poorly understood. Duration of diabetes is one of
the strongest determinants of DN, regardless of ethnicity or type of diabetes.
Other risk factors include hyperglycemia, hypertension, and hyperlipidemia.
However, many individuals develop DN, despite relatively modest
hyperglycemia, and some individuals with many years of prolonged
hyperglycemia never develop nephropathy so genetic factors seem to determine
individual risk for development and progression of DN (Alvarez and DiStefano,
2013).
Introduction
2
Tumor necrosis factor alpha (TNF-α), also known as cachectin and, is the
prototypic ligand of the TNF superfamily (Idriss and Naismith, 2000). It is a
pleiotropic molecule that plays a central role in inflammation, immune system
development, apoptosis, and lipid metabolism (Hehlgans & Pfeffer, 2005; Chen
et al, 2009; Salek-Ardakani & Croft, 2010; Van Herreweghe et al, 2010).
TNF-𝛼 is produced by activated monocytes-macrophages and also by activated
native kidney cells (glomerular mesangial, epithelial and endothelial cells, and
tubular epithelial cells) (Navarro-González et al, 2011).
The multiple actions of TNF-α are mediated by specific cell surface
receptors. Binding of TNF-α to its receptors activates a number of signal
transduction pathways that result in the expression of a variety of transcription
factors, cytokines, growth factors, receptors, cell adhesion molecules, mediators
of inflammatory processes and acute-phase proteins. Furthermore, the binding of
TNF-α to a cell surface receptor results in intracellular metabolic changes that
mediate apoptotic and necrotic cell death (Sedger and McDermott, 2014).
TNF-α has been implicated in several diseases affecting glomerular function,
including crescentic glomerulonephritis, lupus nephritis, and idiopathic
membranous nephropathy, acute kidney injuries, and podocyte damage in
Alport’s syndrome. TNF signaling has also been implicated in the progression of
DN (Abkhezr et al, 2015).
As a pleiotropic cytokine, TNF-𝛼 exerts multiple effects and it can contribute
to the development of DN through several mechanisms, including reduction of
the glomerular blood flow and glomerular filtration rate, vasoconstriction
induced by increased endothelin-1 production, and disruption of the glomerular
filtration barrier which is mediated by the interaction with the intercellular
Introduction
3
junctions and leads to proteinuria. Increased production of TNF-𝛼 can also
produce oxidative stress, through the activation of nicotinamide adenine
dinucleotide phosphate (NADPH) in mesangial cells. Finally, TNF-𝛼 appears to
have a direct apoptotic and cytotoxic effect on glomerular cells (Lampropoulou
et al., 2014).
Polymorphisms in the 5’ regulatory region of the TNF- 𝛼 gene have been
correlated with many infectious and inflammatory diseases. The association of
polymorphisms of TNF- 𝛼 gene -863C/A (rs1800630) and -1031T/C (rs1799964)
are associated with many inflammatory diseases like asthma, Crohn’s, gout, and
systemic lupus erythromatosis (SLE) (Qidwai and Khan, 2011).
Very little studies had examined the association between the −1031T/C
(rs1799964) and −863C/A (rs1800630) polymorphisms of the promoter region of
TNF-𝛼 gene with DN, so the current study aimed at investigating the association
between -863C/A (rs1800630) and -1031T/C (rs1799964) polymorphisms in
TNF- α gene with DN among subjects with T2DM.
Aim of the Work