NFκB and Its Inhibitor IκB in Relation to Type 2 Diabetes and Its Microvascular and Atherosclerotic Complications
Introduction
Diabetic nephropathy (DN) is the major cause of chronic renal failure in patients with diabetes mellitus. Nearly 30% of both type 1 and type 2 diabetic patients develop DN independently of glycemic control. The fact that DN manifests in only a subset of diabetics, together with racial/ethnic differences in the prevalence and family clustering, demonstrates its genetic independence from diabetes mellitus [1]. The risk factors that have been identified for the development of DN in longitudinal and cross-sectional studies include: race, genetic susceptibility, hypertension, hyperglycemia, hyperfiltration, smoking, advanced age, male sex, and a high-protein diet [2].
Nuclear factor κ B (NFκB) is a transcription factor that has been shown to be involved in the regulation of many genes that encode mediators of the immune response, embryo and cell lineage development, cell apoptosis, inflammation, cell cycle, oncogenesis, viral replication, and a variety of autoimmune diseases. Because it is activated by a variety of stimuli, the activation of NFκB is thought to be part of the stress response. These activating stimuli include reactive oxygen species and advanced glycation end products, which are toxic products of nonenzymatic glycation caused by long-term hyperglycemia and oxidative stress. At the cellular level, NFκB is activated through phosphorylation of an inhibitor of NFκB (IκB). Phosphorylated IκB is released from NFκB/IκB complex, allowing the translocation of NFκB molecules into the nucleus. Once in the nucleus, they bind to the consensus sequence (5′-GGGACTTTCC-3′) of various genes, thereby activating their transcription [3, 4]. Recent studies have investigated the role of NFκB in the pathogenesis of various human diseases including neurologic disorders, immune deficiency, carcinogenesis, and atherogenesis. In addition, the possible link between NFκB and the development of insulin resistance and type 2 diabetes has also been suggested [3, 5, 6, 7, 8].
The NFκB transcription factor complex has two alternative DNA binding subunits, nuclear factor kappa B p 105 subunit (NFKB1) and NFKB2. The gene coding for NFKB1 is located on chromosome 4q23-q24 [9]. A polymorphic dinucleotide CA repeat, with 18 described alleles, has been identified close to the coding region of the human NFKB1 gene [10]. This polymorphism has recently been investigated for its role relative to increased susceptibility to type 1 diabetes mellitus (Kolostova et al., article in press) [11]. Encouraged by other studies that also suggest that an increased activation of NFκB is associated with the development of diabetic microvascular complications [12, 13], we examined the CA repeat polymorphism of the NFKB1 gene in relation to diabetic nephropathy.
The gene coding for IκB (NFKBIA) has been mapped to chromosome 14q13, and A/G point variation in the 3′UTR region of NFKBIA has been detected. We also examined single nucleotide polymorphism of the IκB gene, looking for its involvement in the induction or progression of diabetic microvascular complications in the kidney.
In both analyses, we compared the entire group of diabetic patients (both those with and those without renal complications) with healthy controls drawn from Czech and German populations.
In addition, we also tested NFKBIA polymorphism in a second disease, systemic lupus erythematosus (SLE), to confirm or refute a specific association between NFκB and diabetic complications or diabetes itself.
Section snippets
Subjects
The study of polymorphisms in the NFKBIA and NFKB1 genes involved 395 persons consisting of 246 diabetic patients and 159 control subjects. All subjects were of Caucasian descent and lived in either the Czech Republic or Germany.
The group of diabetic patients, most of whom were type 2 diabetics (n = 211), were subdivided into three groups based on their renal status. The first group of patients (n = 50) included persons with nondiabetic renal disease (NDRD). Diseases in this group included
Inhibitor of NFKBIA
Our study used PCR-based genotyping to investigate single-nucleotide polymorphism (A→G) in the 3′-UTR region of the NFKBIA gene in an attempt to access its possible role in the development or progression of DN in diabetic patients.
To determine whether this possible association is related to just nephropathy we compared diabetic patients with renal disease (n = 117) with those diabetic patients without renal disease (n = 78). We found no significant differences in allele or genotype frequencies
Discussion
In this study we performed genetic analyses of two genes encoding NFKB1 and its inhibitor (NFKBIA) in patients with type 2 diabetes mellitus and SLE. The patients came from three central-European Caucasian populations. More than 200 type 2 diabetic patients, having had diabetes for at least 15 years, were tested. The diabetic patients were divided into a group of patients without complications, a group of patients with diabetic microvascular (DN) complications, and a group with macrovascular
Acknowledgments
This study was financially supported by the Research Program of the Czech Ministry of Education and Youth: Identification code: MSM 0021620814: Prevention, diagnostics and therapy of diabetes mellitus, metabolic and endocrine damage of organism. D. Hohenadel received a travel grant from the Federal Ministry of Education and Research, Germany (Project number: CZE 03/014).
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