ABSTRACT
Nuclear factor kappa B (NFkappaB) is an important transcription factor that together with its inhibitor (IkappaB) participates in the activation of genes involved in immune responses. We examined the CA repeat polymorphism of the NFKB1 gene (encoding for NFkappaB) and A/G point variation in the 3'UTR region of the nuclear factor kappa B inhibitor alpha (NFKBIA) gene (encoding for IkappaB) in Czech and German patients with type 2 diabetes. The sample consisted of 211 patients, both with and without kidney complications, and 159 controls. Additionally, 152 patients with systemic lupus erythematosus (SLE) were genotyped for NFKBIA polymorphism. We observed a significant increase in the homozygous AA genotype of the NFKBIA gene when compared with the control group (the highest value was in diabetics without diabetic nephropathy [p(c)* = 0.0015, odds ratio = 3.59]). No differences were seen between the SLE and control groups. With regard to the polymorphism of the NFKB1 gene, we did not observe any significant differences between the groups. Since the AA genotype of the NFKBIA gene presents a risk for type 2 diabetes development but not for diabetic nephropathy alone, we believe that the NFkappaB gene polymorphism can influence the pathogenesis of diabetes mellitus and affect its complications. Negative findings relative to other inflammatory autoimmune diseases, such as SLE, suggest a specific relationship between NFkappaB and type 2 diabetes mellitus.
Subject(s)
Atherosclerosis/etiology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Diabetic Nephropathies/etiology , I-kappa B Kinase/genetics , NF-kappa B/genetics , Aged , Capillaries/pathology , Diabetes Mellitus, Type 2/metabolism , Diabetic Nephropathies/epidemiology , Female , Genotype , Humans , Kidney/blood supply , Lupus Erythematosus, Systemic/genetics , Male , Middle Aged , Polymerase Chain Reaction , Polymorphism, GeneticABSTRACT
The risk of diabetic nephropathy is partially genetically determined. Diabetic nephropathy is linked to a gene locus on chromosome 18q22.3-q23. We aimed to identify the causative gene on chromosome 18 and to study the mechanism by which the product of this gene could be involved in the development of diabetic nephropathy. DNA polymorphisms were determined in 135 case (diabetic nephropathy) and 107 control (diabetes without nephropathy) subjects. The effect of carnosine on the production of extracellular matrix components and transforming growth factor-beta (TGF-beta) after exposure to 5 and 25 mmol/l d-glucose was studied in cultured human podocytes and mesangial cells, respectively. A trinucleotide repeat in exon 2 of the CNDP1 gene, coding for a leucine repeat in the leader peptide of the carnosinase-1 precursor, was associated with nephropathy. The shortest allelic form (CNDP1 Mannheim) was more common in the absence of nephropathy (P = 0.0028, odds ratio 2.56 [95% CI 1.36-4.84]) and was associated with lower serum carnosinase levels. Carnosine inhibited the increased production of fibronectin and collagen type VI in podocytes and the increased production of TGF-beta in mesangial cells induced by 25 mmol/l glucose. Diabetic patients with the CNDP1 Mannheim variant are less susceptible for nephropathy. Carnosine protects against the adverse effects of high glucose levels on renal cells.
Subject(s)
Carnosine/physiology , Diabetic Nephropathies/prevention & control , Dipeptidases/genetics , Leucine , Repetitive Sequences, Amino Acid , Aged , Carnosine/pharmacology , Cells, Cultured , Diabetes Mellitus, Type 1 , Diabetes Mellitus, Type 2 , Diabetic Nephropathies/genetics , Dipeptidases/blood , Female , Gene Expression , Genetic Predisposition to Disease , Glucose/pharmacology , Humans , Kidney/chemistry , Male , Middle Aged , RNA, Messenger/analysis , Sequence AlignmentABSTRACT
Diabetic nephropathy (DN) is a common complication of diabetes types 1 and 2. One of the hallmarks of DN is the development of mesangial expansion, which occurs through accumulation of extracellular matrix (ECM) components. Altered local gene expression of humoral factors (eg, transforming growth factor-b, connective tissue growth factor, and platelet-derived growth factor) can lead to increased production of ECM components (eg, fibronectin and collagen IV) or decreased degradation through matrix metalloproteinases (eg, MMP-1, MMP-2). In recent years, new techniques for examination of gene expression have been developed. Because of their large scale and high-throughput character, it is now possible to examine differential gene expression in a large number of samples. This paper provides an overview of techniques used and results obtained in studies of DN. Newly developed concepts of how altered gene expression may affect histomorphologic features or clinical symptoms are also discussed.
