Association of intercellular adhesion molecule 1 (ICAM1) with diabetes and diabetic nephropathy

Abstract

Diabetes and diabetic nephropathy are complex diseases affected by genetic and environmental factors. Identification of the susceptibility genes and investigation of their roles may provide useful information for better understanding of the pathogenesis and for developing novel therapeutic approaches. Intercellular adhesion molecule 1 (ICAM1) is a cell surface glycoprotein expressed on endothelial cells and leukocytes in the immune system. The ICAM1 gene is located on chromosome 19p13 within the linkage region of diabetes. In the recent years, accumulating reports have implicated that genetic polymorphisms in the ICAM1 gene are associated with diabetes and diabetic nephropathy. Serum ICAM1 levels in diabetes patients and the icam1 gene expression in kidney tissues of diabetic animals are increased compared to the controls. Therefore, ICAM1 may play a role in the development of diabetes and diabetic nephropathy. In this review, we present genomic structure, variation, and regulation of the ICAM1 gene, summarized genetic and biological studies of this gene in diabetes and diabetic nephropathy and discussed about the potential application using ICAM1 as a biomarker and target for prediction and treatment of diabetes and diabetic nephropathy.

Keywords: diabetic nephropathy; end-stage renal disease; intercellular adhesion molecule 1; type 1 diabetes mellitus; type 2 diabetes mellitus.

FIGURE 1

Genomic DNA structure, variation, and regulation of the ICAM1 gene. The ICAM1 gene is consisted of seven exons and six introns. There are several non-synonymous SNPs, which reside one each in exons 2–6. In the gene promoter, there are CpG islands for methylation and epigenetically silence by histone modifications as well as transcription binding sites for the proteins, including NF-kappaB, NF-kappaB1, STAT3, δCREB, STAT1, STAT1α, and STAT1β. In addition, microRNA (miR-221) in the region of 3′-UTR may down-regulate the ICAM1 gene expression.

FIGURE 2

Genotype distribution of the ICAM1 K469E polymorphism. The genotype distribution of the ICAM1 K469E polymorphism is represented from a genetic association study in Swedish population (Ma et al., 2006). Three genotypes of the ICAM1 K469E polymorphism are shown in as light gray color for K469K, gray for K469E, and dark for E469E. Obviously, the heterozygous index is high compared to the percentage of homozygous and increased from the group of non-diabetic control subjects, to type 1 diabetes (T1D) patients without diabetic nephropathy and the patients with diabetic nephropathy.

FIGURE 3

Possible role of ICAM1 in the development of diabetic nephropathy. Under a diabetic condition with hyperglycemia, the ICAM1 gene transcription in the nuclei is increased and the ICAM1 gene expression on the surface of endothelium cells is up-regulated. ICAM1 protein binding activity with leukocyte adhesion protein-1 (LFA-1) is increased and more lymphocytes from blood are transferred into cells of glomeruli and peritubular capillaries of nephron in kidney. Consequently, serum ICAM1 levels are increased. Injury in kidney glomeruli and tubular is occurred and the proteins are released to urine.