Role of the receptor for advanced glycation endproducts (RAGE) in retinal vasodegenerative pathology during diabetes in mice

Aims/hypothesis: The receptor for AGEs (RAGE) is linked to proinflammatory pathology in a range of tissues. The objective of this study was to assess the potential modulatory role of RAGE in diabetic retinopathy. Methods: Diabetes was induced in wild-type (WT) and Rage mice (also known as Ager mice) using streptozotocin while non-diabetic control mice received saline. For all groups, blood glucose, HbA and retinal levels of methylglyoxal (MG) were evaluated up to 24\ua0weeks post diabetes induction. After mice were killed, retinal glia and microglial activation, vasopermeability, leucostasis and degenerative microvasculature changes were determined. Results: Retinal expression of RAGE in WT diabetic mice was increased after 12\ua0weeks (p < 0.01) but not after 24\ua0weeks. Rage mice showed comparable diabetes but accumulated less MG and this corresponded to enhanced activity of the MG-detoxifying enzyme glyoxalase I in their retina when compared with WT mice. Diabetic Rage mice showed significantly less vasopermeability, leucostasis and microglial activation (p < 0.05–0.001). Rage mice were also protected against diabetes-related retinal acellular capillary formation (p < 0.001) but not against pericyte loss. Conclusions/interpretation: Rage in diabetic mice is protective against many retinopathic lesions, especially those related to innate immune responses. Inhibition of RAGE could be a therapeutic option to prevent diabetic retinopathy

Short tandem repeat (STR) haplotypes in HLA: an integrated 50-kb STR/linkage disequilibrium/gene map between the RING3 and HLA-B genes and identification of STR haplotype diversification in the class III region

We present a dense STR/linkage disequilibrium(LD)/gene map between the RING3 and HLA-B loci, reference allelic sizes on the most prevalent HLA haplotypes and their allelic frequencies in pedigree founders. This resource will facilitate LD, evolution and gene mapping studies, including comparisons of HLA and STR haplotypes and identification of HLA recombinants. The map was constructed by testing novel and previously reported STRs using a panel of 885 individuals in 211 families and 60 DNA samples from cell lines and bone marrow donors homozygous in the HLA-A, -B and -DR loci selected from over 15 000 entries into the registry of Swedish bone marrow donors. We have also analysed the variability of STR alleles/haplotypes on the most prevalent HLA haplotypes to identify STRs useful for fine mapping of disease genes in the region previously implicated in susceptibility to many disorders. The analysis of 40 HLA-A*01, B*0801, DRB1*03011, DQB1*0201 haplotypes in homozygous donors showed a surprising stability in 23 STRs between the class II recombination hot spot and HLA-B, with the average of 1.9% (16/838) variant alleles. However, 40% variant alleles were found at the D6S2670 locus in intron 19 of the tenascin-X gene both in the families and homozygous donors. The nucleotide sequence analysis of this STR showed a complex polymorphism consisting of tetra- (CTTT)8-18 and penta-nucleotide (CTTTT)1-2 repeats, separated by an intervening non-polymorphic sequence of 42 bp. The HLA-A1, B*0801, DRB1*03011, DQB1*0201 haplotypes had five (CTTT)14-18/(CTTTT)2 variants with a predominant (CTTT)16 allele, implicating the tetranucleotide component as the source of this ancestral haplotype diversification, which may be due to the location of D6S2670 in the region of the highest GC content in the human MH