Soluble RAGE but not endogenous secretory RAGE is associated with albuminuria in patients with type 2 diabetes

Aims

Type 2 diabetes is characterised by increased plasma concentrations of pro-inflammatory cytokines such as tumour necrosis factor – alpha; TNF-α] and soluble forms of adhesion molecules involved in leukocyte – endothelial interactions. These molecules are synthesised as transmembrane proteins and the plasma soluble forms are generated by ectodomain cleavage from the cell surface by members of the ADAM a disintegrin and metalloproteinase] proteinase family. We hypothesised that plasma low density lipoprotein LDL] from subjects with Type 2 diabetes would influence in vitro monocytic ADAM and matrix metalloproteinase MMP] gene expression differently compared to control LDL.

Methods

We examined relative mRNA expression by real time PCR in a monocytic cell line THP-1] cultured for 4, 8 and 24 hrs with human plasma LDL derived from subjects with n = 5] or without n = 4] Type 2 diabetes. Gene expression for MMP-1 and 9, and ADAM – 8, 15, 17 and 28 was studied.

Results

Type 2 diabetes LDL significantly increased gene expression of MMP – 1 p < 0.01] MMP – 9 p < 0.001], and ADAM 17 p < 0.05], – 28 p < 0.01] and – 15 p < 0.01] compared to control LDL. Type 2 diabetes LDL had disparate effects on inhibitors of MMP.

Conclusion

These data suggest that Type 2 diabetes LDL could lead to increased adhesion molecule and TNF alpha cell surface shedding, and vascular plaque instability, by promoting increased expression of ADAM and MMP genes.