The Receptor for Advanced Glycation End-products (RAGE) belongs to the family of pattern-recognition
receptors and is significantly involved in the molecular mechanisms mediating pro-inflammatory
action of hyperglycemia in diabetes. The aim of the current study was to elucidate
the possible functional impact of the genetic variability in the AGER gene constituting previously identified risk haplotype for diabetic nephropathy (−429C/-374T/2184G)
by testing the haplotype-specific effect on the AGER gene transcriptional activity in vitro. Promotor and intron 8 constructs carrying respective substitutions were amplified
and cloned into pGL3-Basic reporter vector and subsequently used for transfection
of HEK293 cells. Following 48hrs incubation in either normo- (5 mM/L) or hyperglycemic
(25 mM/L) culture medium luciferase activity was measured to assess transcriptional
efficiency. Risk haplotype was associated with the highest transcriptional activity
in hyperglycemia and greatest relative increase of activity between normo- and hyperglycemia
conditions (approx. 3-times). We conclude that ascertained functional differences
in the regulatory regions of the AGER gene might have significant consequences for the development of hyperglycemia-related
pathology in diabetics.
diabetes - autoimmunity - receptors - signal transduction - cardiovascular risk management
- cardiovascular incidences
