Influence of RAGE and aging on CREB and cAMP/CREB-regulated genes in lung tissue

Various signalling pathways can activate the transcription factor CREB with subsequent activation of CREB-regulated genes. In lung tissue the cell surface molecule RAGE (receptor for advanced glycation end-products) is highly expressed and might be involved in the activation (phosphorylation) of CREB and CREB-regulated genes. Moreover, ageing of the lung tissue could affect the CREB pathway. Therefore, we analysed the effect of RAGE and age on the expression and phosphorylation of CREB and selected target genes in lung from young, adult and old (6, 15 and 25 month, respectively) C57B/6 wild-type or RAGE knock out mice. These analyses showed an age-dependent reduction of the CREB and P-CREB protein level, which was independent of RAGE. In the case of CREB protein we determined 5.6 rel.U. ±1.3 in young mice, 5.6 rel.U. ±1.7 in adult mice and 3.9 rel.U. ±1.7 in old mice; P<0.0003 vs. young mice. In this regard, the mRNA expression of the CREB-regulated gene PEPCK1 was also reduced in response to age but not to RAGE, whereas the mRNA expressions of other cAMP/CREB-regulated genes were not altered in parallel with the CREB alterations (for instance CREB1, CREM, EGF). The age-dependent reduction of the CREB protein expression can be supported by cell culture experiments showing a reduced CREB protein level in human lung fibroblasts (WI-38) after replicative senescence. Our results suggest that aging leads to the reduced expression of CREB in lung tissue, in which the senescence of lung cells might play a critical role.