Fructose is metabolized differently than glucose with up to 75% of orally absorbed fructose being metabolized by the liver. Moreover, the key enzyme of fructose metabolism, fructokinase is not feedback regulated by fructose metabolites. Thus, all of the orally absorbed fructose is phosphorylated by fructokinase. Unregulated AbMole Mepiroxol metabolism of fructose causing ATP depletion, oxidative stress and decrease in nitric oxide production has been proposed as one of the mechanisms of fructose-induced increase in blood pressure. Both glucose and fructose are precursors of MG formation and MG is also a well-established trigger for increased oxidative stress through multiple pathways. MG is also a major precursor of the formation of AGEs. The aorta and the kidney of fructose treated rats had significantly elevated MG AbMole 12-O-Tiglylphorbol-13-isobutyrate levels which implicates MG as a factor in hypertension development. The kidney had increased protein expression of renin, which in turn would produce more Ang II and its multiple effects. The increased Ang II may be responsible for the increased a1D receptor expression. The increased Ang II, AT1 and a1D receptors in the aorta signify increased vascular tone. We were not able to harvest enough tissue from the mesenteric artery for western blot and PCR analysis. GSH levels were reduced in the aorta and the kidney of fructose treated rats. GSH plays a central role in the degradation of MG by binding MG and making it available to the glyoxalase enzymes. A reduction in GSH would decrease MG degradation, increase its levels, and set up a vicious cycle. We addressed the possibility that MG was increasing oxidative stress, which has been implicated in the pathogenesis of hypertension. The effect of MG on RAGE has not been reported before. RAGE is currently under intense investigation as a target to prevent diabetic complications. The activation of RAGE by AGEs has been reported to increase two key transcription factors, NF-kB and early growth response-1, and cause oxidative stress. We observed increased RAGE and NF-kB in the aorta and the kidney of fructose treated rats. These results suggest that fructose treatment increases MG levels, which in turn can activate RAGE, which then increases NFkB and oxidative stress. The increased oxidative stress increases expression of Ang II, AT1 and a1D receptors. The increased Ang II in turn can increase NF-kB and oxidative stress and set up a vicious cycle. Our results suggest a possible sequence of molecular events resulting from elevated endogenous MG levels which have been reported in high carbohydrate diet fed animals and in diabetic patients. Metformin is used clinically as an oral anti-diabetic drug in patients with type 2 diabetes. Metformin has multiple effects in vivo. For example, it inhibits mitochondrial respiration and gluconeogenesis in the liver, activates AMP-activated protein kinase, increases insulin sensitivity, antagonizes the action of glucagon and increases fatty acid oxidation. These in vivo antidiabetic actions of metformin can make interpretation of results difficult, making it a less than ideal experimental MG scavenger. Even though the MG scavenging ability of metformin has been studied in specific experiments and reported before, we tested the MG scavenging ability of metformin in cultured vascular smooth muscle cells treated with MG, where multiple in vivo, especially hepatic, actions of metformin do not come into play. We also performed an in vitro MG scavenging assay for metformin. In cultured vascular smooth muscle cells metformin attenuated the increased expression of a1D and AT1 receptors, and Ang II.