Oxidative stress-associated rise of hepatic protein glycation increases inflammatory liver injury in uncoupling protein-2 deficient mice.

Mitochondrial dysfunction seems to be intrinsically involved in the pathogenesis of multiple organ failure because of enhanced production of reactive oxygen species and induction of oxidative damage. Chronic oxidative stress in turn causes an accumulation of advanced glycation end products (AGEs). To investigate whether mitochondrial dysfunction-associated oxidative stress leads to increased formation and accumulation of AGE, we studied hepatic glycation in uncoupling protein-2 (UCP2-/-) knockout mice. Using the galactosamine/lipopolysaccharide (G/L)-induced liver injury model, we further tested the hypothesis that a mitochondrial dysfunction-associated increase of hepatic glycation is causative for increased liver injury. Under baseline conditions, UCP2-/- mice showed higher malondialdehyde levels and reduced glutathione/glutathione disulfide ratios as well as significantly higher hepatic levels of AGE and hepatic expression of receptor for AGE (RAGE) when compared with UCP2+/+ mice, indicative for increased oxidative stress and hepatic glycation. Further, livers of G/L-challenged UCP2-/- mice revealed significantly more pronounced tissue injury and were found to express higher levels of AGE and RAGE compared with wild-type mice. Functional blockade of RAGE by application of recombinant RAGE significantly diminished liver damage particularly in UCP2-/- mice. This in turn increased survival from 30% in UCP2+/+ mice to 50% in UCP2-/- mice. In summary, we show for the first time that mitochondrial dysfunction-associated oxidative stress enhances hepatic protein glycation, which aggravates inflammation-induced liver injury. Targeting the AGE/RAGE interaction by the blockade of RAGE might be of therapeutic value for the oxidative stress-exposed liver.