Genotoxicity of advanced glycation end products: involvement of oxidative stress and of angiotensin II type 1 receptors.
In patients with chronic renal failure, cancer incidence is increased. This may be related to an elevated level of genomic damage, which has been demonstrated by micronuclei formation as well as by comet assay analysis. Advanced glycation end products (AGEs) are markedly elevated in renal failure. In the comet assay, the model AGEs methylglyoxal- and carboxy(methyl)lysine-modified bovine serum albumin (BSA) induced significant DNA damage in colon, kidney, and liver cells. The addition of antioxidants prevented AGE-induced DNA damage, suggesting enhanced formation of reactive oxygen species (ROS). The coincubation with dimethylfumarate (DMF), an inhibitor of NF-kappaB translocation, reduced the genotoxic effect, thereby underscoring the key role of NF-kappaB in this process. One of the genes induced by NF-kappaB is angiotensinogen. The ensuing proteolytic activity yields angiotensin II, which evokes oxidative stress as well as proinflammatory responses. A modulator of the renin-angiotensin system (RAS), the angiotensin II (Ang II) receptor 1 antagonist, candesartan, yielded a reduction of the AGE-induced DNA damage, connecting the two signal pathways, RAS and AGE signaling. We were able to identify important participants in AGE-induced DNA damage: ROS, NF-kappaB, and Ang II, as well as modulators to prevent this DNA damage: antioxidants, DMF, and AT1 antagonists.
Schupp
Nicole
N
Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany. nicole.schupp@toxi.uni-wuerzburg.de
Schinzel
Reinhard
R
Heidland
August
A
Stopper
Helga
H
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D017127:Glycation End Products, Advanced / Q000633:toxicity*; D006801:Humans; D007668:Kidney; D007676:Kidney Failure, Chronic / Q000503:physiopathology*; D008954:Models, Biological; D009153:Mutagens / Q000633:toxicity*; D018384:Oxidative Stress / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D015398:Signal Transduction; D014511:Uremia / Q000503:physiopathology
D017127:Glycation End Products, Advanced; D009153:Mutagens; D044140:Receptor, Angiotensin, Type 1