gms | German Medical Science

28. Wissenschaftlicher Kongress der Deutschen Hochdruckliga

24. bis 27.11.2004, Hannover

Genotoxicity of AGEs: Protective Effects of Modulators of the Renin-Angiotensin System

Gentoxizität fortgeschritten glykierter Proteine: Protektive Wirkung von Modulatoren des Renin-Angiotensin-Systems

Meeting Abstract (Hypertonie 2004)

Suche in Medline nach

  • presenting/speaker N. Schupp - Institute of Pharmacology and Toxicology, Department of Internal Medicine, Würzburg, D
  • presenting/speaker U. Lakner - Institute of Pharmacology and Toxicology, Department of Internal Medicine, Würzburg, D
  • presenting/speaker U. Heidland - Institute of Pharmacology and Toxicology, Department of Internal Medicine, Würzburg, D
  • presenting/speaker H. Stopper - Institute of Pharmacology and Toxicology, Department of Internal Medicine, Würzburg, D

Hypertonie 2004. 28. Wissenschaftlicher Kongress der Deutschen Hochdruckliga. Hannover, 24.-27.11.2004. Düsseldorf, Köln: German Medical Science; 2005. Doc04hochP12

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/hoch2004/04hoch012.shtml

Veröffentlicht: 10. August 2005

© 2005 Schupp et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

In patients with chronic renal failure cardiovascular complications and cancer incidence are enhanced, which may be partly related to an elevated genomic damage, as has been demonstrated by investigations of DNA-repair, micronuclei formation and comet-assay analysis. Advanced glycation end products (AGEs) are markedly elevated in renal failure.

We could show in the comet-assay that the AGEs methylglyoxal- and carboxymethyllysine-BSA could induce significant DNA damage in kidney tubule cells (LLC-PK1 cells). Pre-treatment of the cells with proteases abolished the AGE-induced comet formation suggesting that the observed genotoxicity may be receptor-mediated and that proteases inactivated the external domain of the cellular receptor for AGEs (RAGE).

Binding of AGEs to RAGE is known to lead to enhanced formation of reactive oxygen species and subsequent activation of NF-κB. In our system coincubation with dimethylfumarate, an inhibitor of NF-κB translocation, reduced the genotoxic effect underlining its key role in this process. One of the genes induced by NF-κB is angiotensinogen. Following proteolytic activity yields angiotensin II which, in our studies, generates DNA damage in physiological concentrations probably via the generation of oxidative stress.

We identified the components of the renin-angiotensin system (RAS) in LLC-PK1 cells. Subsequently we investigated the effects of modulators of RAS, angiotensin II receptor 1 antagonists (AT1-A) and angiotensin I converting enzyme inhibitors (ACE-I). First results of the incubation of LLC-PK1 with the AT1-A candesartan and the ACE-I ramiprilat showed a significant reduction of the AGE-induced DNA-damage.