title: Angiotensin II-induced genomic damage in renal cells can be prevented by angiotensin II type 1 receptor blockage or radical scavenging.
abstract: Hypertensive patients exhibit elevated cancer incidence, especially of cancers of the kidney. Elevated levels of ANG II, the active peptide of the renin-angiotensin system, regulating blood pressure and cardiovascular homeostasis, are known to cause hypertension and kidney diseases. There is evidence that ANG II is an activator of NAD(P)H oxidase, leading to the formation of free radicals, which are known to participate in the induction of DNA damage. This study was undertaken to characterize ANG II-induced DNA damage. DNA damage was measured by comet assay and micronucleus frequency test. Incubation of pig kidney cells (LLC-PK(1)) in vitro with ANG II concentrations between 85 and 340 nM led to a 6- to 15-fold increase of DNA damage compared with the control as revealed by comet assay analysis. Micronuclei were induced about fourfold compared with the control in pig and rat kidney cells (LLC-PK(1), NRK) and in human promyelocytic cells (HL-60). ANG II-induced DNA damage could be prevented by coincubation with the ANG II type 1 receptor blocker candesartan and the antioxidants N-acetylcysteine and alpha-tocopherol. The ANG II type 2 receptor antagonist PD123319 could not reduce ANG II-induced DNA damage. Measurement of reactive oxygen species (ROS) by flow cytometry showed an enhanced formation after exposure to ANG II and a reduction of ROS after candesartan, N-acetylcysteine, and alpha-tocopherol. The present findings support our hypothesis that ANG II causes DNA damage via ANG II type 1 receptor binding and subsequent formation of oxidative stress.
authors.affiliation: Institute of Pharmacology and Toxicology,University of Würzburg, Würzburg, Germany. nicole.schupp@toxi.uni-wuerzburg.de
authors.forename: Nicole
authors.initials: N
authors.lastname: Schupp
authors.forename: Ursula
authors.initials: U
authors.lastname: Schmid
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Rutkowski
authors.forename: Ursula
authors.initials: U
authors.lastname: Lakner
authors.forename: Nilesh
authors.initials: N
authors.lastname: Kanase
authors.forename: August
authors.initials: A
authors.lastname: Heidland
authors.forename: Helga
authors.initials: H
authors.lastname: Stopper
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002460:Cell Line; D002467:Cell Nucleus / Q000648:ultrastructure; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016166:Free Radical Scavengers; D007093:Imidazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; D024502:alpha-Tocopherol; C081643:candesartan; D000111:Acetylcysteine