title: Angiotensin II induces DNA damage via AT1 receptor and NADPH oxidase isoform Nox4.
abstract: Epidemiological studies revealed increased renal cancer incidences and higher cancer mortalities in hypertensive individuals. Activation of the renin-angiotensin-aldosterone system leads to the formation of reactive oxygen species (ROS). In vitro, in renal cells, and ex vivo, in the isolated perfused mouse kidney, we could show DNA-damaging potential of angiotensin II (Ang II). Here, the pathway involved in the genotoxicity of Ang II was investigated. In kidney cell lines with properties of proximal tubulus cells, an activation of NADPH oxidase and the production of ROS, resulting in the formation of DNA strand breaks and micronuclei induction, was observed. This DNA damage was mediated by the Ang II type 1 receptor (AT1R), together with the G protein G   (   α-q/11   )   . Subsequently, phospholipase C (PLC) was activated and intracellular calcium increased. Both calcium stores of the endoplasmic reticulum and extracellular calcium were involved in the genotoxicity of Ang II. Downstream, a role for protein kinase C (PKC) could be detected, because its inhibition hindered Ang II from damaging the cells. Although PKC was activated, no involvement of its known target, the NADPH oxidase isoform containing the Nox2 subunit, could be found, as tested by small-interfering RNA down-regulation. Responsible for the DNA-damaging activity of Ang II was the NADPH oxidase isoform containing the Nox4 subunit. In summary, in kidney cells the DNA-damaging activity of Ang II depends on an AT1R-mediated activation of NADPH oxidase via PLC, PKC and calcium signalling, with the NADPH subunit Nox4 playing a crucial role.
authors: Institute of Pharmacology and Toxicology, Versbacher Str. 9, University of Würzburg,   97078 Würzburg, Germany.
authors: Gholamreza
authors: G
authors: Fazeli
authors: Helga
authors: H
authors: Stopper
authors: Reinhard
authors: R
authors: Schinzel
authors: Chih-Wen
authors: CW
authors: Ni
authors: Hanjoong
authors: H
authors: Jo
authors: Nicole
authors: N
authors: Schupp
mesh_terms: D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D002118:Calcium; D020013:Calcium Signaling; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects*; D015536:Down-Regulation; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D011493:Protein Kinase C; D010738:Type C Phospholipases; D002118:Calcium