title: The angiotensin II-AT1 receptor stimulates reactive oxygen species within the cell nucleus.
abstract: We and others have reported significant expression of the Ang II Type 1 receptor (AT1R) on renal nuclei; thus, the present study assessed the functional pathways and distribution of the intracellular AT1R on isolated nuclei. Ang II (1nM) stimulated DCF fluorescence, an intranuclear indicator of reactive oxygen species (ROS), while the AT1R antagonist losartan or the NADPH oxidase (NOX) inhibitor DPI abolished the increase in ROS. Dual labeling of nuclei with antibodies against nucleoporin 62 (Nup62) and AT1R or the NADPH oxidase isoform NOX4 revealed complete overlap of the Nup62 and AT1R (99%) by flow cytometry, while NOX4 was present on 65% of nuclei. Treatment of nuclei with a PKC agonist increased ROS while the PKC inhibitor GF109203X or PI3 kinase inhibitor LY294002 abolished Ang II stimulation of ROS. We conclude that the Ang II-AT1R-PKC axis may directly influence nuclear function within the kidney through a redox sensitive pathway.
authors.affiliation: The Hypertension and Vascular Research Center, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: Karl D
authors.initials: KD
authors.lastname: Pendergrass
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Gwathmey
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Michalek
authors.forename: Jason M
authors.initials: JM
authors.lastname: Grayson
authors.forename: Mark C
authors.initials: MC
authors.lastname: Chappell
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007211:Indoles; D008301:Maleimides; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D011493:Protein Kinase C; D019808:Losartan; C070515:bisindolylmaleimide I