title: Angiotensin-(1-7)-angiotensin-converting enzyme 2 attenuates reactive oxygen species formation to angiotensin II within the cell nucleus.
abstract: The angiotensin (Ang) type 1 receptor (AT(1)R) is highly expressed on renal nuclei and stimulates reactive oxygen species (ROS). It is not known whether other functional components of the Ang system regulate the nuclear Ang II-AT(1)R ROS pathway. Therefore, we examined the expression of Ang receptors in nuclei isolated from the kidneys of young adult (1.5 years) and older adult (3.0 to 5.0 years) sheep. Binding studies in renal nuclei revealed the AT(2)R as the predominant receptor subtype ( approximately 80%) in young sheep, with the Ang-(1-7) (AT(7)R; Mas protein) and AT(1)R antagonists competing for the remaining sites. Conversely, in older sheep, the AT(1)R accounted for approximately 85% of nuclear sites, whereas the Ang type 2 receptor and AT(7)R subtypes comprise approximately 20% of remaining sites. Ang II increased nuclear ROS to a greater extent in older (97+/-22%; n=6) versus young animals (7+/-2%; P=0.01; n=4), and this was abolished by an AT(1)R antagonist. The AT(7)R antagonist D-Ala(7)-Ang-(1-7) increased ROS formation to Ang II by approximately 2-fold (174+/-5% versus 97+/-22%; P<0.05) in older adults. Immunoblots of renal nuclei revealed protein bands for the AT(7)R and Ang-converting enzyme 2 (ACE2), which metabolizes Ang II to Ang-(1-7). The ACE2 inhibitor MLN4760 also exacerbated the Ang II-dependent formation of ROS (156+/-15%) and abolished the generation of Ang-(1-7) from Ang II. We conclude that an ACE2-Ang-(1-7)-AT(7)R pathway modulates Ang II-dependent ROS formation within the nucleus, providing a unique protective mechanism against oxidative stress and cell damage.
authors: Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. tgwathme@wfubmc.edu
authors: TanYa M
authors: TM
authors: Gwathmey
authors: Karl D
authors: KD
authors: Pendergrass
authors: Sean D
authors: SD
authors: Reid
authors: James C
authors: JC
authors: Rose
authors: Debra I
authors: DI
authors: Diz
authors: Mark C
authors: MC
authors: Chappell
mesh_terms: D000803:Angiotensin I / Q000378:metabolism*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D007672:Kidney Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011945:Receptors, Angiotensin / Q000378:metabolism; D012756:Sheep; D013997:Time Factors
chemical_list: C486469:2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid; C092006:7-Ala-angiotensin (1-7); D057911:Angiotensin Receptor Antagonists; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010446:Peptide Fragments; D011725:Pyridines; D017382:Reactive Oxygen Species; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C073402:PD 123319; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D000085962:Angiotensin-Converting Enzyme 2; D007930:Leucine; C118790:angiotensin I (1-7); D019808:Losartan