title: Angiotensin-(1-7) modulates renal vascular resistance through inhibition of p38 mitogen-activated protein kinase in apolipoprotein E-deficient mice.
abstract: Apolipoprotein E-deficient (apoE(-/-)) mice fed on Western diet are characterized by increased vascular resistance and atherosclerosis. Previously, we have shown that chronic angiotensin (Ang)-(1-7) treatment ameliorates endothelial dysfunction in apoE(-/-) mice. However, the mechanism of Ang-(1-7) on vasoconstrictor response to Ang II is unknown. To examine Ang-(1-7) function, we used apoE(-/-) and wild-type mice fed on Western diet that were treated via osmotic minipumps either with Ang-(1-7) (82 μg/kg per hour) or saline for 6 weeks. We show that Ang II-induced renal pressor response was significantly increased in apoE(-/-) compared with wild-type mice. This apoE(-/-)-specific response is attributed to reactive oxygen species-mediated p38 mitogen-activated protein kinase activation and subsequent phosphorylation of myosin light chain (MLC(20)), causing renal vasoconstriction. Here, we provide evidence that chronic Ang-(1-7) treatment attenuated the renal pressor response to Ang II in apoE(-/-) mice to wild-type levels. Ang-(1-7) treatment significantly decreased renal inducible nicotinamide adenine dinucleotide phosphate subunit p47phox levels and, thus, reactive oxygen species production that in turn causes decreased p38 mitogen-activated protein kinase activity. The latter has been confirmed by administration of a specific p38 mitogen-activated protein kinase inhibitor SB203580 (5 μmol/L), causing a reduced renal pressor response to Ang II in apoE(-/-) but not in apoE(-/-) mice treated with Ang-(1-7). Moreover, Ang-(1-7) treatment had no effect in Mas(-/-)/apoE(-/-) double-knockout mice confirming the specificity of Ang-(1-7) action through the Mas-receptor. In summary, Ang-(1-7) modulates vascular function via Mas-receptor activation that attenuates pressor response to Ang II in apoE(-/-) mice by reducing reactive oxygen species-mediated p38 mitogen-activated protein kinase activity.
authors.affiliation: Department of Nephrology, Medical Faculty, Heinrich-Heine University, Moorenstr. 5, 40225 Düsseldorf, Germany. johannes.stegbauer@med.uni-duesseldorf.de.
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Potthoff
authors.forename: Michael
authors.initials: M
authors.lastname: Fähling
authors.forename: Tilman
authors.initials: T
authors.lastname: Clasen
authors.forename: Susanne
authors.initials: S
authors.lastname: Mende
authors.forename: Bassam
authors.initials: B
authors.lastname: Ishak
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Suvorava
authors.forename: Stefanie
authors.initials: S
authors.lastname: Stamer
authors.forename: Manuel
authors.initials: M
authors.lastname: Thieme
authors.forename: Sema H
authors.initials: SH
authors.lastname: Sivritas
authors.forename: Georg
authors.initials: G
authors.lastname: Kojda
authors.forename: Andreas
authors.initials: A
authors.lastname: Patzak
authors.forename: Lars C
authors.initials: LC
authors.lastname: Rump
authors.forename: Johannes
authors.initials: J
authors.lastname: Stegbauer
mesh_terms: D000803:Angiotensin I / Q000378:metabolism / Q000494:pharmacology*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009281:Naphthalenes / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D012079:Renal Circulation / Q000187:drug effects* / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010671:Phenylurea Compounds
chemical_list: D000803:Angiotensin I; D000804:Angiotensin II; D001057:Apolipoproteins E; D009281:Naphthalenes; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D043562:Receptors, G-Protein-Coupled; D048051:p38 Mitogen-Activated Protein Kinases; C452139:doramapimod; D010671:Phenylurea Compounds; C118790:angiotensin I (1-7)
keywords: angiotensin-(1–7); apolipoprotein E; p38 mitogen-activated protein kinase