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Medientyp:
E-Artikel
Titel:
Angiotensin-(1–7) Modulates Renal Vascular Resistance Through Inhibition of p38 Mitogen-Activated Protein Kinase in Apolipoprotein E–Deficient Mice
Beteiligte:
Potthoff, Sebastian A.;
Fähling, Michael;
Clasen, Tilman;
Mende, Susanne;
Ishak, Bassam;
Suvorava, Tatsiana;
Stamer, Stefanie;
Thieme, Manuel;
Sivritas, Sema H.;
Kojda, Georg;
Patzak, Andreas;
Rump, Lars C.;
Stegbauer, Johannes
Beschreibung:
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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
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), 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.
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