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.