Fibrosis is an important component of large conduit artery disease in hypertension. The endogenous tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) has anti-inflammatory and anti-fibrotic effects in the heart and kidney. However, it is not known whether Ac-SDKP has an anti-inflammatory and anti-fibrotic effect on conduit arteries such as the aorta. We hypothesize that in Ang II-induced hypertension Ac-SDKP prevents aortic fibrosis and that this effect is associated with decreased protein kinase C (PKC) activation, leading to reduced oxidative stress and inflammation and a decrease in the pro-fibrotic cytokine, transforming growth factor-1 (TGF-1), and phosphorylation of its second messenger Smad2. To test this hypothesis we used rats with Ang II-induced hypertension and treated with either vehicle or Ac-SDKP. In this hypertensive model we found an increased collagen deposition and collagen type I and III mRNA expression in the aorta. These changes were associated with increased PKC activation, oxidative stress, intracellular adhesion molecules-1 (ICAM-1) mRNA expression, and macrophage infiltration. TGF-1 expression and Smad2 phosphorylation also increased. Ac-SDKP prevented these effects without decreasing blood pressure or aortic hypertrophy. Ac-SDKP also enhanced expression of the inhibitory Smad7. These data indicate that in Ang II-induced hypertension, Ac-SDKP has an aortic anti-fibrotic effect. This effect may be due in part to inhibition of PKC activation, which in turn could reduce oxidative stress, ICAM-1 expression and macrophage infiltration. Part of the effect of Ac-SDKP could also be due to reduced expression of the pro-fibrotic cytokine TGF-1 and inhibition of Smad-2 phosphorylation.