Vascular oxidative stress upregulates angiotensin II type I receptors via mechanisms involving nuclear factor kappa B.

Abstract The association of oxidative stress with hypertension is well known. However, a causal role of oxidative stress in hypertension is unclear. Vascular angiotensin II type 1 receptor (AT1R) upregulation is a prominent contributor to pathogenesis of hypertension. However, the mechanisms causing this upregulation are unknown. Oxidative stress is an important regulator of protein expression via activation of transcription factors such as nuclear factor kappa B (NFκB). The present study was carried out to test the hypothesis that oxidative stress contributes to vascular AT1R upregulation via NFκB in human aortic smooth muscle cells (HASMC) and spontaneously hypertensive rats (SHR). HASMC exposed to oxidative stress exhibited a robust increase in AT1R mRNA in HASMC. Furthermore, oxidative stress failed to upregulate AT1Rs in the presence of either an antioxidant catalase or siRNA against p65 subunit of NFκB. To test the role of oxidative stress and NFκB in hypertension, prehypertensive SHR were treated with NFκB inhibitor pyrrolidine dithiocarbamate from 5 weeks to 11-12 weeks of age. At 11-12 weeks of age, SHR exhibited increased NFκB expression, AT1R upregulation and exaggerated Ang II-induced vasoconstriction as compared to age-matched Wistar Kyoto (WKY) rats. PDTC treatment of SHR lowered NFκB expression, normalized AT1R expression and Ang II-induced vasoconstriction. More importantly, PDTC treatment significantly attenuated hypertension development in SHR. In conclusion, vascular oxidative can upregulate AT1R, via mechanisms involving NFκB, and contribute to the development of hypertension.