Angiotensin-(1–7) prevents radiation-induced inflammation in rat primary astrocytes through regulation of MAP kinase signaling

Abstract

About 500,000 new cancer patients will develop brain metastases in 2013. The primary treatment modality for these patients is partial or whole brain irradiation which leads to a progressive, irreversible cognitive impairment. Although the exact mechanisms behind this radiation-induced brain injury are unknown, neuroinflammation in glial populations is hypothesized to play a role. Blockers of the renin-angiotensin system (RAS) prevent radiation-induced cognitive impairment and modulate radiation-induced neuroinflammation. Recent studies suggest that RAS blockers may reduce inflammation by increasing endogenous concentrations of the anti-inflammatory heptapeptide angiotensin-(1–7) [Ang-(1–7)]. Ang-(1–7) binds to the AT(1–7) receptor and inhibits MAP kinase activity to prevent inflammation. This study describes the inflammatory response to radiation in astrocytes characterized by radiation-induced increases in (i) IL-1β and IL-6 gene expression; (ii) COX-2 and GFAP immunoreactivity; (iii) activation of AP-1 and NF-κB transcription factors; and (iv) PKCα, MEK, and ERK (MAP kinase) activation. Treatment with U-0126, a MEK inhibitor, demonstrates that this radiation-induced inflammation in astrocytes is mediated through the MAP kinase pathway. Ang-(1–7) inhibits radiation-induced inflammation, increases in PKCα, and MAP kinase pathway activation (phosphorylation of MEK and ERK). Additionally Ang-(1–7) treatment leads to an increase in dual specificity phosphatase 1 (DUSP1). Furthermore, treatment with sodium vanadate (Na3VO4), a phosphatase inhibitor, blocks Ang-(1–7) inhibition of radiation-induced inflammation and MAP kinase activation, suggesting that Ang-(1–7) alters phosphatase activity to inhibit radiation-induced inflammation. These data suggest that RAS blockers inhibit radiation-induced inflammation and prevent radiation-induced cognitive impairment not only by reducing Ang II but also by increasing Ang-(1–7) levels.