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Transactivation of RAGE mediates angiotensin-induced inflammation and atherogenesis
Raelene J. Pickering, … , Kevin D.G. Pfleger, Merlin C. Thomas
Raelene J. Pickering, … , Kevin D.G. Pfleger, Merlin C. Thomas
Published December 10, 2018
Citation Information: J Clin Invest. 2019;129(1):406-421. https://doi.org/10.1172/JCI99987.
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Research Article Cell biology Vascular biology

Transactivation of RAGE mediates angiotensin-induced inflammation and atherogenesis

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Abstract

Activation of the type 1 angiotensin II receptor (AT1) triggers proinflammatory signaling through pathways independent of classical Gq signaling that regulate vascular homeostasis. Here, we report that the AT1 receptor preformed a heteromeric complex with the receptor for advanced glycation endproducts (RAGE). Activation of the AT1 receptor by angiotensin II (Ang II) triggered transactivation of the cytosolic tail of RAGE and NF-κB–driven proinflammatory gene expression independently of the liberation of RAGE ligands or the ligand-binding ectodomain of RAGE. The importance of this transactivation pathway was demonstrated by our finding that adverse proinflammatory signaling events induced by AT1 receptor activation were attenuated when RAGE was deleted or transactivation of its cytosolic tail was inhibited. At the same time, classical homeostatic Gq signaling pathways were unaffected by RAGE deletion or inhibition. These data position RAGE transactivation by the AT1 receptor as a target for vasculoprotective interventions. As proof of concept, we showed that treatment with the mutant RAGE peptide S391A-RAGE362–404 was able to inhibit transactivation of RAGE and attenuate Ang II–dependent inflammation and atherogenesis. Furthermore, treatment with WT RAGE362–404 restored Ang II–dependent atherogenesis in Ager/Apoe-KO mice, without restoring ligand-mediated signaling via RAGE, suggesting that the major effector of RAGE activation was its transactivation.

Authors

Raelene J. Pickering, Christos Tikellis, Carlos J. Rosado, Despina Tsorotes, Alexandra Dimitropoulos, Monique Smith, Olivier Huet, Ruth M. Seeber, Rekhati Abhayawardana, Elizabeth K.M. Johnstone, Jonathan Golledge, Yutang Wang, Karin A. Jandeleit-Dahm, Mark E. Cooper, Kevin D.G. Pfleger, Merlin C. Thomas

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Figure 5

The AT1 receptor and RAGE form a functional heteromeric complex.

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The AT1 receptor and RAGE form a functional heteromeric complex.
(A) BRE...
(A) BRET saturation curves with AT1-Rluc8 and RAGE-Venus generated 60 minutes after the addition of Ang II or vehicle. (B) Ang II–induced recruitment of β-arrestin2–Venus to AT1-Rluc8 and CCL22-induced recruitment of β-arrestin2–Venus to CCR4-Rluc8 as a control. (C) Ang II–induced recruitment of β-arrestin2–Venus proximal to RAGE-Rluc8 only in the presence of AT1 following exposure to Ang II, and not in the presence of CCR4 following exposure to CCL22. (D) CCL22-induced BRET signal was observed when Gαi-Nluc and Gγ2-Venus were coexpressed in the presence of untagged CCR4, serving as an additional control. (E) Ang II–induced trafficking of RAGE-Rluc8 in the presence of AT1 using markers of specific subcellular compartments. (F) BRET between mCherry-RAGE338–361 and Nluc-AT1 was increased with Ang II. (G) BRET between AT1-Rluc8 and RAGE-Venus was inhibited by mCherry-RAGE338–361. (H) BRET between AT1-Nluc and RAGE-Venus was reduced by Ang II but not affected by mCherry-RAGE362–404. (I) Ang II–mediated proinflammatory signaling in HMEC1 inhibited by RAGE338–361 was rescued by mCherry-RAGE362–404. Data are presented as the mean ± SD. n = 3 (B–D and H), n = 5 (E and F), n = 6–8 (I), or data were combined from 3 independent experiments (A and G). *P < 0.05 versus vehicle or pretreatment or 0 minutes; #P < 0.05 versus other treated conditions. P values were determined by 2-way ANOVA.
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