Transactivation of RAGE mediates angiotensin-induced inflammation and atherogenesis

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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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.

Original languageEnglish
Pages (from-to)406-421
Number of pages16
JournalJournal of Clinical Investigation
Volume129
Issue number1
DOIs
Publication statusPublished - 2 Jan 2019

Cite this

Pickering, R. J., Tikellis, C., Rosado, C. J., Tsorotes, D., Dimitropoulos, A., Smith, M., Huet, O., Seeber, R. M., Abhayawardana, R., Johnstone, E. K. M., Golledge, J., Wang, Y., Jandeleit-Dahm, K. A., Cooper, M. E., Pfleger, K. D. G., & Thomas, M. C. (2019). Transactivation of RAGE mediates angiotensin-induced inflammation and atherogenesis. Journal of Clinical Investigation, 129(1), 406-421. https://doi.org/10.1172/JCI99987