Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation

Aurélie Philippe*, Gunnar Kleinau, Jason Jannis Gruner, Sumin Wu, Daniel Postpieszala, David Speck, Harald Heidecke, Simon J. Dowell, Gabriela Riemekasten, Peter W. Hildebrand, Julian Kamhieh-Milz, Rusan Catar, Michal Szczepek, Duska Dragun, Patrick Scheerer*

*Corresponding author for this work
2 Citations (Scopus)


The angiotensin II (Ang II) type 1 receptor (AT1 R) is involved in the regulation of blood pressure (through vasoconstriction) and water and ion homeostasis (mediated by interaction with the endogenous agonist). AT1 R can also be activated by auto-antibodies (AT1 R-Abs), which are associated with manifold diseases, such as obliterative vasculopathy, preeclampsia and systemic sclerosis. Knowledge of the molecular mechanisms related to AT1 R-Abs binding and associated signaling cascade (dys-)regulation remains fragmentary. The goal of this study was, therefore, to investigate details of the effects of AT1 R-Abs on G-protein signaling and subsequent cell proliferation, as well as the putative contribution of the three extracellular receptor loops (ELs) to Abs-AT1 R signaling. AT1 R-Abs induced nuclear factor of activated T-cells (NFAT) signaling, which reflects Gq/11 and Gi activation. The impact on cell proliferation was tested in different cell systems, as well as activation-triggered receptor internalization. Blockwise alanine substitutions were designed to potentially investigate the role of ELs in AT1 R-Abs-mediated effects. First, we demonstrate that Ang II-mediated internalization of AT1 R is impeded by binding of AT1 R-Abs. Secondly, exclusive AT1 R-Abs-induced Gq/11 activation is most significant for NFAT stimulation and mediates cell proliferation. Interestingly, our studies also reveal that ligand-independent, baseline AT1 R activation of Gi signaling has, in turn, a negative effect on cell proliferation. Indeed, inhibition of Gi basal activity potentiates proliferation triggered by AT1 R-Abs. Finally, although AT1 R containing EL1 and EL3 blockwise alanine mutations were not expressed on the human embryonic kidney293T (HEK293T) cell surface, we at least confirmed that parts of EL2 are involved in interactions between AT1 R and Abs. This current study thus provides extended insights into the molecular action of AT1 R-Abs and associated mechanisms of interrelated pathogenesis.

Original languageEnglish
Article number3984
JournalInternational Journal of Molecular Sciences
Issue number7
Publication statusPublished - 01.04.2022

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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