The angiotensin II (Ang II) type 1 receptor (AT1R) is involved in the regulation of blood
pressure (through vasoconstriction) and water and ion homeostasis (mediated by interaction with
the endogenous agonist). AT1R can also be activated by auto-antibodies (AT1R-Abs), which are
associated with manifold diseases, such as obliterative vasculopathy, preeclampsia and systemic
sclerosis. Knowledge of the molecular mechanisms related to AT1R-Abs binding and associated
signaling cascade (dys-)regulation remains fragmentary. The goal of this study was, therefore, to
investigate details of the effects of AT1R-Abs on G-protein signaling and subsequent cell proliferation,
as well as the putative contribution of the three extracellular receptor loops (ELs) to Abs-AT1R
signaling. AT1R-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 AT1R-Abs-mediated effects. First, we demonstrate that Ang
II-mediated internalization of AT1R is impeded by binding of AT1R-Abs. Secondly, exclusive AT1RAbs-
induced Gq/11 activation is most significant for NFAT stimulation and mediates cell proliferation.
Interestingly, our studies also reveal that ligand-independent, baseline AT1R activation of Gi signaling
has, in turn, a negative effect on cell proliferation. Indeed, inhibition of Gi basal activity potentiates proliferation triggered by AT1R-Abs. Finally, although AT1R 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 AT1R and Abs. This
current study thus provides extended insights into the molecular action of AT1R-Abs and associated
mechanisms of interrelated pathogenesis.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:89091 |
| Date | 17 January 2024 |
| Creators | Philippe, Aurelie, Kleinau, Gunnar, Gruner, Jason Jannis, Wu, Sumin, Postpieszala, Daniel, Speck, David, Heidecke, Harald, Dowell, Simon J., Riemekasten, Gabriela, Hildebrand, Peter W., Kamhieh-Milz, Julian, Catar, Rusan, Szczepek, Michal, Dragun, Duska, Scheerer, Patrick |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 3984 |
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