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Article

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

1
Berlin Institute of Health at Charité—Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, D-10178 Berlin, Germany
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Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Nephrology and Medical Intensive Care, Campus Virchow Klinikum, D-13353 Berlin, Germany
3
Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Cardiovascular Research, D-10117 Berlin, Germany
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Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, D-10117 Berlin, Germany
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Vivantes Humboldt-Klinikum, Department of Urology, D-13509 Berlin, Germany
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CellTrend GmbH, D-14943 Luckenwalde, Germany
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GlaxoSmithKline, Stevenage SG1 2NY, UK
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Priority Area Asthma & Allergy, Research Center Borstel, Airway Research Center North (ARCN), Members of the German Center for Lung Research (DZL), D-23845 Borstel, Germany
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University of Lübeck, University Clinic Schleswig-Holstein, Department of Rheumatology and Clinical Immunology, Campus Lübeck, D-23538 Lübeck, Germany
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Leipzig University, Medical Faculty Leipzig, Institute for Medical Physics and Biophysics, D-04107 Leipzig, Germany
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Berlin Institute of Health at Charité—Universitätsmedizin Berlin, D-10178 Berlin, Germany
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Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Transfusion Medicine, D-10117 Berlin, Germany
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DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, D-13353 Berlin, Germany
*
Authors to whom correspondence should be addressed.
Duska Dragun deceased on 28 December 2020.
Academic Editor: Anastasios Lymperopoulos
Int. J. Mol. Sci. 2022, 23(7), 3984; https://doi.org/10.3390/ijms23073984
Received: 10 March 2022 / Revised: 30 March 2022 / Accepted: 30 March 2022 / Published: 2 April 2022
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 AT1R-Abs-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. View Full-Text
Keywords: angiotensin II type 1 receptor; AT1R; auto-antibodies; G protein-coupled receptors; systemic sclerosis; angiotensin; endothelin angiotensin II type 1 receptor; AT1R; auto-antibodies; G protein-coupled receptors; systemic sclerosis; angiotensin; endothelin
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MDPI and ACS Style

Philippe, A.; Kleinau, G.; Gruner, J.J.; Wu, S.; Postpieszala, D.; Speck, D.; Heidecke, H.; Dowell, S.J.; Riemekasten, G.; Hildebrand, P.W.; Kamhieh-Milz, J.; Catar, R.; Szczepek, M.; Dragun, D.; Scheerer, P. Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation. Int. J. Mol. Sci. 2022, 23, 3984. https://doi.org/10.3390/ijms23073984

AMA Style

Philippe A, Kleinau G, Gruner JJ, Wu S, Postpieszala D, Speck D, Heidecke H, Dowell SJ, Riemekasten G, Hildebrand PW, Kamhieh-Milz J, Catar R, Szczepek M, Dragun D, Scheerer P. Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation. International Journal of Molecular Sciences. 2022; 23(7):3984. https://doi.org/10.3390/ijms23073984

Chicago/Turabian Style

Philippe, Aurélie, 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, and Patrick Scheerer. 2022. "Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation" International Journal of Molecular Sciences 23, no. 7: 3984. https://doi.org/10.3390/ijms23073984

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