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

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

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  • Media type: E-Article
  • Title: Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation
  • Contributor: Philippe, Aurelie [Author]; Kleinau, Gunnar [Author]; Gruner, Jason Jannis [Author]; Wu, Sumin [Author]; Postpieszala, Daniel [Author]; Speck, David [Author]; Heidecke, Harald [Author]; Dowell, Simon J. [Author]; Riemekasten, Gabriela [Author]; Hildebrand, Peter W. [Author]; Kamhieh-Milz, Julian [Author]; Catar, Rusan [Author]; Szczepek, Michal [Author]; Dragun, Duska [Author]; Scheerer, Patrick [Author]
  • Published: Basel: MDPI, [2024]
  • Published in: International Journal of Molecular Sciences ; 23, (2022)
  • Language: English
  • Keywords: endothelin ; angiotensin II type 1 receptor ; AT1R ; G protein-coupled receptors ; auto-antibodies ; systemic sclerosis ; angiotensin
  • Origination:
  • Footnote:
  • Description: The angiotensin II (Ang II) type 1 receptor (AT1R) is involved in the regulation of bloodpressure (through vasoconstriction) and water and ion homeostasis (mediated by interaction withthe endogenous agonist). AT1R can also be activated by auto-antibodies (AT1R-Abs), which areassociated with manifold diseases, such as obliterative vasculopathy, preeclampsia and systemicsclerosis. Knowledge of the molecular mechanisms related to AT1R-Abs binding and associatedsignaling cascade (dys-)regulation remains fragmentary. The goal of this study was, therefore, toinvestigate 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-AT1Rsignaling. AT1R-Abs induced nuclear factor of activated T-cells (NFAT) signaling, which reflectsGq/11 and Gi activation. The impact on cell proliferation was tested in different cell systems, as wellas activation-triggered receptor internalization. Blockwise alanine substitutions were designed topotentially investigate the role of ELs in AT1R-Abs-mediated effects. First, we demonstrate that AngII-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 signalinghas, 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 blockwisealanine 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. Thiscurrent study thus provides extended insights into the molecular action of AT1R-Abs and associatedmechanisms of interrelated pathogenesis.
  • Access State: Open Access
  • Rights information: Attribution (CC BY)