RAGE ligands stimulate angiotensin II type I receptor (AT1) via RAGE/AT1 complex on the cell membrane

Abstract

The receptor for advanced glycation end-products (RAGE) and the G protein-coupled angiotensin II (AngII) type I receptor (AT1) play a central role in cardiovascular diseases. It was recently reported that RAGE modifies AngII-mediated AT1 activation via the membrane oligomeric complex of the two receptors. In this study, we investigated the presence of the different directional crosstalk in this phenomenon, that is, the RAGE/AT1 complex plays a role in the signal transduction pathway of RAGE ligands. We generated Chinese hamster ovary (CHO) cells stably expressing RAGE and AT1, mutated AT1, or AT2 receptor. The activation of two types of G protein α-subunit, Gq and Gi, was estimated through the accumulation of inositol monophosphate and the inhibition of forskolin-induced cAMP production, respectively. Rat kidney epithelial cells were used to assess RAGE ligand-induced cellular responses. We determined that RAGE ligands activated Gi, but not Gq, only in cells expressing RAGE and wildtype AT1. The activation was inhibited by an AT1 blocker (ARB) as well as a RAGE inhibitor. ARBs inhibited RAGE ligand-induced ERK phosphorylation, NF-κB activation, and epithelial–mesenchymal transition of rat renal epithelial cells. Our findings suggest that the activation of AT1 plays a central role in RAGE-mediated cellular responses and elucidate the role of a novel molecular mechanism in the development of cardiovascular diseases.

Aerobic Exercise Training Reduces Atherogenesis Induced by Low-Sodium Diet in LDL Receptor Knockout Mice

“…For instance, dietary sodium restriction promoted important adverse effects on systemic glycolipid metabolism and vascular injuries, many of which were inhibited by AET, however, we did not examine intracellular signaling pathways that modulate the demonstrated biological responses presented in our study. Previous studies showed a complex crosstalk between the RAAS and the AGE/RAGE axis [53][54][55][56], however, such signaling pathways were not explored and were just inferred in this experimental model as a theoretical basis to support the results from the present study.…”

“…AT1 receptor signaling triggers oxidative stress, inflammatory response, and lipid peroxidation [ 51 , 52 ], which favor the CML generation and RAGE expression in the arterial wall in a positive-feedback loop, as previously demonstrated in sodium restriction [ 8 ]. It has been reported that the interplay between the RAAS signaling pathways and the AGE/RAGE axis sets up an effective positive-feedback loop that promotes arterial dysfunction and injury [ 53 , 54 , 55 ]. In this regard, chronic infusion of ANG II in Sprague–Dawley rats increased plasma and renal concentration of AGE, effects that were antagonized by pyridoxamine, an inhibitor of AGE generation [ 55 ].…”

Characterization of ACE Inhibitors and AT1R Antagonists with Regard to Their Effect on ACE2 Expression and Infection with SARS-CoV-2 Using a Caco-2 Cell Model

“…Therefore, we investigated whether ACE inhibitors (captopril, lisinopril) or AT 1 R antagonists (telmisartan, olmesartan) regulate ACE2 mRNA expression. For that purpose, Caco-2 cells were incubated with increasing drug concentrations for 24 h, 48 h, and 72 h. The selected concentrations are in the range of c max plasma levels in humans [ 17 , 18 , 19 , 20 , 21 , 22 ], high enough to inhibit ACE [ 23 ] or block AT 1 R receptor [ 24 ] and typically used for in vitro experiments [ 25 , 26 , 27 ]. However, there was no concentration-dependent alteration of the ACE2 mRNA expression ( Figure 1 ).…”

RAGE pathway activation and function in chronic kidney disease and COVID-19

“…Moreover, both AGE-induced MAPK activity and epithelial mesenchymal transition (EMT) in rat NRK-52E cells are blocked by treatment with AT1R blockers (e.g., olemesartan, irbesartan, losartan) ( 64 ). In NRK-52E epithelial cells, DIAPH1 is a necessary factor in the production of TGF-β1, type I collagen, profilin1, and α-SMA.…”