Interaction Between the Angiotensin-(1–7) Mas Receptor and the Dopamine D2 Receptor

Abstract

Ang (angiotensin) 1–7 MasR (Mas receptor) and D2R (dopamine D2 receptor) stimulation is coupled to anti-inflammatory responses. In the present work, we investigated the hypothesis that the anti-inflammatory action mediated by both receptors results from MasR-D2R heteromerization. Human monocyte (THP-1) cells differentiated to macrophages and exposed to lipopolysaccharide were employed. Ang (1–7) and the D2R agonist SUM (sumanirole) induced a decrease in proinflammatory IL (interleukin) 6 release in human macrophages exposed to a proinflammatory stimulus. The Ang (1–7)–induced decrease in IL-6 was blocked by the D2R antagonist. Conversely, the SUM induced decrease in IL-6 was prevented by the MasR antagonist and when MasR expression was downregulated, suggesting MasR-D2R interaction. Co-immunoprecipitation assay in THP-1 cells and in human monocyte differentiated macrophages from peripheral blood mononuclear cells confirmed MasR-D2R interaction. To avoid the influence from other receptors, MasR-D2R interaction was characterized in transfected human embryonic kidney 293T cells. Fluorescence resonance energy transfer analysis showed that MasR and D2R formed a constitutive heteromer, which was not modified by their agonists. Ang (1–7) and dopamine stimulated ERK (extracellular signal-regulated kinase) 1/2 and Akt (protein kinase B) phosphorylation only in cells expressing MasR-D2R heteromers, but not in cells expressing each receptor alone. Ang (1–7)–stimulated ERK1/2 and Akt phosphorylation was prevented by D2R blockade while the effect of dopamine was prevented by MasR blockade, reinforcing the fact that MasR-D2R heteromers are involved in ERK1/2 and Akt activation induced by their agonists. Our findings provide new evidence regarding the mechanisms underlying the cross-talk between the Ang (1–7)/MasR axis and the dopaminergic system in response to a proinflammatory process.

Inverse Salt Sensitivity of Blood Pressure Is Associated with an Increased Renin-Angiotensin System Activity

“…In addition to the contribution of the D 2 R in the maintenance of homeostasis by the regulation of renal sodium transport and BP, another protective action of the D 2 R via the suppression of reactive oxygen species (ROS) production and inflammation [ 44 , 59 , 60 , 72 , 79 , 80 , 89 , 90 , 91 , 92 , 93 , 100 , 101 , 102 ]. This occurs, in part, through heterodimerization with receptors and proteins such as DJ1 which prevents the degradation of the antioxidant NRF2 [ 78 ].…”

“…We have shown that NRF2 is lower in individuals with ISS than individuals with SR under low, but not high, sodium concentration, which could be at least one mechanism why a decrease in the expression of D 2 R increases inflammation [ 57 , 80 ]. uRPTCs from ISS individuals have reduced NRF2 expression, as well as reduced expression of several downstream genes of NRF2, such as superoxide dismutase (SOD2), and CTCF [ 101 ]. CTCF stimulates the D 2 R so that the reduced expression of CTCF in ISS may be part of the mechanism that decreases D 2 R expression.…”

“…We have reported 14 additional micro RNAs to be associated with ISS [ 33 ]. Among the 14 studied miRNAs is miRNA 30c-1-3p which is pro-inflammatory [ 115 ]; its role in the inflammation that occurs with decreased D 2 R expression [ 44 , 57 , 59 , 60 , 89 , 93 , 100 , 101 , 102 ] remains to be determined.…”

Diabetes, Metformin and the Clinical Course of Covid-19: Outcomes, Mechanisms and Suggestions on the Therapeutic Use of Metformin

“…However, S680 phosphorylation of ACE2 may also slow the degradation of ACE2, potentially increasing its concentration. Plasma ACE2 promotes antihypertensive and anti-inflammatory effects via the production of angiotensin-(1–7) which then acts via the Mas receptor ( Rodrigues Prestes et al, 2017 ; Rukavina Mikusic et al, 2021 ). This provides a further possible route through which metformin might reduce the pathology of Covid-19 infection ( Vial et al, 2019 ).…”

The Arcuate Nucleus of the Hypothalamus and Metabolic Regulation: An Emerging Role for Renin–Angiotensin Pathways

“…Angiotensin-(1-7) is a ligand of the Mas G-protein coupled receptor (MasR), with most data supporting that physiological actions of angiotensin-(1-7) are prevented by either MasR antagonism with A779 or genetic MasR deletion [51]. Emerging reports, however, describe potential heterodimerization and functional interactions between MasR and AT 1 R, AT 2 R, bradykinin B2, endothelin B, and dopamine D2 receptors [54,55]. In animal models and clinical populations, circulating angiotensin-(1-7) levels appear reduced with obesity, suggesting deficiency of this protective hormone [56][57][58].…”