The biological functions of angiotensin II are mediated by AT₁ and AT₂ receptors. Both belong to the G-protein coupled receptor superfamily and are comprised of seven hydrophobic transmembrane segments forming α helices in the lipid bilayer of the cell membrane, an extracellular N-terminus and an intracellular N-terminus¹.

Two highly homologous isoforms of the receptor, AT_1A and AT_1B have been identified in rodents. The AT_1A receptor accounts for 90% of the total binding, and is predominant in the kidney, vascular smooth muscle cells, heart, liver, and in some areas of the brain, while the AT_1B receptor is found predominantly in the pituitary and adrenal glands, placenta, lung, and brain. These isoforms are pharmacologically indistinguishable and are both selectively antagonized by losartan.

Through AT₁ receptor, angiotensin II stimulates multiple signaling pathways, cross-talks with several tyrosine kinases, and trans-activates growth factor receptors. Phosphorylation of the receptor by GPCR kinases terminates receptor activation and promotes β-arrestin recruitment. β-arrestin-scaffolded signaling mediates ‘secondary signaling’ that involves multiple kinases that link to cell protective downstream signaling molecules².

In a model of diet-induced obese mice, AT₁ receptor inhibition demonstrates beneficial pleiotropic effects. Mice receiving the treatment exhibit enhanced pancreatic duodenal homeobox 1 (PDX1) and GLP-1 pancreatic islet expression. PDX1 islets are essential for the expression of glucokinase and GLUT2. Greater GLP-1 levels, islet vascularization and reduced apoptosis and macrophage infiltration are also observed³.