Jorge Andrés Narváez Pardo

Aim: Despite increasing evidence for the cardiometabolic protective effects of angiotensin II Type 2 receptor (AT ₂ R) activation, the underlying molecular mechanisms remain incompletely understood. This study aimed to determine how AT ₂ R activation modulates cellular metabolism and to identify pathways relevant to its tissue‐protective actions. Methods: 3T3‐L1 adipocytes, endothelial cells, and renal proximal tubular epithelial cells were treated with the specific AT ₂ R agonist Compound 21 (C21). Targeted liquid chromatography–tandem mass spectrometry was used to quantify amino acids and metabolites involved in energy metabolism and redox homeostasis. Functional analyses included nitrate/nitrite determination and cystathionine β‐synthase (CBS) activity. Results: Compound 21 induced shared and cell type‐specific metabolic changes. Arginine, citrulline, glucose, and glyceraldehyde 3‐phosphate increased consistently across all cell types, whereas citrate decreased. Sulfur‐containing metabolites and glutathione‐related intermediates increased predominantly in adipocytes and renal cells. Pathway analysis highlighted three metabolic axes affected by C21: arginine biosynthesis, central carbon metabolism, and amino acid‐linked redox pathways. Functionally, C21 increased nitrate/nitrite accumulation in BAECs and CBS activity in RPTECs. Conclusion: Treatment with C21 was associated with a conserved metabolic signature across adipocytes, renal epithelial cells, and endothelial cells involving arginine biosynthesis, central carbon metabolism, and amino acid‐linked redox homeostasis. While the response differed among cell types, coordinated changes in arginine, citrulline, glucose, glyceraldehyde 3‐phosphate, citrate, and GSH‐related metabolites suggest that AT ₂ R signaling is associated with cellular pathways involved in nitric oxide metabolism, energy metabolism, and redox homeostasis. Increased NOx production in BAECs and CBS activity in RPTECs support the cell type‐specific metabolic effects of C21.

The angiotensin II type 2 (AT₂) receptor has a role in promoting insulin sensitivity. However, the mechanisms underlying the AT₂ receptor-induced facilitation of insulin are still not completely understood. Therefore, we investigated whether acute in vivo administration of AT₂ receptor agonist compound 21 (C21) could activate insulin signaling molecules in insulin-target tissues. We report that, in male C57BL/6 mice, an acute (5 min, 0.25 mg/kg; i.v.) injection of C21 induces the phosphorylation of Akt and ERK1/2 at activating residues (Ser473 and Thr202/Tyr204, respectively) in both epididymal white adipose tissue (WAT) and heart tissue. In WAT, the extent of phosphorylation (p) of Akt and ERK1/2 induced by C21 was approximately 65% of the level detected after a bolus injection of a dose of insulin known to induce maximal activation of the insulin receptor (IR). In the heart, C21 stimulated p-Akt to a lesser extent than in WAT and stimulated p-ERK1/2 to similar levels to those attained by insulin administration. C21 did not modify p-IR levels in either tissue. We conclude that in vivo injection of the AT₂ receptor agonist C21 activates Akt and ERK1/2 through a mechanism that does not involve the IR, indicating the participation of these enzymes in AT₂R-mediated signaling.

Human immunodeficiency virus type 1 (HIV-1) is the etiological agent of acquired immunodeficiency syndrome (AIDS), a pandemic with high economic and social costs. The envelope glycoprotein (env) of the virus mediates the infectious process by binding to and entering the host cell, one of the main target components of studies since its discovery. Its endodomain or C-terminal tail (CTT) participates in late replicative cycle processes, such as intracellular trafficking, activation, and cell death, which occurs because it interacts with multiple cellular factors through motifs or signal sequences present throughout its structure. Although these interactions have not been fully understood at specific levels, studies over more than three decades leave no doubt that this domain plays a fundamental role in the biology of the virus and probably the development of the disease. This review describes the studies carried out to date that demonstrate the importance of the CTT, focusing on the motifs responsible for its interactions and its possible roles in the pathogenicity of the infection.