The apelin/APJ system as a complementary target to RAAS blockade in cardiorenal disease

Background: Cardiorenal disease emerges from reciprocal injury among the heart, vasculature, kidney, and metabolic organs, with maladaptive neurohormonal activation as a central pathobiological driver. Although renin-angiotensin-aldosterone system (RAAS) blockade has transformed cardiorenal care, substantial residual risk persists despite contemporary multidrug therapy, including mineralocorticoid receptor antagonists and sodium-glucose cotransporter 2 inhibitors Objective and scope: This review summarizes mechanistic and translational evidence linking apelin/APJ signaling to RAAS regulation in cardiorenal disease, with emphasis on APJ-AT1R interaction, ACE2/Ang-(1-7)/Mas signaling, endothelial and metabolic protection, autophagy, inflammatory-fibrotic remodeling, apelin resistance, and emerging APJ agonists. Conclusions: Current evidence supports the apelin/APJ system as a compensatory cardiorenal network that may complement, rather than replace, evidence-based RAAS-directed therapy. Future studies should move beyond descriptive associations toward standardized apelin/Elabela assays, phenotype-specific disease models, combination-treatment experiments, and early clinical trials with renal, cardiovascular, biomarker, congestion, and safety endpoints.