Targeting the Renin-Angiotensin-Aldosterone System: Preclinical and Clinical Developments

The classical renin-angiotensin-aldosterone system (RAAS) remains one of the most important pharmacological targets in the treatment of cardiorenovascular diseases, including hypertension, heart failure, and chronic kidney disease. Pharmacological modulation of the RAAS has transformed clinical practice over the past decades. The earliest agents targeting this pathway were mineralocorticoid receptor antagonists, which were followed by ACE (angiotensin-converting enzyme) inhibitors, Ang (angiotensin) AT 1 R (AT 1 receptor) blockers, and direct renin inhibitors. These drug classes continue to represent the cornerstone of guideline-directed therapy, and newer compounds within these categories are being developed to enhance efficacy, improve organ protection, and minimize adverse effects such as hyperkalemia, hypotension, and renal dysfunction. In addition to established therapies, innovative strategies targeting the classical RAAS are emerging. These include RNA-based therapeutics designed to suppress hepatic angiotensinogen synthesis and small-molecule inhibitors of aldosterone synthase. Such approaches may offer improved cardiovascular and renal outcomes by intervening earlier, more sustainably, or selectively in the RAAS cascade. Beyond the classical axis, increasing attention is being directed toward the so-called protective or alternative renin-angiotensin system (RAS). This pathway centers on ACE2, Ang-(1–7), alamandine, and their associated receptors, including Mas, MrgD (Mas-related G-protein–coupled receptor D), and the Ang AT 2 R (AT 2 receptor). Activation of this axis exerts vasodilatory, anti-inflammatory, antifibrotic, and cardioprotective effects, thereby counterbalancing the deleterious actions of the classical RAAS. Growing experimental and clinical evidence supports its therapeutic potential not only in cardiovascular disease but also in metabolic, fibrotic, and inflammatory disorders. This review summarizes the current state of pharmacological interventions targeting both the classical and protective RAAS and highlights emerging therapeutic directions that may shape the next generation of cardiovascular treatments.