renin–angiotensin system

Renin–Angiotensin System

Pathway | Wikidata: Q898218

Overview

The renin–angiotensin system (RAS), also referred to as the renin–angiotensin–aldosterone system (RAAS), is a hormonal cascade that serves as a master regulator of Blood Pressure, fluid volume, electrolyte balance, and vascular tone. The pathway is initiated when the kidney releases the protease renin in response to reduced renal perfusion pressure, hypovolemia, or sympathetic stimulation. Renin cleaves hepatic angiotensinogen into the decapeptide angiotensin I, which is subsequently converted to the biologically active octapeptide angiotensin II by angiotensin-converting enzyme (ACE), primarily in the pulmonary vasculature. Angiotensin II exerts its effects through AT₁ and AT₂ receptors, promoting vasoconstriction, aldosterone secretion from the adrenal cortex, renal sodium and water retention, and sympathetic nervous system potentiation. Collectively, these actions increase arterial pressure and restore circulating volume, though chronic overactivation of the system is a central driver of hypertension, cardiac hypertrophy, renal fibrosis, and Cardiometabolic comorbidity.

Beyond its classical cardiovascular role, the RAS has emerged as a key mediator of end-organ responses in diverse pathophysiological states. Pharmacological blockade of the system—through ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid antagonists—remains a cornerstone of treatment for hypertension, heart failure, diabetic nephropathy, and chronic kidney disease. Emerging research has expanded the functional landscape of the RAS to include regulation of autophagy pathways, iron metabolism, inflammatory signaling, and oxidative stress responses, linking its dysregulation to neurological injury, metabolic syndrome, and complex organ failure syndromes.

Focus of Latest Publications

Recent publications have examined the renin–angiotensin system (RAS) in both cardiovascular and neurological disease models, as well as in cancer-related therapeutic contexts. In a rat model of peri-pubertal high-fat diet exposure, adult cardiovascular dysfunction was linked to disruption of the renin–angiotensin axis, with increased arterial pressure, enhanced pressor responses to angiotensin II, a greater depressor response to enalapril, higher circulating angiotensin II, lower angiotensin (1-7), and altered receptor expression in the heart and aorta, including increased AT1R and reduced AT2R and MAS receptor mRNA. These findings support a role for RAS imbalance in diet-associated hypertension and metabolic syndrome.

In ischemic stroke, the RAS was studied in the rostral ventrolateral medulla as part of a proposed RAS-autophagy-iron axis. Transient middle cerebral artery occlusion in rats induced imbalance between pressor and depressor RAS signaling, disrupted autophagic flux, altered iron storage protein expression, and was associated with elevated blood pressure and sympathetic dysregulation. Transcranial direct current stimulation attenuated these abnormalities by downregulating RAS pressor signaling, restoring autophagic activity including autophagic ferritin degradation, and reducing iron accumulation-associated oxidative stress in the brainstem.

Several recent oncology studies focused on RAS as a therapeutic target in RAS-mutant cancers. Daraxonrasib, an oral RAS(ON) multiselective inhibitor, was evaluated in previously treated advanced RAS-mutated pancreatic cancer, reflecting continued clinical development of direct RAS inhibition in a disease where activating RAS mutations are present in most tumors. Another study described a RAS inhibitor doublet combining two ON-state RAS inhibitors, one mutant-selective and one targeting all RAS forms, which reduced the development of drug resistance in preclinical lung cancer models and showed strong synergy with checkpoint inhibitor therapy, leading to complete immune elimination of highly refractory cancers with immune-cold tumor microenvironments.

Mechanistic work also addressed resistance to RAS-targeted agents. In patients treated with daraxonrasib, recurrent alterations were identified at baseline and on treatment, and structural and functional analyses showed that resistance could arise either from mutations that disrupt inhibitor binding to RAS, such as RAS Y64 mutations, or from changes that enhance native RAS-RAF signaling, including RAS Y71 or kinase-dead/hypoactive BRAF mutations. These findings led to the identification of a tri-complex inhibitor active against RAS Y64 mutants and suggested combination strategies for resistance driven by kinase-dead BRAF, providing a mechanistic framework for improving efficacy in RAS-driven malignancies.

Key Publications

NEWJul Robinin Attenuates Xenobiotic Enzymes, Inflammation, and Apoptosis on DMH-Induced Colon Cancer via Modulating Ras/PI3K/Akt/mTOR and NF-κB/Bax/Caspase-3 Signalling Pathways in Wistar Rats. (Journal of biochemical and molecular toxicology, 2026, PMID 42365609): "Targeting important signalling pathways, such as NF-κB and PI3K/Akt/mTOR/Ras, facilitated these results."
Jun Sensitizing Lung Cancer to Immunotherapy with a RAS(ON) Inhibitor Doublet. (Cancer discovery, 2026, PMID 42220008): "...a combination of two ON-state RAS inhibitors, one mutant-selective and one targeting all RAS forms, shows greatly reduced development of drug resistance."
Jun Transcranial Direct Current Stimulation Attenuates Ischemic Stroke-Induced Autonomic and Behavioral Dysfunction via a RAS-Autophagy-Iron Axis in the Brainstem. (Journal of neurochemistry, 2026, PMID 42212720): "In this study, we examined the regulatory interplay between the renin-angiotensin system (RAS), autophagy, and iron metabolism in the RVLM in a transient middle cerebral artery occlusion model (MCAO) of ischemic stroke in Sprague-Dawley rats."
Jun Adult cardiovascular dysfunction induced by peri-pubertal high-fat diet exposure is mediated by the renin-angiotensin axis in male rats. (Nutrition research (New York, N.Y.), 2026, PMID 42107303): "This study investigated whether the renin-angiotensin system (RAS) is associated with the hypertension and metabolic syndrome induced by high-fat diet exposure during the peri-pubertal phase in rats."
May Disrupted molecular glue complex drives RAS inhibitor resistance. (Cell, 2026, PMID 42092352): "Tri-complex inhibitors (TCIs) are molecular glues that bind the active, guanosine triphosphate (GTP)-bound state of RAS and recruit cyclophilin A (CYPA) to form a synthetic complex that blocks oncogenic signaling."
May Prognostic impact of ASXL1 mutations in acute myeloid leukemia treated with lower intensity therapy. (Cancer, 2026, PMID 42089434): "the European LeukemiaNet introduced a four-gene genetic risk classifier in 2024 that categorizes ASXL1 MUT as favorable risk in the absence of FLT3-ITD, RAS, and TP53 mutations."
May Daraxonrasib in Previously Treated Advanced RAS-Mutated Pancreatic Cancer. (The New England journal of medicine, 2026, PMID 42090791): "Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective inhibitor that targets guanosine triphosphate-bound mutant and wild-type RAS."
May A convergent uPAR-positive tumor ecosystem creates broad vulnerability to CAR T cell therapy. (Cell, 2026, PMID 41916312): "Integrative analyses now reveal that uPAR is broadly expressed in solid tumors enriched for TP53 and RAS pathway mutations."
May MECP2-Dependent Cancers Can Be Targeted by Epigenetic Drugs: A New Role for Epigenetic Cancer Therapy. (Molecular cancer therapeutics, 2026, PMID 41379640): "Activated RAS and other activators of the MAPK pathway caused resistance to these therapies, giving insight into their novel mode of action and demonstrating specificity."