renin–angiotensin system

Renin–Angiotensin System

Pathway | Wikidata: Q898218

Overview

The renin–angiotensin system (RAS), also called the renin–angiotensin–aldosterone system (RAAS), is the hormonal cascade regulating Blood Pressure, fluid volume, electrolyte balance and vascular tone. It begins when the kidney releases the protease renin in response to reduced renal perfusion pressure, hypovolemia or sympathetic stimulation. Renin cleaves hepatic angiotensinogen to the decapeptide angiotensin I, which angiotensin-converting enzyme (ACE), chiefly in the pulmonary vasculature, converts to the octapeptide angiotensin II. Angiotensin II acts predominantly through the AT₁ receptor to produce vasoconstriction, aldosterone secretion from the adrenal cortex, renal sodium and water retention, thirst, and potentiation of sympathetic outflow; the AT₂ receptor generally opposes these actions, favoring vasodilation and natriuresis. A counter-regulatory arm balances the axis further: Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II to angiotensin-(1–7), which signals through the Mas receptor to vasodilate and to limit fibrosis and inflammation, so the system's net effect reflects the ratio between the two arms rather than angiotensin II alone.

Together these actions raise arterial pressure and restore circulating volume — appropriate acutely, damaging when sustained. Chronic overactivation drives hypertension, cardiac hypertrophy and remodeling, renal fibrosis and Cardiometabolic comorbidity, and the injury is mediated as much by AT₁-driven inflammation, oxidative stress through NADPH oxidase, and aldosterone-dependent fibrosis as by pressure itself. That distinction is why blockade helps even when blood pressure is already controlled.

Pharmacological interruption is accordingly a cornerstone of cardiovascular and renal medicine, available at every step: direct renin inhibition, ACE inhibitors, angiotensin receptor antagonist agents acting at AT₁, and mineralocorticoid receptor antagonists, used in hypertension, heart failure, diabetic nephropathy and chronic kidney disease. The classes are not interchangeable — ACE inhibitors also block bradykinin degradation, which produces their characteristic dry cough and rare angioedema and is absent with receptor blockers — and combined blockade at two levels raises hyperkalemia and renal risk without adding benefit. Research continues to extend the system's functional landscape to autophagy pathways, iron metabolism and inflammatory signaling, linking its dysregulation to neurological injury, metabolic syndrome and multi-organ failure.

Recent Publications Summary

Recent studies have examined the renin–angiotensin system (RAS) in diverse disease settings, most prominently as a mechanistic contributor to cardiovascular and neurovascular dysfunction. In male rats exposed to a peri-pubertal high-fat diet, adult hypertension and metabolic syndrome-like changes were associated 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 increased cardiac AT1R mRNA expression, supporting involvement of the renin–angiotensin axis in diet-induced cardiovascular dysfunction 42107303May. In a transient middle cerebral artery occlusion model of ischemic stroke, investigators found that stroke disrupted the balance between RAS pressor and depressor signaling in the rostral ventrolateral medulla, alongside impaired autophagic flux and altered iron-handling proteins; transcranial direct current stimulation mitigated these abnormalities by downregulating RAS pressor signaling, restoring autophagy, and reducing iron accumulation-associated oxidative stress 42212720May.

The RAS was also studied extensively in oncology, particularly in the context of RAS-mutant Cancers and RAS-targeted therapies. A preclinical study of a doublet of ON-state RAS inhibitors reported reduced development of drug resistance and strong synergy with immune checkpoint blockade, producing complete immune elimination of highly refractory Cancers with immune-cold tumor microenvironments 42220008Jun. In pancreatic ductal adenocarcinoma, daraxonrasib (RMC-6236), an oral RAS(ON) multiselective inhibitor targeting guanosine triphosphate-bound mutant and wild-type RAS, was evaluated in previously treated advanced RAS-mutated disease 42090791May. Resistance to RAS inhibition was further characterized in paired baseline and end-of-treatment samples from patients treated with daraxonrasib, where recurrent alterations disrupted molecular glue binding or enhanced RAS-RAF interaction; the study identified RAS Y64 and Y71 alterations and kinase-dead/hypoactive BRAF mutations as resistance mechanisms and proposed next-step inhibitors and combinations to address them 42092352May.

Additional work linked RAS pathway alterations to broader tumor biology and therapeutic vulnerability. In solid tumors enriched for TP53 and RAS pathway mutations, a uPAR-positive tumor ecosystem was shown to support a progenitor-like state and to be susceptible to uPAR-directed CAR T cells, which eliminated tumor cells and stromal support and produced durable regressions across models 41916312Mar. In another study, MECP2-dependent Cancers were reported to respond to epigenetic drugs, but activated RAS and other MAPK pathway activators conferred resistance, indicating that RAS signaling can modulate response to epigenetic therapy 41379640Dec.

What Changes, What Holds

1. Diet and stroke data extend RAS biology into metabolic and neurovascular dysregulation
NEW DIRECTION High-fat diet and stroke models do not overturn the core blood-pressure and volume-regulating account, but they show the system participating in diet-induced hypertension, altered angiotensin balance, and brainstem control of pressor tone. The stroke findings also connect RAS imbalance to autophagy and iron-linked oxidative injury, broadening the baseline’s mention of oxidative stress into a more specific neurovascular mechanism 42107303May42212720May.

2. RAS inhibition is becoming a therapeutic strategy in mutant Cancers, but resistance remains a major constraint
NEW DIRECTION These studies move RAS beyond cardiovascular physiology into oncology, where pathway blockade is being used as a direct antitumor approach rather than as supportive care. That does not conflict with the baseline, which is silent on cancer, but it does sharpen the idea that RAS can be a druggable oncogenic dependency. The resistance mechanisms argue that durable benefit will likely require rational combinations and next-generation inhibitors 42220008Jun42092352May.

3. RAS signaling can determine whether epigenetic therapy works in some tumors
NEW DIRECTION Activated RAS here functions as a resistance factor to epigenetic treatment, adding a new layer to the baseline’s cancer-related signaling roles. Because the overview does not discuss epigenetic therapy response, this is an added application rather than a contradiction. The practical implication is that RAS status may need to be considered when selecting or combining therapies in MECP2-dependent disease 41379640Dec.

Overview update candidates: RAS involvement in diet-induced hypertension and metabolic syndrome-like change; RAS imbalance in stroke-linked brainstem autophagy/iron/oxidative stress; RAS-targeted therapy and resistance mechanisms in mutant Cancers; RAS-mediated resistance to epigenetic therapy in selected tumors.