Srinivasan A, Dhivya P. Dysregulation of renin-angiotensin-aldosterone axis in septic shock: Emerging roles of angiotensin-(1-5) and alamandine. World J Crit Care Med 2026; 15(1): 114670 [DOI: 10.5492/wjccm.v15.i1.114670]
Corresponding Author of This Article
Arunkumaar Srinivasan, Consultant, Department of GI and Renal Critical Care, Apollo Hospital, Greams Lane, Chennai 600006, Tamil Nadu, India. arundec06@gmail.com
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Critical Care Medicine
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Mar 9, 2026 (publication date) through Mar 3, 2026
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World Journal of Critical Care Medicine
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Srinivasan A, Dhivya P. Dysregulation of renin-angiotensin-aldosterone axis in septic shock: Emerging roles of angiotensin-(1-5) and alamandine. World J Crit Care Med 2026; 15(1): 114670 [DOI: 10.5492/wjccm.v15.i1.114670]
World J Crit Care Med. Mar 9, 2026; 15(1): 114670 Published online Mar 9, 2026. doi: 10.5492/wjccm.v15.i1.114670
Dysregulation of renin-angiotensin-aldosterone axis in septic shock: Emerging roles of angiotensin-(1-5) and alamandine
Arunkumaar Srinivasan, Ponnsusamy Dhivya
Arunkumaar Srinivasan, Department of GI and Renal Critical Care, Apollo Hospital, Chennai 600006, Tamil Nadu, India
Ponnsusamy Dhivya, Department of Pediatrics, Sri Lalithambigai Medical College and Hospital, Chennai 600095, Tamil Nadu, India
Co-first authors: Arunkumaar Srinivasan and Ponnsusamy Dhivya.
Author contributions: Srinivasan A and Dhivya P contributed equally in preparing the manuscript as co-first authors.
Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.
Corresponding author: Arunkumaar Srinivasan, Consultant, Department of GI and Renal Critical Care, Apollo Hospital, Greams Lane, Chennai 600006, Tamil Nadu, India. arundec06@gmail.com
Received: September 25, 2025 Revised: November 21, 2025 Accepted: January 26, 2026 Published online: March 9, 2026 Processing time: 156 Days and 12.8 Hours
Abstract
The renin-angiotensin-aldosterone system (RAAS) undergoes profound dysregulation during septic shock, defined by persistent hypotension requiring vasopressors to maintain mean arterial pressure ≥ 65 mmHg plus lactate > 2 mmol/L, with mortality exceeding 40%. The classical RAAS pathway becomes impaired with elevated renin but paradoxically low angiotensin (Ang) II levels, correlating with poor outcomes. The alternative Ang-converting enzyme 2-Ang-(1-7)-mas receptor axis provides counter-regulatory effects but represents a “double-edged sword” in sepsis. Elevated circulating Ang-converting enzyme 2 paradoxically predicts worse outcomes, possibly through excessive Ang II depletion contributing to vasoplegia. Downstream metabolites including Ang-(1-5) and alamandine show cardioprotective properties in experimental models. Ang-(1-5) may serve as a biomarker reflecting RAAS dysregulation severity. Elevated dipeptidyl peptidase 3 exacerbates dysfunction by degrading Ang II. Experimental Ang-(1-7) infusion prevented septic shock and reduced vasopressor requirements. However, human randomized trials remain limited. Future research should focus on biomarker-guided patient stratification and multicenter trials establishing clinical utility of alternative RAAS modulation.
Core Tip: Septic shock, as defined by sepsis-3, is a severe form of sepsis marked by high mortality, requiring vasopressors to maintain mean arterial pressure ≥ 65 mmHg and lactate > 2 mmol/L despite fluids. It involves circulatory and metabolic failure. Normally, the renin-angiotensin-aldosterone axis and sympathetic nervous system maintain vascular tone and volume. In septic shock, dysregulation occurs: Reduced angiotensin (Ang)-converting enzyme activity lowers Ang II and blunts vasoconstriction, while counter-regulatory pathways via Ang-converting enzyme 2-Ang-(1–7)-mas receptor promote vasodilation. Emerging metabolites like Ang-(1–5) and alamandine show cardioprotective roles, suggesting therapeutic potential in rebalancing renin-Ang-aldosterone signaling for refractory shock.
