Dysregulation of renin-angiotensin-aldosterone axis in septic shock: Emerging roles of angiotensin-(1-5) and alamandine

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.