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Chappell, M. C., Schaich, C. L., Busse, L. W., et al. | Clin Sci (Lond) (2025) 139(1):43-53 | Higher circulating ACE2 and DPP3 but reduced ACE and angiotensinogen in hyperreninemic sepsis patients

November 29, 2025

Background: Sepsis and septic shock are global healthcare problems associated with high mortality rates. Activation of the renin-angiotensin-aldosterone system (RAAS) is an early event in sepsis, and elevated renin may be predictive of worse outcomes. In a subset of patients enrolled in the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial, elevated levels of active renin (median value >189 pg/mL or 5.1 pM) at baseline (day 0) were strongly associated with mortality; however, corresponding plasma levels of the vasopressor hormone angiotensin II were not substantially increased, nor was angiotensin II associated with disease severity.

Methods: This study assessed RAAS components that may affect the angiotensin II response in control subjects, normal renin sepsis (NRS, renin <5.1 pM), and high renin sepsis (HRS, renin >5.1 pM) patients.

Results: NRS and HRS subjects exhibited a similar reduction in ACE (40%), but increased levels of ACE2 and DPP3. The ACE-to-DPP3 ratio was higher in controls, but this relationship was reversed in both NRS and HRS subjects. Intact angiotensinogen was 50% lower in HRS subjects than in control or NRS subjects, whereas the intact angiotensinogen-to-renin ratio was <10% of that observed in control or NRS subjects.

Conclusions: Altered expression of ACE, ACE2, DPP3, and angiotensinogen may attenuate the expected increase in angiotensin II, particularly in sepsis patients with high renin concentrations.