Higher circulating ACE2 and DPP3 but reduced ACE and angiotensinogen in hyperreninemic sepsis patients

Abstract

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 sepsis 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. The current study assessed RAAS components that may impact 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. 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 the HRS than control or NRS subjects, whereas the intact angiotensinogen to renin ratio was <10% of control or NRS subjects. We conclude that altered expression of ACE, ACE2, DPP3 and angiotensinogen may attenuate the expected increase in Angiotensin II, particularly in sepsis subjects with high renin concentrations.

Keywords: ACE; ACE2; Angiotensinogen; Angiotnesin II; Angiotnesin-(1-7); Sepsis.

Figure 1. Comparison of circulating renin, Ang II and Ang-(1-7) in controls and sepsis subjects.

A: Renin content (picomolar; pM) was higher in the high renin VICTAS group (HRS, renin > 5.1 pM) as compared with control subjects (controls); no difference between controls and the normal renin group (NRS, active renin < 5.1 pM). B: Ang II content was lower in the NRS versus both controls and the HRS group. C: Ang-(1-7) content was higher in the HRS groups versus controls. D: Peptide ratio of Ang II to Ang-(1-7) (AII:A7 ratio) was higher in controls versus the NRS group. Statistical comparisons by one-way ANOVA with Kruskal-Wallis post hoc test among all groups.

Figure 2. Comparison of circulating ACE, ACE2 and DPP3 in controls and sepsis subjects.

A: Serum ACE (nanomolar, nM) was lower in NRS and HRS groups as compared with controls. B: Serum ACE2 content (nM) was higher in the HRS group as compared with controls. C: Serum ACE:ACE2 ratios are lower in NRS and HRS groups as compared with controls. D: Serum DPP3 levels (nM) were higher in the NRS and HRS groups as compared with controls. Statistical comparisons by one-way ANOVA with Tukey’s (A,B) or Kruskal-Wallis (C,D) post hoc tests among all groups.

Figure 3. Circulating levels of intact and total angiotensinogen in control and sepsis groups.

A: Serum levels (nanomolar, nM) of intact angiotensinogen (Aogen) were lower in HRS versus the controls or NRS group. B: The intact Aogen to renin ratio was also lower in the HRS compared with the controls or NRS patients. C: Total Aogen levels were also lower in the HRS versus controls or NRS groups. D: Total Aogen to renin ratio was reduced in the HRS versus controls or NRS groups. Statistical comparisons by one-way ANOVA with Tukey’s (A,C) or Kruskal-Wallis (B,D) post hoc tests among all groups.

Figure 4. Potential mechanisms that contribute to an attenuated Ang II response in hyperreninemic sepsis.

In sepsis patients with high renins, inappropriate low levels of Ang II would stimulate renin release owing to loss of negative feedback (attenuated short feedback loop), as well as reduced blood pressure and increased sympathetic tone. Lower ACE but higher ACE2 and DPP3 may reduce circulating levels of Ang II. Higher Ang-(1-7) levels may reflect increased ACE2 but lower ACE that reduces metabolism of Ang-(1-7) to Ang-(1-5). Lower Ang II may also contribute to the reduced release of Aogen from the liver that may further suppress the Ang II response. Reduced expression of the AT₁R and/or reduced signalling (-) in the kidney and liver of sepsis patients may also contribute to high renin levels (attenuated negative feedback) but reduced Aogen release into the circulation.