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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 &amp;gt; 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 &amp;lt; 5.1 pM) and high renin sepsis (HRS, renin &amp;gt; 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 &amp;lt;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.<\/jats:p>","DOI":"10.1042\/cs20242168","type":"journal-article","created":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T12:07:43Z","timestamp":1734610063000},"page":"43-53","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Higher circulating ACE2 and DPP3 but reduced ACE and angiotensinogen in hyperreninemic sepsis patients"],"prefix":"10.1042","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5869-6037","authenticated-orcid":false,"given":"Mark C.","family":"Chappell","sequence":"first","affiliation":[{"name":"1Hypertension Center, Wake Forest University School of Medicine, Winston-Salem, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.","family":"Schaich","sequence":"additional","affiliation":[{"name":"1Hypertension Center, Wake Forest University School of Medicine, Winston-Salem, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence W.","family":"Busse","sequence":"additional","affiliation":[{"name":"2Department of Medicine, Emory University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Clark Files","sequence":"additional","affiliation":[{"name":"3Department of Internal Medicine, Section of Pulmonary, Critical Care, Allergy, and Immunologic Diseases, Wake Forest University School of Medicine, Winston-Salem, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg S.","family":"Martin","sequence":"additional","affiliation":[{"name":"4Pulmonary and Critical Care, Emory University School of Medicine, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan E.","family":"Sevransky","sequence":"additional","affiliation":[{"name":"2Department of Medicine, Emory University, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremiah S.","family":"Hinson","sequence":"additional","affiliation":[{"name":"5Johns Hopkins School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard E.","family":"Rothman","sequence":"additional","affiliation":[{"name":"5Johns Hopkins School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish K.","family":"Khanna","sequence":"additional","affiliation":[{"name":"1Hypertension Center, Wake Forest University School of Medicine, Winston-Salem, NC"},{"name":"6Department of Anesthesiology, Section on Critical Care Medicine, Wake Forest University School of Medicine, Winston-Salem, NC"},{"name":"7Outcomes Research Consortium, Cleveland, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2025,1,15]]},"reference":[{"key":"2025012915412091400_CS-2024-2168C1","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The third lnternational consensus definitions for sepsis and septic shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"2025012915412091400_CS-2024-2168C2","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1007\/s00134-021-06506-y","article-title":"Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021","volume":"47","author":"Evans","year":"2021","journal-title":"Intensive Care Med."},{"key":"2025012915412091400_CS-2024-2168C3","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1055\/s-0041-1733915","article-title":"What is the utility of measuring lactate Levels in patients with sepsis and septic shock?","volume":"42","author":"Weinberger","year":"2021","journal-title":"Semin. 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