Classic and Nonclassic Renin-Angiotensin Systems in the Critically Ill

Abstract

Classic and nonclassic renin-angiotensin systems (RAS) are 2 sides of an ubiquitous endocrine/paracrine cascade regulating blood pressure and homeostasis. Angiotensin II and angiotensin-converting enzyme (ACE) levels are associated with severity of disease in the critically ill, and are central to the physiology and the pathogenesis of circulatory shock. Angiotensin (1-7) and ACE2 act as an endogenous counterregulatory arm to the angiotensin II/ACE axis. The tissue-based RAS has paracrine effects dissociated from those of the circulating RAS. Exogenous angiotensin II or ACE2 may improve the outcome of septic shock and acute respiratory distress syndrome, respectively.

Keywords: Acute kidney injury; Acute respiratory distress syndrome; Angiotensin; Angiotensin-converting enzyme; Inflammation; Renin; Sepsis; Septic shock.

Fig. 1

Localization of RASs. Presented here are the organs or tissues in which at least 1 component of classic and/or nonclassic systems have been identified and are considered as being locally generated and/or secreted.

Fig. 2

RASs enzymatic cascades. AP-A, aminopeptidase A; AP-B, aminopeptidase B; AP-N, aminopeptidase N.

Fig. 3

Mirrorlike physiologic effects of the pivotal peptides of the classic and nonclassic RASs. BP, blood pressure; CNS, central nervous system. The question mark indicates the unknown/unexplored effect of Angiotensin (1-7), in regard to that observed with Angiotensin II upregulation.

Fig. 4

ACE2 controls acute lung failure. Lung elastance (A) after acute lung injury in wild-type (WT) and Ace2 knockout (KO) mice induced by cecal ligation perforation (CLP). CLP-treated Ace2 KO mice had significantly higher elastance than CLP-treated WT mice (^a P<.01). Wet-to-dry weight ratios of lungs (B) in CLP-treated Ace2 KO mice after 4 hours of ventilation was significantly increased, compared with CLP-treated WT and sham. Histopathology (C) showed increased lung edema and inflammatory infiltrate in CLP-treated Ace2 knockout mice, compared to CLP-treated WT and sham. ^bP<.05 between CLP-treated WT and Ace2 KO mice.

Fig. 5

The paradigm of classic and nonclassic RAS roles in critical illness.