Novel aspects of the renin-angiotensin-aldosterone system in septic shock

Sepsis and septic shock are associated with high mortality rates that constitute the primary cause of death in intensive care units worldwide. Activation of the circulating renin-angiotensin-aldosterone system (RAAS) is early event and elements of the RAAS including renin, angiotensinogen, and ACE2 may be predictive of worse outcomes and higher mortality that reflect a failure to increase the circulating levels of the vasopressor Ang II. Emerging evidence suggests that dipeptidyl peptidase III (DPP3) is involved in the metabolism of Ang II and higher DPP3 in septic shock may also contribute to lower Ang II tone. The current review considers the role of a dysfunctional RAAS to maintain blood pressure and adequate tissue perfusion in septic shock. Dysregulation of the Renin-Angiotensin-Aldosterone System in Sepsis. A: Normal activation of the renin-angiotensin-aldosterone system (RAAS) occurs by the release of renal renin and subsequent hydrolysis of Angiotensinogen (Aogen) to generate angiotensin I (Ang I), which is rapidly hydrolyzed by ACE to Ang II. Ang II binds to the AT 1 receptor (AT 1 R) to increase blood pressure and sustain tissue perfusion, in part through stimulating aldosterone, endothelin-1 and vasopressin (not depicted). Ang II feedback through AT 1 R inhibits renin release by increasing intracellular cAMP levels to restore balance to the RAAS. Ang II may undergo metabolism by DPP3 to Ang-(3-8)/Ang-(5-8) and by ACE2 to Ang-(1-7). In contrast to renin regulation, Ang II exerts positive feedback on Aogen release from the liver. B: In sepsis and septic shock, renin stimulation by reduced blood pressure, lower renal perfusion, and/or higher sympathetic activation to augment Ang II may be blunted by reduced ACE and Aogen, but higher cDPP3 and ACE2. Symbols (+) and (-) connotate stimulation and inhibition, respectively. • The renin-angiotensin-aldosterone system (RAAS) is comprised of two functional arms termed the classical axis that supports blood pressure and the non-classical axis that may reduce blood pressure. • The classical axis includes renin, ACE, Ang II and its receptor AT1 while the non-classical axis includes ACE2, DPP3, Ang-(1-7) and its receptor Mas. • In sepsis and septic shock, there may occur an imbalance in the two arms of the RAAS that favor the non-classical RAAS and an inability to support blood pressure and tissue perfusion.