Renin-Angiotensin-Aldosterone System and Immunomodulation: A State-of-the-Art Review

Abstract

The renin-angiotensin system (RAS) has long been described in the field of cardiovascular physiology as the main player in blood pressure homeostasis. However, other effects have since been described, and include proliferation, fibrosis, and inflammation. To illustrate the immunomodulatory properties of the RAS, we chose three distinct fields in which RAS may play a critical role and be the subject of specific treatments. In oncology, RAS hyperactivation has been associated with tumor migration, survival, cell proliferation, and angiogenesis; preliminary data showed promise of the benefit of RAS blockers in patients treated for certain types of cancer. In intensive care medicine, vasoplegic shock has been associated with severe macro- and microcirculatory imbalance. A relative insufficiency in angiotensin II (AngII) was associated to lethal outcomes and synthetic AngII has been suggested as a specific treatment in these cases. Finally, in solid organ transplantation, both AngI and AngII have been associated with increased rejection events, with a regional specificity in the RAS activity. These elements emphasize the complexity of the direct and indirect interactions of RAS with immunomodulatory pathways and warrant further research in the field.

Keywords: immunomodulation; oncology; renin–angiotensin system; shock; transplantation.

Figure 1

Effects of the renin–angiotensin system (RAS) and its features in oncology, vasoplegic shock, and transplantation. Abbreviations: AngI: angiotensin I, AngII: angiotensin II.

Figure 2

Renin–angiotensin system: classical and counter regulatory pathways. Abbreviations: ACE: angiotensin converting enzyme; ACE 2: angiotensin-converting enzyme type 2, ACEIs: angiotensin-converting enzyme inhibitors; ARBs: angiotensin-2 receptor 1 blockers, AT1R: angiotensin II receptor type1, AT2R: angiotensin II receptor type 2.

Figure 3

Signal transduction pathways induced by the renin–angiotensin system, associated with cell proliferation, migration, invasion, inhibition of apoptosis, and angiogenesis. AT1R: angiotensin II receptor type 1; AKT: protein kinase B; c-SRC: non-receptor tyrosine kinase c-SRC protein; EGFR: epidermal growth factor receptor, JAK: Jun activating kinase; JNK: Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; mTor: mechanistic target of rapamycin; NADPH oxidase: nicotinamide adenine dinucleotide phosphate oxidase; NFκB: nuclear factor κB; PI3k: phosphoinositide 3-kinase; ROS: reactive oxygen species; STAT3: signal transducer and activator of transcription 3; VEGFA: vascular endothelial growth factor A; VEGFR: vascular endothelial growth factor receptor.