The potential therapeutic use of renin–angiotensin system inhibitors in the treatment of inflammatory diseases

Abstract

Inflammation is a normal part of the immune response to injury or infection but its dysregulation promotes the development of inflammatory diseases, which cause considerable human suffering. Nonsteroidal anti-inflammatory agents are the most commonly prescribed agents for the treatment of inflammatory diseases, but they are accompanied by a broad range of side effects, including gastrointestinal and cardiovascular events. The renin-angiotensin system (RAS) is traditionally known for its role in blood pressure regulation. However, there is increasing evidence that RAS signaling is also involved in the inflammatory response associated with several disease states. Angiotensin II increases blood pressure by binding to angiotensin type 1 (AT ) receptor, and direct renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors and AT receptor blockers (ARBs) are clinically used as antihypertensive agents. Recent data suggest that these drugs also have anti-inflammatory effects. Therefore, this review summarizes these recent findings for the efficacy of two of the most widely used antihypertensive drug classes, ACE inhibitors and ARBs, to reduce or treat inflammatory diseases such as atherosclerosis, arthritis, steatohepatitis, colitis, pancreatitis, and nephritis.

Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications

“…For example, when the renal blood flow is reduced, the kidneys' juxtaglomerular cells secrete renin directly into the blood circulation. This secreted renin converts angiotensinogen released by the liver to be angiotensin1 (Ang1), which is then converted to be angiotensin2 (Ang2) by ACE in pulmonary vascular endothelial cells [117,118,123]. Ang2 plays a central role in the RAS by acting on the angiotensin type 2 receptors AT1R and AT2R.…”

Cutaneous inflammation differentially regulates the expression and function of Angiotensin‐II types 1 and 2 receptors in rat primary sensory neurons

“…The most widely used antihypertensive drug classes, angiotensin‐converting enzyme inhibitors and Ang‐II receptor blockers (ARBs), are used to treat inflammatory diseases through actions independent of their effects on blood pressure (Ranjbar et al ). Of notice, AT1R are up‐regulated in inflamed tissues.…”

Response to recent commentaries regarding the involvement of angiotensin‐converting enzyme 2 (ACE2) and renin‐angiotensin system blockers in SARS‐CoV‐2 infections

“…At this time the effects of ATR1 blockers and ACE inhibitors on membrane bound ACE2 in human lung is unknown, so any suggestion that they increase SARS‐CoV‐2 infectivity currently lacks a sound rationale (Danser, Epstein, & Batlle, 2020; Vaduganathan et al, 2020). ACE2 plays an important role in inactivating angiotensin (Ang) II as well as to generate Ang 1–7 (Lazartigues, Feng, & Lavoie, 2007; Warner, Smith, Hooper, & Turner, 2004), and any reduction in its activity could increase the ability of Ang II to stimulate AT 1 receptors, which mediate both the pressor and proinflammatory actions of Ang II (Forrester et al, 2018; Piqueras & Sanz, 2020; Ranjbar et al, 2019; Zhou, Ando, Macova, Dou, & Saavedra, 2005) as well as reduce formation of Ang 1–7 which is reported to have cytoprotective properties in the lung and its vasculature (Y. Li et al, 2016; Ye & Liu, 2020). Moreover, it is unlikely that inhibitors of ACE2 activity would significantly compete for the same or overlapping binding sites on ACE2, as the active site of ACE2 is the HEMGH domain at amino acids 374–378, while the putative SARS‐CoV‐2 spike protein binding domains are amino acids 30–41, 82–84, and 353–357 https://www-ncbi-nlm-nih-gov.ezproxylocal.library.nova.edu/protein/NP_001358344.1.…”

“…Since inflammation is one of the major causes of morbidity of SARS‐CoV‐2 infection, and AT 1 receptors are known to cause inflammation (Forrester et al, 2018; Piqueras & Sanz, 2020; Ranjbar et al, 2019; Zhou et al, 2005), AT 1 receptor blockers (ARBs) present an additional therapeutic modality to minimize complications of the respiratory impairments caused by this virus. While ACE inhibitors present an equivalent therapeutic option to ARBs for treatment of hypertension and cardiovascular and renovascular disease, their ability to protect bradykinin from degradation, manifested as the ACE inhibitor cough, as well as the increased risk of angioedema could be a cause for concern (Messerli, Bangalore, Bavishi, & Rimoldi, 2018).…”