The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases

Abstract

The renin-angiotensin system (RAS) is undisputedly one of the most prominent endocrine (tissue-to-tissue), paracrine (cell-to-cell) and intracrine (intracellular/nuclear) vasoactive systems in the physiological regulation of neural, cardiovascular, blood pressure, and kidney function. The importance of the RAS in the development and pathogenesis of cardiovascular, hypertensive and kidney diseases has now been firmly established in clinical trials and practice using renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, type 1 (AT1) angiotensin II (ANG II) receptor blockers (ARBs), or aldosterone receptor antagonists as major therapeutic drugs. The major mechanisms of actions for these RAS inhibitors or receptor blockers are mediated primarily by blocking the detrimental effects of the classic angiotensinogen/renin/ACE/ANG II/AT1/aldosterone axis. However, the RAS has expanded from this classic axis to include several other complex biochemical and physiological axes, which are derived from the metabolism of this classic axis. Currently, at least five axes of the RAS have been described, with each having its key substrate, enzyme, effector peptide, receptor, and/or downstream signaling pathways. These include the classic angiotensinogen/renin/ACE/ANG II/AT1 receptor, the ANG II/APA/ANG III/AT2/NO/cGMP, the ANG I/ANG II/ACE2/ANG (1–7)/Mas receptor, the prorenin/renin/prorenin receptor (PRR or Atp6ap2)/MAP kinases ERK1/2/V-ATPase, and the ANG III/APN/ANG IV/IRAP/AT4 receptor axes. Since the roles and therapeutic implications of the classic angiotensinogen/renin/ACE/ANG II/AT1 receptor axis have been extensively reviewed, this article will focus primarily on reviewing the roles and therapeutic implications of the vasoprotective axes of the RAS in cardiovascular, hypertensive and kidney diseases.

Comorbidities in COVID-19: Outcomes in hypertensive cohort and controversies with renin angiotensin system blockers

“…Fig. 1 a) Rationale and Evidence for Harm: There is evidence that ACE-2 expression increases with the use of ACE inhibitors and ARB, especially in heart and kidney [35,36]. This has raised a theoretical concern that by increasing ACE-2 expression, ACEIs and ARBs could facilitate the entry of virus into the host cell and increase the chances of infection or its severity [17].…”

Angiotensin II Stimulates the NLRP3 Inflammasome to Induce Podocyte Injury and Mitochondrial Dysfunction

“…Angiotensin II (Ang II), a major bioactive product of the renin-angiotensin system, plays a critical role in maintaining blood pressure and fluid homeostasis [1, 2]. However, Ang II also contributes to the pathogenesis of various diseases, mainly by inducing oxidative stress, inflammation, cholesterol accumulation, and fibrosis [3-5].…”

Contentious issues and evolving concepts in the clinical presentation and management of patients with COVID-19 infectionwith reference to use of therapeutic and other drugs used in Co-morbid diseases (Hypertension, diabetes etc)

“…Despite these small studies suggesting the benefit of drugs acting on RAS pathway, there is some data, albeit scarce, from animal models and human studies that treatment with ACE inhibitors and ARB could causeup regulation of ACE2 [24]. Ibuprofen and thiazolidinediones have also been shown to do the same [25,26].…”