Angiotensin-(1-7)—A Potential Remedy for AKI: Insights Derived from the COVID-19 Pandemic

Abstract

Membrane-bound angiotensin converting enzyme (ACE) 2 serves as a receptor for the Sars-CoV-2 spike protein, permitting viral attachment to target host cells. The COVID-19 pandemic brought into light ACE2, its principal product angiotensin (Ang) 1-7, and the G protein-coupled receptor for the heptapeptide (MasR), which together form a still under-recognized arm of the renin–angiotensin system (RAS). This axis counteracts vasoconstriction, inflammation and fibrosis, generated by the more familiar deleterious arm of RAS, including ACE, Ang II and the ang II type 1 receptor (AT1R). The COVID-19 disease is characterized by the depletion of ACE2 and Ang-(1-7), conceivably playing a central role in the devastating cytokine storm that characterizes this disorder. ACE2 repletion and the administration of Ang-(1-7) constitute the therapeutic options currently tested in the management of severe COVID-19 disease cases. Based on their beneficial effects, both ACE2 and Ang-(1-7) have also been suggested to slow the progression of experimental diabetic and hypertensive chronic kidney disease (CKD). Herein, we report a further step undertaken recently, utilizing this type of intervention in the management of evolving acute kidney injury (AKI), with the expectation of renal vasodilation and the attenuation of oxidative stress, inflammation, renal parenchymal damage and subsequent fibrosis. Most outcomes indicate that triggering the ACE2/Ang-(1-7)/MasR axis may be renoprotective in the setup of AKI. Yet, there is contradicting evidence that under certain conditions it may accelerate renal damage in CKD and AKI. The nature of these conflicting outcomes requires further elucidation.

Diabetic Nephropathy and COVID-19: The Potential Role of Immune Actors

“…Furthermore, a reduction and/or inactivation of ACE2 caused by SARS-CoV-2 binding can increase the ACE/Angiotensin II signaling pathway and related pathologies [10]. Thus, the COVID-19 disease was shown to be characterized by ACE2 depletion, probably playing a key role in the devastating cytokine storm embodying this disorder [11].…”

“…Conversely, it was suggested that ACE2 has the potential of slowing the progression of experimental diabetic chronic kidney disease [11], and it was found to be highly and significantly expressed in the kidney among individuals with chronic kidney diseases or DN [12].…”

“…Many outcomes indicate that triggering the ACE2/Angiotensin (1-7)/MasR axis may be nephroprotective in the context of AKI [11]. However, there are still conflicting outcomes that indicate it may accelerate renal damage in CKD and AKI under certain conditions [11].…”

Pathophysiology and Clinical Manifestations of COVID-19-Related Acute Kidney Injury—The Current State of Knowledge and Future Perspectives

“…Attention should be drawn to the potential therapeutic approach based on restoration of the impaired RAAS balance during COVID-19 infection [130]. It is suggested that the cytokine storm and the coagulopathy during COVID-19 infection may be linked to the depletion of ACE2 and AG1-7, which, in the conditions of homeostasis, has a visible renoprotective impact [130]. Stimulation of the ACE2/AG1-7/MasR axis may be a potential target for COVID-19-associated AKI treatment.…”

The relationship between autoantibodies targeting GPCRs and the renin-angiotensin system associates with COVID-19 severity

“…Autoantibodies have been identified in patients with coronavirus disease 2019 (COVID- 19), suggesting that the infection by severe acute respiratory syndrome virus 2 (SARS-CoV-2) can evolve to a systemic autoimmune disease [1][2][3][4][5] . For instance, high levels of antiphospholipid autoantibodies have been linked to severe respiratory disease by inducing neutrophil extracellular traps (NETs) and venous thrombosis 4,[6][7][8][9] .…”