Journal of Clinical Medicine Review Angiotensin-(1-7)—A Potential Remedy for AKI: Insights Derived from the COVID-19 Pandemic Samuel N. Heyman 1, *, Thomas Walther 2,3 and Zaid Abassi 4,5   Citation: Heyman, S.N.; Walther, T.; Abassi, Z. Angiotensin-(1-7)—A Potential Remedy for AKI: Insights Derived from the COVID-19 Pandemic. J. Clin. Med. 2021, 10, 1200. https://doi.org/10.3390/ jcm10061200 Academic Editor: Clive N. May Received: 9 February 2021 Accepted: 8 March 2021 Published: 13 March 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Medicine, Hadassah Hebrew University Hospital, Mt. Scopus, Jerusalem 91240, Israel 2 Department of Pharmacology and Therapeutics, School of Medicine and School of Pharmacy, University College Cork, T12 YN60 Cork, Ireland; t.walther@ucc.ie 3 Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, 17489 Greifswald, Germany 4 Department of Physiology and Biophysics, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3200003, Israel; abassi@technion.ac.il 5 Department of Laboratory Medicine, Rambam Health Campus, Haifa 3109601, Israel * Correspondence: Heyman@cc.huji.ac.il 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. Keywords: COVID-19; acute kidney injury; angiotensin 1-7; Mas receptor; ACE2; RAAS 1. Introduction Acute kidney injury (AKI) remains a principal cause of morbidity and mortality among hospitalized patients, and plays an important role in the initiation and progression of chronic kidney disease (CKD). We now better understand AKI as a heterogeneous disease entity with diverse etiologies and pathophysiologies, including tubular injury generated by hypoxia, oxidative stress, direct cytotoxicity and inflammation [1]. However, most interventions aimed at the prevention or amelioration of evolving AKI so far have failed, perhaps, in part, because nearly all strategies and innovations were tested using flawed experimental animal models that do not replicate the relevant clinical scenario [1,2]. Angiotensin (Ang) 1-7, mainly generated by the angiotensin converting enzyme (ACE)2, until recently a disregarded axis of the renin–angiotensin system (RAS) [3], exerts renal vasodilation and attenuates inflammation, oxidative stress, apoptosis and fibrosis. Although known about for over 20 years, the interest in Ang-(1-7) and its downstream J. Clin. Med. 2021, 10, 1200. https://doi.org/10.3390/jcm10061200 https://www.mdpi.com/journal/jcm