Angiotensin-Converting Enzyme 2 in the Pathogenesis of Renal Abnormalities Observed in COVID-19 Patients

Abstract

Coronavirus disease 2019 (COVID-19) was first reported in late December 2019 in Wuhan, China. The etiological agent of this disease is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the high transmissibility of the virus led to its rapid global spread and a major pandemic (ongoing at the time of writing this review). The clinical manifestations of COVID-19 can vary widely from non-evident or minor symptoms to severe acute respiratory syndrome and multi-organ damage, causing death. Acute kidney injury (AKI) has been recognized as a common complication of COVID-19 and in many cases, kidney replacement therapy (KRT) is required. The presence of kidney abnormalities on hospital admission and the development of AKI are related to a more severe presentation of COVID-19 with higher mortality rate. The high transmissibility and the broad spectrum of clinical manifestations of COVID-19 are in part due to the high affinity of SARS-CoV-2 for its receptor, angiotensin (Ang)-converting enzyme 2 (ACE2), which is widely expressed in human organs and is especially abundant in the kidneys. A debate on the role of ACE2 in the infectivity and pathogenesis of COVID-19 has emerged: Does the high expression of ACE2 promotes higher infectivity and more severe clinical manifestations or does the interaction of SARS-CoV-2 with ACE2 reduce the bioavailability of the enzyme, depleting its biological activity, which is closely related to two important physiological systems, the renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS), thereby further contributing to pathogenesis. In this review, we discuss the dual role of ACE2 in the infectivity and pathogenesis of COVID-19, highlighting the effects of COVID-19-induced ACE2 depletion in the renal physiology and how it may lead to kidney injury. The ACE2 downstream regulation of KKS, that usually receives less attention, is discussed. Also, a detailed discussion on how the triad of symptoms (respiratory, inflammatory, and coagulation symptoms) of COVID-19 can indirectly promote renal injury is primary aborded.

The des-Arg9-bradykinin/B1R axis: Hepatic damage in COVID-19

“…Based on previous studies demonstrating that SARS-CoV-2 binds to the ACE2 enzyme ( Jackson et al, 2021 ), it is possible to postulate that SARS-CoV-2/ACE2 binding might impairs the inactivation process of des-Arg 9 -BK, as ACE2 is well-known to degrade des-Arg 9 -BK ( Sodhi et al, 2018 ; Tabassum et al, 2022 ). In this aspect, it has been suggested that kidney injury caused by SARS-CoV-2 could also be due, at least in part, to the exacerbation of des-Arg 9 -BK/B1R axis effects ( Azinheira Nobrega Cruz et al, 2021 ), as it has been shown here. Thus, less des-Arg 9 -BK inactivation combined with its longer systemic blood half-life ( Cyr et al, 2001 ; Jackson et al, 2021 ) might partially explain the higher circulating levels of des-Arg 9 -BK in COVID-19 patients.…”

Effectiveness of vaccination in reducing hospitalization and mortality rates in dialysis patients with Omicron infection in China: A single-center study

“…ACE2 is mainly present in the respiratory system and has also been found in gastrointestinal tract, heart, kidneys, and brain. 5–8 Thus, SARS-CoV-2 affects lungs as well as other organs and patients may die from multiorgan failure. 9 , 10 Kidney disease most commonly associated with SARS-CoV-2 infection is acute kidney injury (AKI) with histopathological alterations such as acute tubular necrosis.…”

Can Renin-Angiotensin System Inhibitors Protect Against Acute Kidney Injury in Patients With COVID-19?

“…Potential explanations for the kidney-related benefits of RAS inhibitors include the ability of ARBs to compete with SARS-CoV-2 for the binding to the ACE2 receptors found in proximal tubular cells (4). In addition, the increased production of angiotensin II seems to drive the occurrence of kidney injury, and RAS inhibitors could block the physiologic effect of angiotensin II (5). Therefore, we urge the performance of clinical trials to investigate the potential protective effects of RAS inhibitors against the development of acute kidney injury in patients with COVID-19.…”

“…Accordingly, our overarching aim was to examine sex determinants of responses to ARBs and ACEis in acute COVID-19. Mechanisms of preferential ARBs' efficacy for AKI in males in acute COVID-19 could include greater renal injury in males due to direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced renal injury, lymphocyte infiltration, diffuse proximal tubule injury, and acute tubular necrosis (4,5). Postmortem renal tissue of COVID-19 patients with AKI shows viral particles in the kidney and SARS-CoV-2 nucleoprotein antigen accumulation in renal tubules (4,5).…”

“…Mechanisms of preferential ARBs' efficacy for AKI in males in acute COVID-19 could include greater renal injury in males due to direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced renal injury, lymphocyte infiltration, diffuse proximal tubule injury, and acute tubular necrosis (4,5). Postmortem renal tissue of COVID-19 patients with AKI shows viral particles in the kidney and SARS-CoV-2 nucleoprotein antigen accumulation in renal tubules (4,5). There is a potential causal role for shock (cardiogenic, obstructive due to pulmonary emboli, or distributive shock) in acute COVID-19induced AKI; consequent use of vasopressors could also contribute to AKI.…”