Angiotensin-converting enzyme 2 decreased expression during kidney inflammatory diseases: implications to predisposing to COVID-19 kidney complications

Abstract

Although angiotensin-converting enzyme 2 (ACE2) is the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into target cells, it has a major anti-inflammatory role by hydrolyzing angiotensin II, a proinflammatory mediator, to angiotensin 1-7, an anti-inflammatory molecule. Kidneys are a common target of SARS-CoV-2 infection. Both roles for direct viral infection and downstream effects of a cytokine storm syndrome have been suggested as mechanisms driving kidney injury in patients with coronavirus disease 2019 (COVID-19).1Naicker S. Yang C.-W. Hwang S.-J. et al.The novel coronavirus 2019 epidemic and kidneys.Kidney Int. 2020; 97: 824-828Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar It was recently reported that patients with glomerulonephritis have higher mortality and risk of acute kidney injury associated with SARS-CoV-2 infection.2Waldman M. Soler M.J. García-Carro C. et al.Results from the IRoc-GN international registry of patients with COVID-19 and glomerular disease suggest close monitoring.Kidney Int. 2021; 99: 227-237Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar We hypothesize that downregulation of the ACE2/angiotensin 1-7 pathway may account for higher kidney complications in these patients. We found both mRNA and protein expression of ACE2 is reduced in models of inflammation targeting glomeruli (anti–glomerular basement glomerulonephritis) and the tubulointerstitium (tubulointerstitial nephritis) compared with a normal kidney (Figure 1a–c). This is consistent with reduced ACE2 mRNA and protein expression in human kidney inflammatory diseases, including diabetic and IgA nephropathies.3Soler M.J. Wysocki J. Batlle D. ACE2 alterations in kidney disease.Nephrol Dial Transplant. 2013; 28: 2687-2697Crossref PubMed Scopus (84) Google Scholar We also identified that angiotensin 1-7, the product of ACE2, inhibits macrophage migration to C-X-C Motif Chemokine Ligand 16 (CXCL16), C-C Motif Chemokine Ligand 2 (CCL2)/Monocyte chemoattractant protein-1 (MCP-1), and C-C Motif Chemokine Ligand 5 (CCL5)/Regulated upon Activation, Normal T-Cell Expressed and Presumably Secreted (RANTES) chemokines (Figure 1d). Angiotensin 1-7 also suppresses glomerular endothelial cell CXCL10/interferon-γ–inducible protein 10 (IP10)–angiotensin II dependent induction (Figure 1e). Notably, angiotensin 1-7 infusion in rats with anti–glomerular basement glomerulonephritis reduced macrophage infiltration and glomerular damage (Figure 1f). These data demonstrate that during kidney inflammation, ACE2 downregulation could dampen the ACE2/angiotensin 1-7 anti-inflammatory pathway, resulting in worse inflammation. Consequently, patients with kidney inflammatory diseases could be more susceptible to kidney complications from COVID-19 (Figure 1g), because inflammation and previous kidney disease predict acute kidney injury and mortality after acute kidney injury.4Murashima M. Nishimoto M. Kokubu M. et al.Inflammation as a predictor of acute kidney injury and mediator of higher mortality after acute kidney injury in non-cardiac surgery.Sci Rep. 2019; 9: 20260Crossref PubMed Scopus (30) Google Scholar Download .pdf (.09 MB) Help with pdf files Supplementary File (PDF) Results from the IRoc-GN international registry of patients with COVID-19 and glomerular disease suggest close monitoringKidney InternationalVol. 99Issue 1PreviewThe effects of SARS-CoV-2 infection on individuals with immune-mediated glomerulonephritis, who are often undergoing immunosuppressive treatments, are unknown. Therefore, we created the International Registry of COVID infection in glomerulonephritis (IRoc-GN) and identified 40 patients with glomerulonephritis and COVID-19 followed in centers in North America and Europe. Detailed information on glomerulonephritis diagnosis, kidney parameters, and baseline immunosuppression prior to infection were recorded, as well as clinical presentation, laboratory values, treatment, complications, and outcomes of COVID-19. Full-Text PDF The Novel Coronavirus 2019 epidemic and kidneysKidney InternationalVol. 97Issue 5PreviewNovel Coronavirus disease (COVID-19) is a newly discovered contagious disease caused by severe acute respiratory syndrome (SARS)–coronavirus (CoV)-2 virus, primarily manifesting as an acute respiratory illness with interstitial and alveolar pneumonia, but it can affect multiple organs such as the kidney, heart, digestive tract, blood, and nervous system.1 The rapidly spreading outbreak, which first emerged in Wuhan, Hubei Province, China, in December 2019, has since been declared a global pandemic. Full-Text PDF