ACE2, From the Kidney to SARS-CoV-2: Donald Seldin Award Lecture 2023

Daniel Batlle*, Luise Hassler, Jan Wysocki

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

ACE2 (angiotensin-converting enzyme 2) is a monocarboxypeptidase that cleaves Ang II (angiotensin II) among other substrates. ACE2 is present in the cell membrane of many organs, most abundantly in epithelial cells of kidney proximal tubules and the small intestine, and also exists in soluble forms in plasma and body fluids. Membrane-bound ACE2 exerts a renoprotective action by metabolizing Ang II and therefore attenuating the undesirable actions of excess Ang II. Therefore, soluble ACE2, by downregulating this peptide, may exert a therapeutic action. Our laboratory has designed ACE2 truncates that pass the glomerular filtration barrier to target the kidney renin-angiotensin system directly and, therefore, compensate for loss of kidney membrane-bound ACE2. Membrane-bound ACE2 is also the essential receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Soluble ACE2 proteins have been studied as a way to intercept SARS-CoV-2 from binding to membrane-bound ACE2 and prevent cell entry of SARS-CoV-2 altogether. We bioengineered a soluble ACE2 protein, termed ACE2 618-DDC-ABD, with increased binding affinity for SARS-CoV-2 and prolonged duration of action, which, when administered intranasally, provides near-complete protection from lethality in k18hACE2 mice infected with different SARS-CoV-2 variants. The main advantage of soluble ACE2 proteins for the neutralization of SARS-CoV-2 is their immediate onset of action and universality for current and future emerging SARS-CoV-2 variants. It is notable that ACE2 is critically involved in 2 dissimilar functions: as a receptor for cell entry of many coronaviruses and as an enzyme in the metabolism of Ang II, and yet in both cases, it is a therapeutic target.

Original languageEnglish (US)
Pages (from-to)166-180
Number of pages15
JournalHypertension
Volume82
Issue number2
DOIs
StatePublished - Feb 1 2025

Funding

The authors are most grateful to the Joseph and Bessie Feinberg Foundation for their philanthropic support to this study. National Institutes of Health grants 1R21 AI166940-01 and 1R43HL160432-01A1, Dr Michael M. Abecassis Transplant Innovation Endowment Grant from the Northwestern Comprehensive Transplant Center and the Chicago Biomedical Consortium.

Keywords

  • COVID-19
  • SARS-CoV-2
  • angiotensin II
  • angiotensin-converting enzyme 2
  • virus internalization

ASJC Scopus subject areas

  • Internal Medicine

Fingerprint

Dive into the research topics of 'ACE2, From the Kidney to SARS-CoV-2: Donald Seldin Award Lecture 2023'. Together they form a unique fingerprint.

Cite this