Transgenic animal models for the functional analysis of ACE2

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase involved in the metabolism of biologically active peptides. Its most important physiological function is the conversion of angiotensin II to angiotensin-(1–7), which initiates the protective arm of the renin–angiotensin system (RAS). To evaluate the physiological relevance of this revision of the RAS, numerous different animal models have been engineered with genetic alterations in ACE2 expression. The characterization of ACE-deficient mice led to the discovery of a second function of the protein being responsible for the trafficking of the neutral amino acid transporter B(0)AT1 to the plasma membrane of gut epithelial cells, thereby promoting the intestinal uptake of certain amino acids. These two different functions are mediated by two domains of ACE2 with homologies to ACE and to collectrin, respectively, which have been fused during evolution. Moreover, some coronaviruses, such as SARS-CoV and SARS-CoV-2, hijack ACE2 for their entry into host cells, and again genetically altered mouse models expressing human ACE2 became instrumental to study virus infection and to develop therapeutic strategies. This chapter will summarize the different transgenic and knockout mouse and rat models with altered expression of ACE2 and the insights they have provided for the functions of this versatile protein. © 2023 Elsevier Inc. All rights reserved.