{"doi":"10.34067/kid.0005592022","title":"ACE2 in the Urine: Where Does It Come From?","abstract":"Introduction An enzyme that metabolizes angiotensin II (Ang II) and other substrates was discovered in 2000, and was termed angiotensin converting enzyme 2 (ACE2) because of its substantial homology with ACE. Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, ACE2 has received unprecedented attention because in its membrane-bound form, it is the essential cell-entry receptor for severe acute respiratory syndrome coronavirus 2 (1). ACE2 has a single zinc metalloprotease active site and acts as a monocarboxypeptidase, cleaving a hydrophobic or basic amino acid (aa) from the C-terminus of small peptides. Within the renin angiotensin system (RAS), enzymatic actions of ACE2 are in opposition to those of its homolog ACE, such that ACE forms Ang II, whereas ACE2 fosters its degradation by forming Ang 1–7. This action is important at the tissue level, and seemingly minor in the systemic circulation, where other RAS enzymes are involved in the metabolism of Ang II (2). The ability of ACE2 to downregulate the RAS within the kidney prompted us to design shorter forms of ACE2 as novel renal therapeutics that can pass the glomerular filtration barrier (3). In this article, we discuss the different forms of enzymatically active ACE2 present in the kidney and urine. Kidney ACE2 A membrane-bound full-length (FL) form of ACE2 is abundantly expressed in the kidney, mainly at the apical surface of proximal tubules, but also in glomerular epithelial cells (podocytes), parietal cells in the Bowman’s capsule, and in the renal vasculature (4). Within the renal vasculature, ACE2 is present in the tunica media, but absent or weakly expressed in endothelial cells (4). Increased albuminuria and kidney lesions were observed in aged ACE2-deficient mice, and after pharmacological ACE2 inhibition in diabetic mice, suggesting that amplifying ACE2 could have therapeutic potential for kidney disease (5). There are different forms of enzymatically active ACE2 that need to be recognized (Figure 1). The tissue form of ACE2 is bound to the cell membrane as an 805 aa–long FL protein. The main part of FL-ACE2 is present in the extracellular space (ectodomain), encompassing the 740 N-terminal aa and containing the catalytic unit, which determines enzyme activity. FL-ACE2 is anchored to the cell membrane by a short transmembrane domain (aa 741–768) and has a small intracellular C-terminal tail (aa 769–805) with cell-signaling properties (6). The ectodomain of the FL-ACE2, when detached from the plasma membrane, is referred to as soluble ACE2. The term soluble means the protein is not membrane or tissue bound, but rather is freely dissolved in plasma, interstitial fluid, and other body fluids, such as the urine and the cerebrospinal fluid. The soluble ACE2 that is shed mainly by the action of a metalloproteinase ADAM17 is catalytically active, and hydrolyzes Ang II to Ang 1–7 (7,8). The FL form of ACE2 can also circulate bound to the membrane of exosomes (9). This form, although circulating, should not be considered soluble ACE2.Figure 1.: Different forms of ACE2 with preserved enzymatic activity and hypothetical formation of small soluble fragments. Upper panel. In kidney tissue, a full-length (FL) angiotensin converting enzyme 2 (ACE2) of 805 amino acids (aa) is a plasma membrane–bound protein with a large part protruding into the extracellular space (ectodomain ACE2 with 740 aa). A small membrane domain (red) anchors the FL-ACE2 in the plasma membrane and a short C-terminal tail (green) with cell-signaling properties appears on the intracellular site of the kidney cell. The 740 aa–long ectodomain dimerizes and the total size of native FL-ACE2 is 98 kDa ×2. The ectodomain contains the catalytic unit (egg shape, brown) responsible for enzyme activity. Lower panel. In the urine, ACE2 can be found as an FL-ACE2 bound to the membrane of exosomes. The FL-ACE2 is the source of soluble ACE2 fragments, which under denaturing conditions (SDS- PAGE), woul","journal":"Kidney360","year":2022,"id":287986,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9594,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":227843,"name":"Daniel Batlle","orcid":"0000-0002-5878-9046","position":1,"is_corresponding":false},{"id":227844,"name":"Jan Wysocki","orcid":"0000-0002-8429-272X","position":0,"is_corresponding":true}],"reference_count":16,"raw_metadata":null,"created_at":"2026-07-19T00:30:11.069895Z","pmid":"36591363","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}