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Renin-angiotensin-aldosterone system inhibitors, such as enalapril, have been used for decades as antiproteinuric, antihypertensive, and kidney-protective agents. Still, the exact cell type of action and the molecular mechanism of drug action are elusive. Previous work has primarily emphasized injury patterns in the proximal nephron, leaving potential contributions of other nephron segments insufficiently characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here, we leveraged state-of-the-art single-cell transcriptomics in the Zucker spontaneously hypertensive fatty obese rat to elucidate potential target cells and driver molecules exerting enalapril drug effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified injured cell states of the distal nephron in the context of prolonged enalapril treatment. We showed cathepsin D, a tissue renin-angiotensin-aldosterone system effector, as an important regulator of enalapril effects and revealed triggering receptor expressed on myeloid cells 2+ residential macrophages as top receivers of distal nephron\u2013derived signals. Finally, we showed that enalapril-associated gene signatures allow stratification of human kidney samples by disease-relevant outcome measures such as kidney function and fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We reported cathepsin D as an important regulator of enalapril effects, involving cross-talk between the distal nephron and triggering receptor expressed on myeloid cells 2+ residential macrophages. We also demonstrated that enalapril-associated gene signatures allow stratification of human kidney samples by disease-relevant outcome measures.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.0000000995","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T17:00:23Z","timestamp":1767805223000},"page":"1438-1456","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":2,"title":["Single-Cell Resolution Drug Effects of Renin-Angiotensin-Aldosterone Blockade in ZSF1 Rat Diabetic Kidney Disease"],"prefix":"10.1681","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0508-1260","authenticated-orcid":false,"given":"Michael S.","family":"Balzer","sequence":"first","affiliation":[{"name":"Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Perelman School of Medicine, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Penn\/CHOP Kidney Innovation Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Department of Nephrology and Medical Intensive Care, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany"},{"name":"Berlin Institute of Health at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charit\u00e9 Clinician Scientist Program, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Perelman School of Medicine, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Penn\/CHOP Kidney Innovation Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8875-0070","authenticated-orcid":false,"given":"Amin","family":"Abedini","sequence":"additional","affiliation":[{"name":"Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Perelman School of Medicine, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Penn\/CHOP Kidney Innovation Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1512-8993","authenticated-orcid":false,"given":"Ziyuan","family":"Ma","sequence":"additional","affiliation":[{"name":"Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Perelman School of Medicine, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Penn\/CHOP Kidney Innovation Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5197-7394","authenticated-orcid":false,"given":"Yanjuan","family":"Hou","sequence":"additional","affiliation":[{"name":"Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Perelman School of Medicine, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania"},{"name":"Penn\/CHOP Kidney Innovation Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tejaswini","family":"Yadav","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Medical Intensive Care, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4473-7851","authenticated-orcid":false,"given":"Manuel","family":"Grundmann","sequence":"additional","affiliation":[{"name":"Pharmaceuticals, Research and Development, Bayer AG, Wuppertal, 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