{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T10:10:26Z","timestamp":1778062226803,"version":"3.51.4"},"reference-count":39,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK076077"],"award-info":[{"award-number":["R01DK076077"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK087635"],"award-info":[{"award-number":["R01 DK087635"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK132630"],"award-info":[{"award-number":["R01DK132630"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK105821"],"award-info":[{"award-number":["R01DK105821"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Genome-wide association studies (GWAS) have identified numerous loci associated with kidney function, but linking non-coding variants to causal effector genes remains challenging. By integrating fine-mapped GWAS data from 2.27 million individuals with kidney expression and epigenomic datasets, we identified KDM1A as a top-prioritized gene at a kidney function locus. KDM1A is broadly expressed across nephron segments in mouse and human kidneys and is consistently upregulated in chronic kidney disease (CKD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We generated lineage-specific Kdm1a knockout mice targeting nephron progenitors (Six2-Cre) or differentiated tubular epithelial cells (Cdh16\/Ksp1-Cre). Renal structure and function were assessed at baseline and following adenine-induced injury or unilateral ureteral obstruction using histology, immunoblotting, and gene expression analyses. Pharmacologic inhibition of KDM1A was evaluated in embryonic kidney explant cultures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Nephron progenitor-specific deletion of Kdm1a resulted in severe developmental defects, including nephron loss, cystic degeneration, tubular atrophy, and early interstitial fibrosis. Mutant kidneys exhibited suppression of progenitor and segment-specific epithelial programs, loss of solute transporter expression, and derepression of developmental signaling pathways, including Notch and Wnt, accompanied by apoptosis and inflammation. In contrast, deletion of Kdm1a in differentiated tubular epithelial cells preserved baseline renal structure and function and did not modify fibrotic responses to injury. Pharmacologic inhibition of KDM1A during kidney development phenocopied genetic loss and led to accumulation of H3K4 methylation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>KDM1A is a genetically supported, developmentally essential chromatin regulator required for nephron differentiation but dispensable in differentiated tubular epithelium. Its reactivation in CKD highlights a context-dependent epigenetic role and cautions against nonspecific KDM1A inhibition..<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ndt\/gfag073","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T12:26:52Z","timestamp":1777638412000},"source":"Crossref","is-referenced-by-count":0,"title":["KDM1A regulates nephron progenitor programs and is associated with human kidney disease risk"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3550-8299","authenticated-orcid":false,"given":"Lakshmi P","family":"Kolligundla","sequence":"first","affiliation":[{"name":"University of Pennsylvania Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, , Philadelphia, PA ,","place":["USA"]},{"name":"Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA ,","place":["USA"]},{"name":"Penn\/CHOP Kidney Innovation Center, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA ,","place":["USA"]},{"name":"Perelman School of Medicine, University of Pennsylvania Department of Genetics, , Philadelphia, PA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dhanunjay","family":"Mukhi","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, , Philadelphia, PA ,","place":["USA"]},{"name":"Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA ,","place":["USA"]},{"name":"Penn\/CHOP Kidney Innovation Center, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA ,","place":["USA"]},{"name":"Perelman School of Medicine, University of Pennsylvania Department of Genetics, , Philadelphia, PA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Levinsohn","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, , Philadelphia, PA ,","place":["USA"]},{"name":"Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA ,","place":["USA"]},{"name":"Penn\/CHOP Kidney Innovation Center, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA ,","place":["USA"]},{"name":"Perelman School of Medicine, University of Pennsylvania Department of Genetics, , Philadelphia, PA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andi","family":"Bergerson","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, , Philadelphia, PA ,","place":["USA"]},{"name":"Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA ,","place":["USA"]},{"name":"Penn\/CHOP Kidney Innovation Center, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA ,","place":["USA"]},{"name":"Perelman School of Medicine, University of Pennsylvania Department of Genetics, , Philadelphia, PA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanjuan","family":"Hou","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, , Philadelphia, PA ,","place":["USA"]},{"name":"Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA ,","place":["USA"]},{"name":"Penn\/CHOP Kidney Innovation Center, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA ,","place":["USA"]},{"name":"Perelman School of Medicine, University of Pennsylvania Department of Genetics, , Philadelphia, PA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongbo","family":"Liu","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, , Philadelphia, PA ,","place":["USA"]},{"name":"Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA ,","place":["USA"]},{"name":"Penn\/CHOP Kidney Innovation Center, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA ,","place":["USA"]},{"name":"Perelman School of Medicine, University of Pennsylvania Department of Genetics, , Philadelphia, PA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brain C","family":"Capell","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine, University of Pennsylvania Department of Dermatology, , Philadelphia, PA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katalin","family":"Susztak","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, , Philadelphia, PA ,","place":["USA"]},{"name":"Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA ,","place":["USA"]},{"name":"Penn\/CHOP Kidney Innovation Center, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA ,","place":["USA"]},{"name":"Perelman School of Medicine, University of Pennsylvania Department of Genetics, , Philadelphia, PA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"2026050605112552100_bib1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI165654","article-title":"Molecular pathways that drive diabetic kidney disease","volume":"133","author":"Mohandes","year":"2023","journal-title":"J Clin Invest"},{"key":"2026050605112552100_bib2","doi-asserted-by":"publisher","first-page":"2632","DOI":"10.1016\/j.immuni.2021.10.004","article-title":"APOL1 risk variants in individuals of African genetic ancestry drive endothelial cell defects that exacerbate sepsis","volume":"54","author":"Wu","year":"2021","journal-title":"Immunity"},{"key":"2026050605112552100_bib3","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1038\/s42255-023-00761-7","article-title":"NAD(+) precursor supplementation prevents mtRNA\/RIG-I-dependent inflammation during kidney injury","volume":"5","author":"Doke","year":"2023","journal-title":"Nat Metab"},{"key":"2026050605112552100_bib4","doi-asserted-by":"publisher","first-page":"eadn3079","DOI":"10.1126\/scitranslmed.adn3079","article-title":"Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) increases kidney disease risk by modulating ferroptosis","volume":"17","author":"Kolligundla","year":"2025","journal-title":"Sci Transl Med"},{"key":"2026050605112552100_bib5","doi-asserted-by":"publisher","first-page":"115462","DOI":"10.1016\/j.celrep.2025.115462","article-title":"The actin and microtubule network regulator WHAMM is identified as a key kidney disease risk gene","volume":"44","author":"Mukhi","year":"2025","journal-title":"Cell Rep"},{"key":"2026050605112552100_bib6","doi-asserted-by":"publisher","DOI":"10.1172\/JCI172963","article-title":"ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules","volume":"134","author":"Mukhi","year":"2023","journal-title":"J Clin Invest"},{"key":"2026050605112552100_bib7","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1016\/j.kint.2024.10.021","article-title":"The critical role of endoplasmic reticulum stress and the stimulator of interferon genes (STING) pathway in kidney fibrosis","volume":"107","author":"Andrade-Silva","year":"2025","journal-title":"Kidney Int"},{"key":"2026050605112552100_bib8","doi-asserted-by":"publisher","first-page":"5253","DOI":"10.1038\/s41467-022-32972-z","article-title":"Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression","volume":"13","author":"Wilson","year":"2022","journal-title":"Nat Commun"},{"key":"2026050605112552100_bib9","doi-asserted-by":"publisher","first-page":"1922","DOI":"10.1038\/s41588-025-02285-0","article-title":"Analysis of individual patient pathway coordination in a cross-species single-cell kidney atlas","volume":"57","author":"Klotzer","year":"2025","journal-title":"Nat Genet"},{"key":"2026050605112552100_bib10","doi-asserted-by":"publisher","first-page":"1712","DOI":"10.1038\/s41588-024-01802-x","article-title":"Single-cell multi-omic and spatial profiling of human kidneys implicates the fibrotic microenvironment in kidney disease progression","volume":"56","author":"Abedini","year":"2024","journal-title":"Nat Genet"},{"key":"2026050605112552100_bib11","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1038\/s41588-019-0407-x","article-title":"A catalog of genetic loci associated with kidney function from analyses of a million individuals","volume":"51","author":"Wuttke","year":"2019","journal-title":"Nat Genet"},{"key":"2026050605112552100_bib12","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1038\/s41588-021-00909-9","article-title":"Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments","volume":"53","author":"Sheng","year":"2021","journal-title":"Nat Genet"},{"key":"2026050605112552100_bib13","doi-asserted-by":"publisher","first-page":"eadp4753","DOI":"10.1126\/science.adp4753","article-title":"Kidney multiome-based genetic scorecard reveals convergent coding and regulatory variants","volume":"387","author":"Liu","year":"2025","journal-title":"Science"},{"key":"2026050605112552100_bib14","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1016\/j.cell.2004.12.012","article-title":"Histone demethylation mediated by the nuclear amine oxidase homolog LSD1","volume":"119","author":"Shi","year":"2004","journal-title":"Cell"},{"key":"2026050605112552100_bib15","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1038\/nature05671","article-title":"Opposing LSD1 complexes function in developmental gene activation and repression programmes","volume":"446","author":"Wang","year":"2007","journal-title":"Nature"},{"key":"2026050605112552100_bib16","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1038\/ng.268","article-title":"The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation","volume":"41","author":"Wang","year":"2009","journal-title":"Nat Genet"},{"key":"2026050605112552100_bib17","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1038\/s41588-023-01392-0","article-title":"CARMA is a new Bayesian model for fine-mapping in genome-wide association meta-analyses","volume":"55","author":"Yang","year":"2023","journal-title":"Nat Genet"},{"key":"2026050605112552100_bib18","doi-asserted-by":"publisher","first-page":"1721","DOI":"10.1038\/s41591-018-0194-4","article-title":"Renal compartment-specific genetic variation analyses identify new pathways in chronic kidney disease","volume":"24","author":"Qiu","year":"2018","journal-title":"Nat Med"},{"key":"2026050605112552100_bib19","doi-asserted-by":"publisher","first-page":"5214","DOI":"10.1038\/sj.emboj.7601381","article-title":"Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney","volume":"25","author":"Self","year":"2006","journal-title":"EMBO J"},{"key":"2026050605112552100_bib20","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1002\/jez.1402490109","article-title":"A staging system for mouse limb development","volume":"249","author":"Wanek","year":"1989","journal-title":"J Exp Zool"},{"key":"2026050605112552100_bib21","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1038\/s41563-024-02019-3","article-title":"Jamming of nephron-forming niches in the developing mouse kidney creates cyclical mechanical stresses","volume":"23","author":"Prahl","year":"2024","journal-title":"Nat Mater"},{"key":"2026050605112552100_bib22","doi-asserted-by":"publisher","first-page":"pdb.prot5558","DOI":"10.1101\/pdb.prot5558","article-title":"Organ culture and immunostaining of mouse embryonic kidneys","volume":"2011","author":"Barak","year":"2011","journal-title":"Cold Spring Harb Protoc"},{"key":"2026050605112552100_bib23","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.devcel.2022.12.008","article-title":"The developing murine kidney actively negotiates geometric packing conflicts to avoid defects","volume":"58","author":"Prahl","year":"2023","journal-title":"Dev Cell"},{"key":"2026050605112552100_bib24","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.stem.2008.05.020","article-title":"Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development","volume":"3","author":"Kobayashi","year":"2008","journal-title":"Cell Stem Cell"},{"key":"2026050605112552100_bib25","doi-asserted-by":"publisher","first-page":"1588","DOI":"10.3389\/fphys.2018.01588","article-title":"Regulation of renal differentiation by trophic factors","volume":"9","author":"Kurtzeborn","year":"2018","journal-title":"Front Physiol"},{"key":"2026050605112552100_bib26","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1038\/ki.2008.250","article-title":"HNF1beta and defective nephrogenesis: a role for interacting partners?","volume":"74","author":"Fischer","year":"2008","journal-title":"Kidney Int"},{"key":"2026050605112552100_bib27","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1046\/j.1523-1755.2001.00767.x","article-title":"Nephron endowment in glial cell line-derived neurotrophic factor (GDNF) heterozygous mice","volume":"60","author":"Cullen-McEwen","year":"2001","journal-title":"Kidney Int"},{"key":"2026050605112552100_bib28","doi-asserted-by":"publisher","first-page":"3232","DOI":"10.15252\/embj.201796525","article-title":"RBPJ\/CBF1 interacts with L3MBTL3\/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A\/LSD1","volume":"36","author":"Xu","year":"2017","journal-title":"EMBO J"},{"key":"2026050605112552100_bib29","doi-asserted-by":"publisher","first-page":"3907","DOI":"10.1242\/dev.143503","article-title":"Notch signaling promotes nephrogenesis by downregulating Six2","volume":"143","author":"Chung","year":"2016","journal-title":"Development"},{"key":"2026050605112552100_bib30","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/nm1731","article-title":"The Notch pathway in podocytes plays a role in the development of glomerular disease","volume":"14","author":"Niranjan","year":"2008","journal-title":"Nat Med"},{"key":"2026050605112552100_bib31","doi-asserted-by":"publisher","article-title":"Lysine-specific demethylase 1a is obligatory for gene regulation during kidney development","author":"Kota","DOI":"10.1101\/2025.02.25.640014"},{"key":"2026050605112552100_bib32","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1681\/ASN.2019080797","article-title":"Dnmt3a and Dnmt3b-decommissioned fetal enhancers are linked to kidney disease","volume":"31","author":"Guan","year":"2020","journal-title":"J Am Soc Nephrol"},{"key":"2026050605112552100_bib33","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.3390\/ijms26031230","article-title":"Conditional knockout Kdm2a reveals crucial involvement in development and function of kidney collecting ducts","volume":"26","author":"Xiong","year":"2025","journal-title":"Int J Mol Sci"},{"key":"2026050605112552100_bib34","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1038\/s42003-025-07695-8","article-title":"KDM5C and KDM5D mutations have different consequences in clear cell renal cell carcinoma cells","volume":"8","author":"Muller","year":"2025","journal-title":"Commun Biol"},{"key":"2026050605112552100_bib35","doi-asserted-by":"publisher","first-page":"1747","DOI":"10.1016\/j.cell.2025.02.023","article-title":"20 years of histone lysine demethylases: from discovery to the clinic and beyond","volume":"188","author":"Gray","year":"2025","journal-title":"Cell"},{"key":"2026050605112552100_bib36","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1016\/j.devcel.2018.05.010","article-title":"Progressive recruitment of mesenchymal progenitors reveals a time-dependent process of cell fate acquisition in mouse and human nephrogenesis","volume":"45","author":"Lindstrom","year":"2018","journal-title":"Dev Cell"},{"key":"2026050605112552100_bib37","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1681\/ASN.2022040460","article-title":"Tet2- and Tet3-mediated cytosine hydroxymethylation in Six2 progenitor cells in mice is critical for nephron progenitor differentiation and nephron endowment","volume":"34","author":"Liang","year":"2023","journal-title":"J Am Soc Nephrol"},{"key":"2026050605112552100_bib38","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1681\/ASN.2018070687","article-title":"DNMT1 in Six2 progenitor cells is essential for transposable element silencing and kidney development","volume":"30","author":"Li","year":"2019","journal-title":"J Am Soc Nephrol"},{"key":"2026050605112552100_bib39","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1186\/s13045-019-0811-9","article-title":"LSD1\/KDM1A inhibitors in clinical trials: advances and prospects","volume":"12","author":"Fang","year":"2019","journal-title":"J Hematol Oncol"}],"container-title":["Nephrology Dialysis Transplantation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ndt\/advance-article-pdf\/doi\/10.1093\/ndt\/gfag073\/68200537\/gfag073.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ndt\/advance-article-pdf\/doi\/10.1093\/ndt\/gfag073\/68200537\/gfag073.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T09:11:37Z","timestamp":1778058697000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ndt\/advance-article\/doi\/10.1093\/ndt\/gfag073\/8666274"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,1]]},"references-count":39,"URL":"https:\/\/doi.org\/10.1093\/ndt\/gfag073","relation":{},"ISSN":["0931-0509","1460-2385"],"issn-type":[{"value":"0931-0509","type":"print"},{"value":"1460-2385","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,1]]},"article-number":"gfag073"}}