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Additionally, Lcn2 was also upregulated in\n                    <jats:italic>Dot1l<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>AC<\/jats:italic>\n                    <\/jats:sup>\n                    mice. Here, we investigated whether and how Lipocalin 2 (Lcn2) contributes to this pathway. We performed in\u00a0vivo studies using multiple mouse models with targeted deletion of\n                    <jats:italic>Dot1l<\/jats:italic>\n                    ,\n                    <jats:italic>Lcn2<\/jats:italic>\n                    , or\n                    <jats:italic>Edn1<\/jats:italic>\n                    in distal nephron segments or globally. Human CKD RNA\u2010seq data analysis and in\u00a0vitro studies in IMCD3 cells were conducted to validate the in\u00a0vivo results. Because\n                    <jats:italic>Lcn2<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mice are available and Lcn2 is barely detectable in IMCD3 cells, Lcn2 down\u2010 and upregulation experiments were performed in mice and IMCD3 cells, respectively. Several approaches, including immunofluorescence staining and in\u00a0situ hybridization, were employed to identify and confirm the Lcn2 profibrotic role. Both\n                    <jats:italic>Dot1l<\/jats:italic>\n                    deletion in AP in\n                    <jats:italic>Dot1l<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>AC<\/jats:italic>\n                    <\/jats:sup>\n                    mice and\n                    <jats:italic>Dot1l<\/jats:italic>\n                    silencing in IMCD3 cells upregulated Lcn2. Global deletion of Lcn2 in\n                    <jats:italic>Dot1l<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>AC<\/jats:italic>\n                    <\/jats:sup>\n                    mice attenuated HDAC2 and ET1 levels and reduced kidney fibrosis, establishing Lcn2 as a downstream effector of\n                    <jats:italic>Dot1l<\/jats:italic>\n                    \u2010deletion\u2010induced kidney fibrosis. Although conditional knockout of\n                    <jats:italic>Edn1<\/jats:italic>\n                    in\n                    <jats:italic>Dot1l<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>AC<\/jats:italic>\n                    <\/jats:sup>\n                    mice showed Lcn2 expression comparable to that in\n                    <jats:italic>Dot1l<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>AC<\/jats:italic>\n                    <\/jats:sup>\n                    mice, they exhibited reduced kidney fibrosis, suggesting that Lcn2 lies upstream of ET1\u2010mediated injury. Reanalysis of a human chronic kidney disease (CKD) dataset revealed that downregulation of\n                    <jats:italic>DOT1L<\/jats:italic>\n                    was coupled with upregulation of LCN2, HDAC2, and ET1, recapitulating our findings in\n                    <jats:italic>Dot1l<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>AC<\/jats:italic>\n                    <\/jats:sup>\n                    mice. These results were further validated in IMCD3 cells, in which Lcn2 was upregulated by\n                    <jats:italic>Dot1l<\/jats:italic>\n                    silencing, and addition of 293 T cells\u2010secreted or recombinant Lcn2 led to increased HDAC2 and ET1 expression. Loss of\n                    <jats:italic>Dot1l<\/jats:italic>\n                    in AP upregulates Lcn2, which promotes kidney fibrosis by increasing HDAC2 and ET1. Our findings add Lcn2 as a new component to define a more complicated Dot1l\u2013Lcn2\u2013HDAC2\u2013ET1 pro\u2010fibrotic pathway that links AP\u2010derived distal renal segments to kidney fibrosis.\n                  <\/jats:p>","DOI":"10.1096\/fj.202600007rr","type":"journal-article","created":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T10:13:24Z","timestamp":1776507204000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lipocalin 2 Links Aquaporin 2\n                    <sup>+<\/sup>\n                    Progenitor Cell\u2010Derived Distal Renal Segments to Kidney Fibrosis"],"prefix":"10.1096","volume":"40","author":[{"given":"Akaki","family":"Tsilosani","sequence":"first","affiliation":[{"name":"Department of Regenerative &amp; Cancer Cell Biology Albany Medical College  Albany New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Regenerative &amp; Cancer Cell Biology Albany Medical College  Albany New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn","family":"Mulroy","sequence":"additional","affiliation":[{"name":"Department of Regenerative &amp; Cancer Cell Biology Albany Medical College  Albany New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noor","family":"Pirzada","sequence":"additional","affiliation":[{"name":"Department of Regenerative &amp; Cancer Cell Biology Albany Medical College  Albany New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sana","family":"Shehzad","sequence":"additional","affiliation":[{"name":"Department of Regenerative &amp; Cancer Cell Biology Albany Medical College  Albany New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreya","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Disease Albany Medical College  Albany New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Disease Albany Medical College  Albany New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enuo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Regenerative &amp; Cancer Cell Biology Albany Medical College  Albany New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunny","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Regenerative &amp; Cancer Cell Biology Albany Medical College  Albany New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Knowles","sequence":"additional","affiliation":[{"name":"Department of Regenerative &amp; Cancer Cell Biology Albany Medical College  Albany New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fizza","family":"Sajjad","sequence":"additional","affiliation":[{"name":"Department of Regenerative &amp; Cancer Cell Biology Albany Medical College  Albany New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Regenerative &amp; Cancer Cell Biology Albany Medical College  Albany New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,18]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"United States D. o. 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