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The epigenetic modifier KDM6A is an X chromosome-expressed lysine demethylase and molecular scaffold that escapes X chromosome inactivation. Here, we compared the effects of deletion of KDM6A from kidney tubule epithelial cells in female and male mice (KDM6A\n                  <jats:sup>TubKO<\/jats:sup>\n                  ). Knockout of KDM6A from tubule cells aggravated kidney fibrosis caused by unilateral ureteral obstruction (UUO) in female mice, whereas male mice were unaffected by KDM6A absence. Unexpectedly, female (but not male) KDM6A\n                  <jats:sup>TubKO<\/jats:sup>\n                  mice developed spontaneous glucosuria that, when stressed by ligation of one ureter, presented as polyuria and a Fanconi renotubular syndrome-like picture affecting the unobstructed kidney. Absence of KDM6A from tubule epithelial cells of female mice caused mitochondrial circularization, tubule cell vacuolization with focal atrophy and lymphoid infiltration, and diminished sodium\/glucose cotransporter 2 (SGLT2). Spatial transcriptomics and untargeted metabolomics revealed that knockout of KDM6A in female mice caused a shift in gene programs and metabolic pathways indicative of tubule cell metabolic dysfunction. In male mice, transcripts of the Y chromosome-expressed gametolog of\n                  <jats:italic>Kdm6a<\/jats:italic>\n                  ,\n                  <jats:italic>Uty<\/jats:italic>\n                  were present in tubule epithelial cells at levels comparable to\n                  <jats:italic>Kdm6a<\/jats:italic>\n                  and they were upregulated with UUO. In summary, KDM6A is essential for normal tubule epithelial cell homeostasis in females but not in males. KDM6A and UTY are a dynamically regulated X-Y gene pair with at least partial compensatory overlap in function necessary for the preservation of kidney health and stress tolerance.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical abstract.<\/jats:title>\n                  <jats:fig position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"740137v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.22.740137","type":"posted-content","created":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T03:55:14Z","timestamp":1784951714000},"source":"Crossref","is-referenced-by-count":0,"title":["Sex-dependent control of renal tubular homeostasis and stress tolerance by KDM6A"],"prefix":"10.64898","author":[{"given":"Lisa Y. 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