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Although antenatal glucocorticoid therapy improves neonatal outcomes, prenatal dexamethasone exposure (PDE) may trigger intrauterine programming that predisposes offspring to chronic kidney disease, yet its mechanisms remain elusive. Here, we show that PDE disrupts podocyte differentiation and induces glomerulosclerosis in adult rat offspring. Mechanistically, PDE downregulated KLF4 and upregulated miR\u2010135a\u20105p, which targets KLF4. In differentiating metanephric mesenchymal stem cells, dexamethasone reduced KLF4 while increasing miR\u2010135a\u20105p expression. Chromatin analyses revealed that activated glucocorticoid receptor (GR) bound the miR\u2010135a\u20105p promoter and recruited P300, enhancing histone acetylation and supporting sustained upregulation of miR\u2010135a\u20105p. Elevated miR\u2010135a\u20105p suppressed KLF4, impairing podocyte development and promoting long\u2010term glomerular injury. Early administration of a miR\u2010135a\u20105p antagomir partially restored podocyte markers and ameliorated PDE\u2010induced sclerosis. These findings identify a previously unrecognized GR\u2013P300\u2013miR\u2010135a\u20105p\/KLF4 epigenetic axis governing fetal programming of podocyte injury. Our work provides mechanistic insight into the developmental origins of glucocorticoid\u2010induced kidney disease and highlights miR\u2010135a\u20105p as a promising biomarker and potential therapeutic target for preventing fetal\u2010origin glomerulosclerosis.<\/jats:p>","DOI":"10.1002\/advs.202519743","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T12:22:33Z","timestamp":1769775753000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["miR\u2010135a\u20105p Is a Promising Target to Prevent the Glomerulosclerosis Associated with Podocyte Developmental Toxicity in Offspring Induced by Prenatal Dexamethasone Exposure"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5894-8155","authenticated-orcid":false,"given":"Xiaoqi","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Pharmacology Wuhan University School of Basic 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