miR‐135a‐5p Is a Promising Target to Prevent the Glomerulosclerosis Associated with Podocyte Developmental Toxicity in Offspring Induced by Prenatal Dexamethasone Exposure

Podocyte developmental defects are pivotal in initiating glomerulosclerosis. 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‐135a‐5p, which targets KLF4. In differentiating metanephric mesenchymal stem cells, dexamethasone reduced KLF4 while increasing miR‐135a‐5p expression. Chromatin analyses revealed that activated glucocorticoid receptor (GR) bound the miR‐135a‐5p promoter and recruited P300, enhancing histone acetylation and supporting sustained upregulation of miR‐135a‐5p. Elevated miR‐135a‐5p suppressed KLF4, impairing podocyte development and promoting long‐term glomerular injury. Early administration of a miR‐135a‐5p antagomir partially restored podocyte markers and ameliorated PDE‐induced sclerosis. These findings identify a previously unrecognized GR–P300–miR‐135a‐5p/KLF4 epigenetic axis governing fetal programming of podocyte injury. Our work provides mechanistic insight into the developmental origins of glucocorticoid‐induced kidney disease and highlights miR‐135a‐5p as a promising biomarker and potential therapeutic target for preventing fetal‐origin glomerulosclerosis.