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<p>Over 800 million people globally suffer from chronic kidney disease (CKD). Maternal obesity has emerged as a risk factor for CKD in offspring, but the mechanisms remain unclear. In this study, we use mouse models of maternal obesity to investigate macrophage involvement in offspring kidneys. Multi-omics analyses revealed that maternal obesity accelerates kidney disease in male offspring through dysregulated crosstalk between proximal tubules (PT) and macrophages. PT-derived 20-hydroxyeicosatetraenoic acid (20-HETE) promotes mitochondrial hyperactivity and macrophage to myofibroblast transition (MMT) via <i>Ffar1</i> in macrophages. Targeting 20-HETE or depleting <i>Ffar1</i> in offspring of obese mothers markedly reduces kidney pathology. Hormone screening identified 3,3,5-Triiodo-L-thyronine (T3) as a factor that enhances <i>Ffar1</i> expression in macrophages. Mechanistically, the T3 receptor (TRβ) binds to an enhancer we identify upstream of the gene, promoting <i>Ffar1</i> transcription via the TRβ-P300-BRD4 regulatory axis. These findings highlight T3 and 20-HETE co-activated MMT as a central mechanism to kidney disease in offspring of obese mothers, offering potential therapeutic targets.</p>

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Maternal obesity induces macrophage to myofibroblast transition in kidneys of male offspring through a pathway driven by 20-hydroxyeicosatetraenoic acid

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月14日

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  • Fengbo Zhong,
  • Xingyu Huang,
  • Huiru Sun,
  • Mengxuan Wang,
  • Qi Qi,
  • Xinlin Song,
  • Kai Lin,
  • Zhuozhuo Li,
  • Jiayun Shen,
  • Qiuyu Lu,
  • Miaomiao Li,
  • Jiaqi Zhang,
  • Ling Yuan,
  • Jia Lv,
  • Xin Wang,
  • Yiyun Cheng,
  • Qihui Wu,
  • Shaohua Fan,
  • Shougang Zhuang,
  • Jia Rao,
  • Dali Li,
  • Yuting Guan

摘要

Over 800 million people globally suffer from chronic kidney disease (CKD). Maternal obesity has emerged as a risk factor for CKD in offspring, but the mechanisms remain unclear. In this study, we use mouse models of maternal obesity to investigate macrophage involvement in offspring kidneys. Multi-omics analyses revealed that maternal obesity accelerates kidney disease in male offspring through dysregulated crosstalk between proximal tubules (PT) and macrophages. PT-derived 20-hydroxyeicosatetraenoic acid (20-HETE) promotes mitochondrial hyperactivity and macrophage to myofibroblast transition (MMT) via Ffar1 in macrophages. Targeting 20-HETE or depleting Ffar1 in offspring of obese mothers markedly reduces kidney pathology. Hormone screening identified 3,3,5-Triiodo-L-thyronine (T3) as a factor that enhances Ffar1 expression in macrophages. Mechanistically, the T3 receptor (TRβ) binds to an enhancer we identify upstream of the gene, promoting Ffar1 transcription via the TRβ-P300-BRD4 regulatory axis. These findings highlight T3 and 20-HETE co-activated MMT as a central mechanism to kidney disease in offspring of obese mothers, offering potential therapeutic targets.