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

  • Nat Commun. 2026 May 14;17(1):6183. doi: 10.1038/s41467-026-73237-3.
Fengbo Zhong  #  1 ,  Xingyu Huang  #  1 ,  Huiru Sun  2 ,  Mengxuan Wang  3 ,  Qi Qi  3 ,  Xinlin Song  1 ,  Kai Lin  1 ,  Zhuozhuo Li  1 ,  Jiayun Shen  1 ,  Qiuyu Lu  1 ,  Miaomiao Li  2 ,  Jiaqi Zhang  2 ,  Ling Yuan  1 ,  Jia Lv  1 ,  Xin Wang  1 ,  Yiyun Cheng  1 ,  Qihui Wu  4 ,  Shaohua Fan  2 ,  Shougang Zhuang  5  6 ,  Jia Rao  7 ,  Dali Li  8  9 ,  Yuting Guan  10
Affiliations
  • 1. Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
  • 2. State Key Laboratory of Genetic Engineering, Lab for Evolutionary Synthesis, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai, China.
  • 3. Department of Pediatric Nephrology, Rheumatology and Immunology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 4. Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 5. Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 6. Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island, USA.
  • 7. Department of Pediatric Nephrology, Rheumatology and Immunology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China. [email protected].
  • 8. Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. [email protected].
  • 9. Shanghai Academy of Natural Sciences (SANS), Shanghai, China. [email protected].
  • 10. Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 42135322 DOI: 10.1038/s41467-026-73237-3
Abstract

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.

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