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

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. Maternal obesity is a risk factor for developing chronic kidney disease in the offspring later in life. Here the authors study male offspring in a mouse model of maternal obesity and identify dysregulated metabolism due to disrupted crosstalk between proximal tubules and macrophages as an important mechanism.