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<p>The fibrotic kidney microenvironment is shaped by cellular crosstalk, extracellular matrix (ECM) remodelling, metabolic reprogramming and spatial heterogeneity. While late-stage ECM changes dominate fibrosis, the role of early-activated matrix proteins remains unclear. Here we show that ECM1 is an early regulator of kidney remodelling. Global <i>Ecm1</i> knockout mice develop spontaneous fibrosis and early death, whereas ECM1 levels markedly increase in biofluids during chronic kidney disease. Targeting <i>Ecm1</i> through AAV9-mediated knockdown or fibroblast-specific deletion substantially reduces renal fibrosis. Mechanistically, <i>Ecm1</i> deletion disrupts the integrin α2β1–RhoC axis, suppressing YAP activity. Reduced YAP nuclear translocation and diminished YAP–TEAD4 complex formation relieve TEAD4-mediated repression of <i>Pgc1a</i>, enhancing mitochondrial oxidative phosphorylation (OXPHOS) and promoting repair. Spatial transcriptomics and proteomics confirm this mechano-metabolic pathway, revealing mitochondrial reprogramming in tubules that counteracts fibrotic progression. Notably, YAP inactivation in fibroblasts limits aberrant activation without impairing their OXPHOS. This selective ECM–mitochondrial crosstalk uncovers a mechano-metabolic pathway in which mitochondrial shifts drive defence against kidney fibrosis.</p>

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Early-activated extracellular matrix proteins shape the metabolic and spatial dynamics of the kidney fibrotic microenvironment

  • 期刊论文

  • 发表日期：

    2026年3月3日

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  • Yuan Gui,
  • Wenxue Li,
  • Jia-Jun Liu,
  • Yuanyuan Wang,
  • Cameron Jones,
  • Riddhi Bansal,
  • Samantha Mae Mallari,
  • Henry Wells Shaffer,
  • Yanbao Yu,
  • Haiyan Fu,
  • Tracy T. Tang,
  • Silvia Liu,
  • Yansheng Liu,
  • Dong Zhou

摘要

The fibrotic kidney microenvironment is shaped by cellular crosstalk, extracellular matrix (ECM) remodelling, metabolic reprogramming and spatial heterogeneity. While late-stage ECM changes dominate fibrosis, the role of early-activated matrix proteins remains unclear. Here we show that ECM1 is an early regulator of kidney remodelling. Global Ecm1 knockout mice develop spontaneous fibrosis and early death, whereas ECM1 levels markedly increase in biofluids during chronic kidney disease. Targeting Ecm1 through AAV9-mediated knockdown or fibroblast-specific deletion substantially reduces renal fibrosis. Mechanistically, Ecm1 deletion disrupts the integrin α2β1–RhoC axis, suppressing YAP activity. Reduced YAP nuclear translocation and diminished YAP–TEAD4 complex formation relieve TEAD4-mediated repression of Pgc1a, enhancing mitochondrial oxidative phosphorylation (OXPHOS) and promoting repair. Spatial transcriptomics and proteomics confirm this mechano-metabolic pathway, revealing mitochondrial reprogramming in tubules that counteracts fibrotic progression. Notably, YAP inactivation in fibroblasts limits aberrant activation without impairing their OXPHOS. This selective ECM–mitochondrial crosstalk uncovers a mechano-metabolic pathway in which mitochondrial shifts drive defence against kidney fibrosis.