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<p>Endotrophin (ETP), a cleavage product of the C5 domain of collagen VI α3 (COL6A3), plays a crucial role in extracellular matrix remodeling. Previously established <i>Col6a3</i>-knockout mouse models primarily reflect the consequences of COL6A3 loss rather than the specific effects of ETP depletion, making it challenging to directly assess the functions of ETP. These models either disrupt COL6A3 along with ETP production or express functionally defective COL6A3 while maintaining ETP production. Here we developed and validated a novel ETP-knockout (ETP<sup>KO</sup>) mouse model that selectively ablates ETP while preserving <i>Col6a3</i> expression to address these limitations. To generate the ETP<sup>KO</sup> model, we introduced <i>lox2272</i> sites and a fluorescent <i>mCherryCAAX</i> reporter into the <i>Col6a3</i> locus, ensuring that ETP expression is turned off and reporter expression is turned on upon Cre-mediated recombination. Crossing the Col6a3-Etp+mCherryCAAX mouse line with CMV-Cre mice yielded ETP<sup>KO</sup> mice, in which successful ETP deletion was confirmed by sequencing of genomic DNA and analysis of mCherryCAAX expression. Using this model, we investigated the role of ETP in kidney fibrosis. ETP<sup>KO</sup> mice subjected to unilateral or bilateral kidney ischemia–reperfusion injury exhibited complete <i>Etp</i> messenger RNA ablation with only a partial reduction in <i>Col6a3</i> mRNA. Notably, ETP depletion significantly attenuated fibrosis progression, demonstrating a critical contribution of ETP to the pathogenesis of kidney fibrosis. The ETP<sup>KO</sup> mouse model provides a targeted and specific approach to study ETP function independently of COL6A3 expression. These findings establish ETP as a key driver of fibrosis and position ETP<sup>KO</sup> mice as a valuable tool for elucidating ETP-mediated mechanisms in preclinical disease models.</p>

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ETP-specific-knockout mice reveal endotrophin as a key regulator of kidney fibrosis in ischemia–reperfusion injury models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月7日

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  • Dae-Seok Kim,
  • Jan-Bernd Funcke,
  • Shiuhwei Chen,
  • Kyounghee Min,
  • Toshiharu Onodera,
  • Min Kim,
  • Qian Lin,
  • Chanmin Joung,
  • Joselin Velasco,
  • Megan Virostek,
  • Katarzyna Walendzik,
  • Chitkale Hiremath,
  • Denise K. Marciano,
  • Philipp E. Scherer

摘要

Endotrophin (ETP), a cleavage product of the C5 domain of collagen VI α3 (COL6A3), plays a crucial role in extracellular matrix remodeling. Previously established Col6a3-knockout mouse models primarily reflect the consequences of COL6A3 loss rather than the specific effects of ETP depletion, making it challenging to directly assess the functions of ETP. These models either disrupt COL6A3 along with ETP production or express functionally defective COL6A3 while maintaining ETP production. Here we developed and validated a novel ETP-knockout (ETPKO) mouse model that selectively ablates ETP while preserving Col6a3 expression to address these limitations. To generate the ETPKO model, we introduced lox2272 sites and a fluorescent mCherryCAAX reporter into the Col6a3 locus, ensuring that ETP expression is turned off and reporter expression is turned on upon Cre-mediated recombination. Crossing the Col6a3-Etp+mCherryCAAX mouse line with CMV-Cre mice yielded ETPKO mice, in which successful ETP deletion was confirmed by sequencing of genomic DNA and analysis of mCherryCAAX expression. Using this model, we investigated the role of ETP in kidney fibrosis. ETPKO mice subjected to unilateral or bilateral kidney ischemia–reperfusion injury exhibited complete Etp messenger RNA ablation with only a partial reduction in Col6a3 mRNA. Notably, ETP depletion significantly attenuated fibrosis progression, demonstrating a critical contribution of ETP to the pathogenesis of kidney fibrosis. The ETPKO mouse model provides a targeted and specific approach to study ETP function independently of COL6A3 expression. These findings establish ETP as a key driver of fibrosis and position ETPKO mice as a valuable tool for elucidating ETP-mediated mechanisms in preclinical disease models.