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<p>Macrophages play a critical role in injury and repair following acute kidney injury (AKI), but their regulatory mechanisms remain incompletely understood. Cellular communication network factor 1 (CCN1), a secreted matricellular protein and early biomarker of AKI, may regulate macrophage function during kidney injury. In this study, we first investigated CCN1’s interaction with macrophages in a murine model of ischemia-reperfusion (I/R)-induced AKI. The role of CCN1 was further investigated using recombinant protein administration, a renal tubular epithelial cell (RTEC)-specific CCN1 knockdown mouse model via adeno-associated virus, and in vitro studies with bone marrow-derived macrophages (BMDMs). We found that in response to injury, RTECs upregulated and secreted CCN1, which colocalized with infiltrating F4/80<sup>+</sup> macrophages. RTEC-specific CCN1 knockdown exacerbated renal injury and reduced macrophage infiltration, as confirmed by H&amp;E, KIM-1 and F4/80 staining. Transcriptomic profiling of kidney tissues revealed that CCN1 expression was associated with immune cell infiltration, particularly macrophages, while RNA-seq analysis of BMDMs demonstrated that CCN1 promoted pro-repair arginase1 <i>(Arg1)</i><sup>+</sup> macrophage differentiation and activated the STAT6 signaling pathway. BayesPrism deconvolution further confirmed the enrichment of <i>Arg1</i><sup>hi</sup> macrophages following CCN1 treatment. Co-immunoprecipitation coupled with mass spectrometry identified integrin α<sub>v</sub>β<sub>5</sub> as a direct CCN1-binding partner mediating STAT6/ARG1 activation. Functionally, CCN1-treated macrophages enhanced RTECs' proliferation in vitro and in vivo, an effect abolished by ARG1 inhibition or macrophage depletion. In conclusion, CCN1 regulates macrophages via the α<sub>v</sub>β<sub>5</sub>-STAT6-ARG1 axis to promote tubular epithelial proliferation and improve kidney function in I/R-AKI, highlighting a novel tubular-immune communication pathway and potential therapeutic targets for ischemic AKI.</p><p></p>

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Tubule-derived CCN1 drives renal repair via αvβ5-STAT6-ARG1-dependent reprogramming of macrophages

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月21日

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  • Ningxin Zhang,
  • Chenyu Li,
  • Yanlu Xin,
  • Zhuo Song,
  • Tianyang Li,
  • Ruizhe Zhao,
  • Minghao Gu,
  • Lingyu Xu,
  • Yanfei Wang,
  • Xiaofei Man,
  • Lin Che,
  • Hang Liu,
  • Chen Guan,
  • Yan Xu

摘要

Macrophages play a critical role in injury and repair following acute kidney injury (AKI), but their regulatory mechanisms remain incompletely understood. Cellular communication network factor 1 (CCN1), a secreted matricellular protein and early biomarker of AKI, may regulate macrophage function during kidney injury. In this study, we first investigated CCN1’s interaction with macrophages in a murine model of ischemia-reperfusion (I/R)-induced AKI. The role of CCN1 was further investigated using recombinant protein administration, a renal tubular epithelial cell (RTEC)-specific CCN1 knockdown mouse model via adeno-associated virus, and in vitro studies with bone marrow-derived macrophages (BMDMs). We found that in response to injury, RTECs upregulated and secreted CCN1, which colocalized with infiltrating F4/80+ macrophages. RTEC-specific CCN1 knockdown exacerbated renal injury and reduced macrophage infiltration, as confirmed by H&E, KIM-1 and F4/80 staining. Transcriptomic profiling of kidney tissues revealed that CCN1 expression was associated with immune cell infiltration, particularly macrophages, while RNA-seq analysis of BMDMs demonstrated that CCN1 promoted pro-repair arginase1 (Arg1)+ macrophage differentiation and activated the STAT6 signaling pathway. BayesPrism deconvolution further confirmed the enrichment of Arg1hi macrophages following CCN1 treatment. Co-immunoprecipitation coupled with mass spectrometry identified integrin αvβ5 as a direct CCN1-binding partner mediating STAT6/ARG1 activation. Functionally, CCN1-treated macrophages enhanced RTECs' proliferation in vitro and in vivo, an effect abolished by ARG1 inhibition or macrophage depletion. In conclusion, CCN1 regulates macrophages via the αvβ5-STAT6-ARG1 axis to promote tubular epithelial proliferation and improve kidney function in I/R-AKI, highlighting a novel tubular-immune communication pathway and potential therapeutic targets for ischemic AKI.