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Background <p>Tubular–immune crosstalk contributes to acute kidney injury (AKI), but the mediators involved in this process remain incompletely understood. Nephroblastoma overexpressed (NOV/CCN3), a secreted matricellular protein, may participate in inflammatory responses during ischemia–reperfusion (I/R)-induced AKI.</p> Methods <p>Serum NOV was measured in cardiac surgery patients with or without postoperative AKI. Renal I/R models, recombinant NOV administration, AAV-mediated tubular NOV knockdown, bone marrow-derived macrophages (BMDMs), co-immunoprecipitation, AlphaFold structural modeling, and DAPT-mediated NOTCH inhibition were used to examine the role and mechanism of NOV.</p> Results <p>Serum NOV was elevated in postoperative AKI patients. In I/R-AKI mice, injured tubular epithelial cells were associated with extracellular NOV accumulation. Recombinant NOV aggravated renal dysfunction and inflammation and promoted pro-inflammatory macrophage infiltration, whereas AAV-mediated NOV knockdown attenuated these responses. In BMDMs, NOV enhanced macrophage inflammatory activation and migration. Mechanistically, NOV-mediated macrophage responses were associated with NOTCH1/RBPJ signaling, and these effects were partially attenuated by the NOTCH inhibitor DAPT.</p> Conclusions <p>Tubular-derived NOV promotes macrophage inflammatory activation via NOTCH1/RBPJ signaling, identifying NOV as a candidate pathway linking tubular injury to macrophage activation in ischemic AKI.</p>

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Injured tubule-derived NOV drives pro-inflammatory macrophage activation through NOTCH1/RBPJ signaling in acute kidney injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月2日

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  • Yanlu Xin,
  • Chen Guan,
  • Ningxin Zhang,
  • Xiao Sun,
  • Liting Wang,
  • Zhuo Song,
  • Minghao Gu,
  • Tianyang Li,
  • Lingyu Xu,
  • Xinning Wang,
  • Yanfei Wang,
  • Lin Che,
  • Long Zhao,
  • Xuefei Shen,
  • Yan Xu

摘要

Background

Tubular–immune crosstalk contributes to acute kidney injury (AKI), but the mediators involved in this process remain incompletely understood. Nephroblastoma overexpressed (NOV/CCN3), a secreted matricellular protein, may participate in inflammatory responses during ischemia–reperfusion (I/R)-induced AKI.

Methods

Serum NOV was measured in cardiac surgery patients with or without postoperative AKI. Renal I/R models, recombinant NOV administration, AAV-mediated tubular NOV knockdown, bone marrow-derived macrophages (BMDMs), co-immunoprecipitation, AlphaFold structural modeling, and DAPT-mediated NOTCH inhibition were used to examine the role and mechanism of NOV.

Results

Serum NOV was elevated in postoperative AKI patients. In I/R-AKI mice, injured tubular epithelial cells were associated with extracellular NOV accumulation. Recombinant NOV aggravated renal dysfunction and inflammation and promoted pro-inflammatory macrophage infiltration, whereas AAV-mediated NOV knockdown attenuated these responses. In BMDMs, NOV enhanced macrophage inflammatory activation and migration. Mechanistically, NOV-mediated macrophage responses were associated with NOTCH1/RBPJ signaling, and these effects were partially attenuated by the NOTCH inhibitor DAPT.

Conclusions

Tubular-derived NOV promotes macrophage inflammatory activation via NOTCH1/RBPJ signaling, identifying NOV as a candidate pathway linking tubular injury to macrophage activation in ischemic AKI.