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<p>The progression of acute kidney injury (AKI) to chronic kidney disease (CKD) remains a major clinical challenge. It is primarily triggered by renal tubular epithelial cell (RTEC) death that leads to persistent sterile inflammation, maladaptive repair and irreversible renal fibrosis. A pivotal event in RTEC death is plasma membrane rupture (PMR), which leads to the release of Damage-Associated Molecular Patterns (DAMPs). In this study, we identified Tripartite Motif-Containing 72 (TRIM72) as a critical regulator of Ninjurin-1 (NINJ1), a key mediator of PMR. Using tubule-specific knockout mice (<i>Ninj1</i><sup><i>fl/fl</i></sup><i>Ksp</i><sup><i>cre</i></sup> and <i>Hmgb1</i><sup><i>fl/fl</i></sup><i>Ksp</i><sup><i>cre</i></sup>) in a folic acid-induced AKI-CKD model, together with in vitro RTEC and immune cell assays, we delineated the TRIM72-NINJ1-HMGB1 signaling axis. We found that TRIM72 functions as an E3 ubiquitin ligase that targets NINJ1 at lysine 111 for proteasomal degradation, thereby restraining NINJ1-mediated PMR. Loss of TRIM72 stabilized NINJ1, exacerbated RTEC membrane rupture, and amplified the release of HMGB1. The resulting HMGB1 release propagated inflammation by promoting both macrophage-myofibroblast transition (MMT) and neutrophil extracellular trap (NET) formation, two major drivers of renal fibrosis. Consistently, tubule-specific deletion of either <i>Ninj1</i> or <i>Hmgb1</i> markedly attenuated the progression from AKI to CKD. Together, these findings establish the TRIM72-NINJ1-HMGB1 cascade as a central molecular pathway dictating the fate of injured RTECs and highlight TRIM72 as a promising therapeutic target for halting the transition from AKI to CKD.</p>

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NINJ1 ubiquitination by TRIM72 protects against plasma membrane rupture and AKI-CKD progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月27日

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  • Keng Ye,
  • Siyi Lin,
  • Caiming Chen,
  • Zhimin Chen,
  • Kongwen Lin,
  • Guoping Li,
  • Huabin Ma,
  • Jianfeng Wu,
  • Tak W. Mak,
  • Li Chen,
  • Yanfang Xu

摘要

The progression of acute kidney injury (AKI) to chronic kidney disease (CKD) remains a major clinical challenge. It is primarily triggered by renal tubular epithelial cell (RTEC) death that leads to persistent sterile inflammation, maladaptive repair and irreversible renal fibrosis. A pivotal event in RTEC death is plasma membrane rupture (PMR), which leads to the release of Damage-Associated Molecular Patterns (DAMPs). In this study, we identified Tripartite Motif-Containing 72 (TRIM72) as a critical regulator of Ninjurin-1 (NINJ1), a key mediator of PMR. Using tubule-specific knockout mice (Ninj1fl/flKspcre and Hmgb1fl/flKspcre) in a folic acid-induced AKI-CKD model, together with in vitro RTEC and immune cell assays, we delineated the TRIM72-NINJ1-HMGB1 signaling axis. We found that TRIM72 functions as an E3 ubiquitin ligase that targets NINJ1 at lysine 111 for proteasomal degradation, thereby restraining NINJ1-mediated PMR. Loss of TRIM72 stabilized NINJ1, exacerbated RTEC membrane rupture, and amplified the release of HMGB1. The resulting HMGB1 release propagated inflammation by promoting both macrophage-myofibroblast transition (MMT) and neutrophil extracellular trap (NET) formation, two major drivers of renal fibrosis. Consistently, tubule-specific deletion of either Ninj1 or Hmgb1 markedly attenuated the progression from AKI to CKD. Together, these findings establish the TRIM72-NINJ1-HMGB1 cascade as a central molecular pathway dictating the fate of injured RTECs and highlight TRIM72 as a promising therapeutic target for halting the transition from AKI to CKD.