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<p>Acute kidney injury (AKI) is driven by maladaptive tubular responses, yet upstream regulators remain incompletely understood. Here, we identify phosphatidylinositol 4-kinase alpha (<i>Pi4ka</i>) as a critical determinant of proximal tubule cell (PTC) homeostasis and injury progression. <i>PI4KA</i> expression was reduced in human diseased kidneys and negatively correlated with renal function. Single-cell RNA sequencing in mouse models revealed that <i>Pi4ka</i> deficiency preferentially perturbs specific PTC states, including <i>Slc34a1</i><sup>+</sup><i>Ccn1</i><sup>+</sup>, and <i>Slc34a1</i><sup>+</sup><i>Apob</i><sup>+</sup> populations, which diverge along distinct maladaptive trajectories. From these trajectories we derived a 40-gene injury signature enriched for lysosome-associated pathways, and functional assays showed that lysosomal dysfunction is an early event linking <i>Pi4ka</i> loss to ER stress, impaired autophagy, and proteostasis disruption. Transcriptional network analysis identified Creb3l2 as a central regulator of lysosomal activation. Notably, Creb3l2 perturbation suppressed stress and cell-death programs while promoting transcriptional programs associated with repair and phospholipid metabolism. Ligand–receptor inference further indicated that <i>Pi4ka</i>-deficient PTCs shape a pro-inflammatory immune microenvironment via immunomodulatory gene activation, an effect abolished by <i>Creb3l2</i> deletion. Collectively, these findings define a <i>Pi4ka</i>–lysosome–<i>Creb3l2</i> axis that coordinates tubular injury, maladaptive remodeling, and immune activation, highlighting potential therapeutic targets to limit AKI progression.</p>

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Pi4ka downregulation triggers Creb3l2-dependent lysosomal dysfunction to promote maladaptive tubular remodeling and immune activation in acute kidney injury

  • 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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  • Zhimin Chen,
  • Jingzhi Xie,
  • Chengkun Wu,
  • Keng Ye,
  • Yue Chen,
  • Yankun Song,
  • Huabin Ma,
  • Jianfeng Wu,
  • Li Chen,
  • Yanfang Xu

摘要

Acute kidney injury (AKI) is driven by maladaptive tubular responses, yet upstream regulators remain incompletely understood. Here, we identify phosphatidylinositol 4-kinase alpha (Pi4ka) as a critical determinant of proximal tubule cell (PTC) homeostasis and injury progression. PI4KA expression was reduced in human diseased kidneys and negatively correlated with renal function. Single-cell RNA sequencing in mouse models revealed that Pi4ka deficiency preferentially perturbs specific PTC states, including Slc34a1+Ccn1+, and Slc34a1+Apob+ populations, which diverge along distinct maladaptive trajectories. From these trajectories we derived a 40-gene injury signature enriched for lysosome-associated pathways, and functional assays showed that lysosomal dysfunction is an early event linking Pi4ka loss to ER stress, impaired autophagy, and proteostasis disruption. Transcriptional network analysis identified Creb3l2 as a central regulator of lysosomal activation. Notably, Creb3l2 perturbation suppressed stress and cell-death programs while promoting transcriptional programs associated with repair and phospholipid metabolism. Ligand–receptor inference further indicated that Pi4ka-deficient PTCs shape a pro-inflammatory immune microenvironment via immunomodulatory gene activation, an effect abolished by Creb3l2 deletion. Collectively, these findings define a Pi4ka–lysosome–Creb3l2 axis that coordinates tubular injury, maladaptive remodeling, and immune activation, highlighting potential therapeutic targets to limit AKI progression.