{
  "abstract": "Efferocytosis is essential for maintaining epithelial homeostasis, yet whether proximal tubules (PTs) can engulf other PTs and how this process contributes to acute kidney injury (AKI) remain unknown. Ceftazidime–avibactam (CAZ-AVI)-induced AKI and proximal tubule-specific Gusb conditional knockout (CKO) mice both exhibit phagolysosomal dysfunction, suggesting a shared mechanism. We investigated whether (i) CAZ-AVI triggers PT-to-PT efferocytosis, (ii) this leads to polyphagolysosomal failure, and (iii) Gusb overexpression protects against these abnormalities. Wild-type, Gusb-CKO, and Gusb-transgenic mice were treated with CAZ-AVI. Kidney injury was assessed by histology, TUNEL staining, immunostaining for Odc1 and 4-HNE, and transmission electron microscopy. PT-intrinsic transcriptional responses were quantified by real-time PCR for Ccl2, C3, Lcn2, Slc7a13, Acsm3, and Aqp8. Ultrastructural features were evaluated to distinguish efferocytosis from phagolysosomal failure. CAZ-AVI markedly reduced Odc1 in PTs and induced apoptosis localized almost exclusively to PTs, indicating PT-to-PT efferocytosis. CAZ-AVI strongly induced Ccl2, C3, and Lcn2, while suppressing Slc7a13, Acsm3, and Aqp8, reflecting inflammatory recruitment, complement-mediated opsonization, oxidative stress, and metabolic collapse. Electron microscopy revealed numerous polyphagolysosomes containing dense bodies, membrane fragments, small vesicles, and mitochondrial remnants with preserved cristae, without nuclear structures or double-membrane phagosomes, consistent with phagolysosomal failure. Importantly, Gusb-CKO mice phenocopied CAZ-AVI injury, showing Odc1 loss, robust 4-HNE accumulation, PT-restricted apoptosis, and abundant polyphagolysosomes even without drug exposure, demonstrating that Gusb deficiency is sufficient to drive PT-to-PT efferocytosis failure. In contrast, Gusb-overexpressing mice preserved Odc1, prevented apoptosis, normalized all six PT-intrinsic genes, and lacked polyphagolysosomes. CAZ-AVI induces PT-to-PT efferocytosis leading to phagolysosomal overload and oxidative failure. Gusb deficiency reproduces this phenotype, whereas Gusb overexpression preserves PT phagolysosomal homeostasis and prevents AKI progression.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Nephrology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan",
    "Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa 359-8513, Japan"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Kazuhiro Hasegawa",
      "orcid": "0000-0003-3113-4522"
    },
    {
      "affs": [
        1
      ],
      "name": "Yusuke Sakamaki"
    },
    {
      "affs": [
        0
      ],
      "name": "Masanori Tamaki",
      "orcid": "0000-0002-0488-0098"
    },
    {
      "affs": [
        0
      ],
      "name": "Sumiyo Yamaguchi"
    },
    {
      "affs": [
        0
      ],
      "name": "Ikuko Shimizu"
    },
    {
      "affs": [
        0
      ],
      "name": "Takahiro Kida"
    },
    {
      "affs": [
        0
      ],
      "name": "Shinji Miyakami"
    },
    {
      "affs": [
        0
      ],
      "name": "Miho Tada"
    },
    {
      "affs": [
        0
      ],
      "name": "Makoto Otsuka"
    },
    {
      "affs": [
        0
      ],
      "name": "Masanori Minato"
    },
    {
      "affs": [
        0
      ],
      "name": "Shu Wakino"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7sgxckytn6f4r.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27209045",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13705548/?tool=EBI",
  "id": "7sgxckytn6f4r",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/20/9045",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2727|Acute Kidney Injury Research"
    ]
  ],
  "openalex": "W7221556608",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13705548/pdf/?tool=EBI",
  "pmcid": "PMC13705548",
  "pmid": null,
  "published": "2026-10-01",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/7sgxckytn6f4r.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:55Z",
      "native_id": "10.3390/ijms27209045",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/20/9045"
    },
    {
      "first_seen": "2026-10-30T12:21:45Z",
      "native_id": "PMC:PMC13705548",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13705548"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2727|Acute Kidney Injury Research",
      "subfield": "general"
    }
  ],
  "title": "Proximal Tubule-to-Proximal Tubule Efferocytosis: Gusb Prevents Efferocytosis Failure and Polyphagolysosomal Overload in CAZ-AVI-Induced Acute Kidney Injury",
  "title_text": "Proximal Tubule-to-Proximal Tubule Efferocytosis: Gusb Prevents Efferocytosis Failure and Polyphagolysosomal Overload in CAZ-AVI-Induced Acute Kidney Injury",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:21:45Z",
  "url": "https://research.draconitic.com/paper/7sgxckytn6f4r",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}