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Proximal Tubule-to-Proximal Tubule Efferocytosis: Gusb Prevents Efferocytosis Failure and Polyphagolysosomal Overload in CAZ-AVI-Induced Acute Kidney Injury

Year: 2026

Type: article

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.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms27209045