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  • Title: Role of ZBP1 Sensing Mitochondrial Z-DNA and triggering Necroptosis in Oxalate-Induced Acute Kidney Injury.
    Author: Chen C, Xie J, Chen Z, Ye K, Wu C, Dai X, Yuan Y, Lin Y, Wang Y, Chen H, Wu J, Ma H, Xu Y.
    Journal: J Am Soc Nephrol; 2024 Oct 07; ():. PubMed ID: 39374087.
    Abstract:
    BACKGROUND: Calcium oxalate-induced acute kidney injury is a severe condition in which the kidneys suffer rapid damage due to the deposition of oxalate crystals. Known factors contributing to cell death induced by calcium oxalate include receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) protein dependent necroptosis, as well as necrosis involving peptidylprolyl isomerase F (PPIF) mediated mitochondrial permeability transition. However, the detailed molecular mechanisms linking mitochondrial dysfunction to RIPK3 activation are not fully understood. METHODS: Mice with gene knock-out of Zbp1, Ripk3, or Mlkl and mice with mutations in the Z-nucleic acid sensing domain of ZBP1 or deletion of Zα1 were used in an oxalate-induced AKI model. Proximal renal tubule cells were isolated and cultured for further investigation. Human oxalate nephropathy biopsy samples were analyzed. RESULTS: Specific gene deletions of Zbp1, Ripk3, or Mlkl in proximal renal tubules significantly reduced the severity of oxalate-induced AKI by preventing necroptosis and subsequent inflammation. Notably, mice with mutations in the Z-nucleic acid sensing domain of ZBP1 or deletion of Zα1 were protected from AKI. In cultured proximal tubular cells, calcium oxalate damaged mitochondria, accompanied by an increase in Bax and a decrease in BCL2 and TAFM, leading to the release of mitochondrial Z-DNA. ZBP1 sensed this mitochondrial Z-DNA and then recruited RIPK3 via the RIP homotypic interaction motifs (RHIM), which in turn activated MLKL through RIPK3 phosphorylation, leading to necroptosis and contributing to AKI. CONCLUSIONS: ZBP1 plays a critical role in sensing mitochondrial Z-DNA and initiating RIPK3/MLKL-mediated necroptosis, contributing to the development of oxalate-induced AKI.
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