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<p>Kidney stones, as prevalent crystalline disorders within the urinary system, pose significant clinical challenges due to their high incidence and recurrence rates. The lack of clear pathological mechanisms has limited therapeutic options to surgical interventions without effective preventive strategies. In this study, integrated in vitro and in vivo models revealed that calcium oxalate (CaOx) exposure induced concurrent accumulation of LC3B-II and p62 autophagy markers. Blockade of autophagic flux at the late stage was validated via mCherry-GFP-LC3 dual fluorescence assays, demonstrating impaired autolysosome formation. Mechanistically, autophagic flux obstruction triggered oxidative stress, apoptosis, and proinflammatory cascades, collectively exacerbating renal tubular injury. Pharmacological inhibition of autophagy initiation with 3-methyladenine (3-MA) disrupted the maladaptive autophagy-reinforcement cycle, improving cellular viability and renal function. Conversely, lysosomal acidification blockade via bafilomycin A1 (BafA1) failed to mitigate cytotoxicity. Molecular screening identified specific downregulation of VAMP7—a SNARE complex component critical for autophagosome-lysosome fusion—as the primary mediator of CaOx-induced fusion defects. Overexpression of VAMP7 restored autophagic homeostasis and attenuated crystallotoxicity. This work pioneers a phase-specific autophagy targeting strategy: either suppression of pathological autophagic overactivation or restoration of terminal fusion machinery effectively alleviates CaOx nephrotoxicity. These findings provide a mechanistic foundation for precision therapeutics in stone disease management.</p>

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Calcium oxalate crystals exacerbate the damage and inflammation of renal tubular epithelial cells by blocking autophagic flux

  • 期刊论文

  • 发表日期：

    2026年4月6日

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  • Zhenyu Song,
  • Xike Mao,
  • Yuehan Yang,
  • Yang Chen,
  • Zongyao Hao,
  • Lvwen Zhang

摘要

Kidney stones, as prevalent crystalline disorders within the urinary system, pose significant clinical challenges due to their high incidence and recurrence rates. The lack of clear pathological mechanisms has limited therapeutic options to surgical interventions without effective preventive strategies. In this study, integrated in vitro and in vivo models revealed that calcium oxalate (CaOx) exposure induced concurrent accumulation of LC3B-II and p62 autophagy markers. Blockade of autophagic flux at the late stage was validated via mCherry-GFP-LC3 dual fluorescence assays, demonstrating impaired autolysosome formation. Mechanistically, autophagic flux obstruction triggered oxidative stress, apoptosis, and proinflammatory cascades, collectively exacerbating renal tubular injury. Pharmacological inhibition of autophagy initiation with 3-methyladenine (3-MA) disrupted the maladaptive autophagy-reinforcement cycle, improving cellular viability and renal function. Conversely, lysosomal acidification blockade via bafilomycin A1 (BafA1) failed to mitigate cytotoxicity. Molecular screening identified specific downregulation of VAMP7—a SNARE complex component critical for autophagosome-lysosome fusion—as the primary mediator of CaOx-induced fusion defects. Overexpression of VAMP7 restored autophagic homeostasis and attenuated crystallotoxicity. This work pioneers a phase-specific autophagy targeting strategy: either suppression of pathological autophagic overactivation or restoration of terminal fusion machinery effectively alleviates CaOx nephrotoxicity. These findings provide a mechanistic foundation for precision therapeutics in stone disease management.