Aminoglycosides are an important class of antibiotics that play a critical role in the treatment of life-threatening infections, but their use is limited by their toxicity. In fact, gentamicin causes severe nephrotoxicity in 17% of hospitalized patients. The kidney proximal tubule is particularly vulnerable to drug-induced nephrotoxicity due to its role in drug transport. In this work, we developed a perfused vascularized model of human kidney tubuloids integrated with tissue-embedded microsensors that track the metabolic dynamics of aminoglycoside-induced renal toxicity in real time. Our model shows that gentamicin disrupts proximal tubule polarity at concentrations 20-fold below its TC₅₀, leading to a 3.2-fold increase in glucose uptake, and reverse TCA cycle flux culminating in a 40-fold increase in lipid accumulation. Blocking glucose reabsorption using the SGLT2 inhibitor empagliflozin significantly reduced gentamicin toxicity by 10-fold. These results demonstrate the utility of sensor-integrated kidney-on-chip platforms to rapidly identify new metabolic mechanisms that may underly adverse drug reactions. The results should improve our ability to modulate the toxicity of novel aminoglycosides.

中文翻译：

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氨基糖苷类药物诱导的脂毒性及其在芯片肾脏中的逆转

氨基糖苷类是一类重要的抗生素，在治疗危及生命的感染中起着关键作用，但它们的使用受到毒性的限制。事实上，庆大霉素在 17% 的住院患者中引起严重的肾毒性。由于其在药物转运中的作用，肾近端小管特别容易受到药物诱导的肾毒性的影响。在这项工作中，我们开发了一种人肾小管的灌注血管化模型，该模型与组织嵌入的微传感器集成，可实时跟踪氨基糖苷类药物诱导的肾毒性的代谢动力学。我们的模型表明，庆大霉素在其 TC _{50以下 20 倍的浓度下会破坏近端小管极性}，导致葡萄糖摄取增加 3.2 倍，并逆转 TCA 循环通量，最终导致脂质积累增加 40 倍。使用 SGLT2 抑制剂 empagliflozin 阻断葡萄糖重吸收可显着降低庆大霉素毒性 10 倍。这些结果证明了传感器集成的肾脏芯片平台在快速识别可能导致药物不良反应的新代谢机制方面的效用。结果应该会提高我们调节新型氨基糖苷类药物毒性的能力。