Bismuth is widely used in metallurgy, cosmetic industry, and medical diagnosis and recently, bismuth nanoparticles (NPs) (BiNP) have been made and proved to be excellent CT imaging agents. Previously, we have synthesized bovine serum albumin based BiNP for imaging purpose but we found a temporary kidney injury by BiNP. Due to the reported adverse events of bismuth on human health, we extended our studies on the mechanisms for BiNP induced nephrotoxicity. Blood biochemical analysis indicated the increase in creatinine (CREA) and blood urea nitrogen (BUN), and intraluminal cast formation with cell apoptosis/necrosis was evident in proximal convoluted tubules (PCTs) of mice. BiNP induced acute kidney injury (AKI) was associated with an increase in LC3II, while the autophagic flux indicator p62 remained unchanged. Chloroquine and rapamycin were used to evaluate the role of autophagy in AKI caused by BiNP. Results showed that BiNP induced AKI was further attenuated by rapamycin, while AKI became severe when chloroquine was applied. In vitro studies further proved BiNP induced autophagy in human embryonic kidney cells 293, presented as autophagic vacuole (AV) formation along with increased levels of autophagy-related proteins including LC3II, Beclin1, and Atg12. Specifically, reactive oxygen species (ROS) generated by BiNP could be the major inducer of autophagy, because ROS blockage attenuated autophagy. Autophagy induced by BiNP was primarily regulated by AMPK/mTOR signal pathway and partially regulated by Akt/mTOR. Our study provides fundamental theory to better understand bismuth induced nephrotoxicity for better clinical application of bismuth related compounds.

中文翻译：

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自噬在通过AMPK / mTOR途径引起的铋纳米颗粒诱导的肾毒性中的保护作用

铋被广泛用于冶金，化妆品工业和医学诊断中，最近，铋纳米颗粒（NPs）（BiNP）已经制成，并被证明是出色的CT成像剂。以前，我们已经合成了基于牛血清白蛋白的BiNP用于成像，但是我们发现BiNP会暂时性肾脏损伤。由于报道了铋对人体健康的不利影响，我们扩展了对BiNP诱导的肾毒性机制的研究。血液生化分析表明，肌酐（CREA）和血尿素氮（BUN）的增加，在小鼠近端曲旋小管（PCTs）中明显出现管腔内铸型，并伴有细胞凋亡/坏死。BiNP诱发的急性肾损伤（AKI）与LC3II的增加有关，而自噬通量指示剂p62保持不变。氯喹和雷帕霉素用于评估自噬在BiNP引起的AKI中的作用。结果表明，雷帕霉素可进一步减弱BiNP诱导的AKI，而使用氯喹时AKI变得更严重。体外研究进一步证明了BiNP诱导的人类胚胎肾细胞293中的自噬，表现为自噬泡（AV）的形成以及自噬相关蛋白（包括LC3II，Beclin1和Atg12）的水平升高。具体而言，BiNP产生的活性氧（ROS）可能是自噬的主要诱因，因为ROS阻滞减弱了自噬。BiNP诱导的自噬主要受AMPK / mTOR信号通路调控，部分受Akt / mTOR调控。我们的研究提供了基础理论，以更好地了解铋诱导的肾毒性，从而更好地将铋相关化合物应用于临床。