a School for Radiological and Interdisciplinary Sciences (RAD-X), State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions , Soochow University , Suzhou , PR China.
b State Key Laboratory of Bioreactor Engineering , East China University of Science and Technology , Shanghai , PR China.
Nanotoxicology. 2018 Aug;12(6):586-601. doi: 10.1080/17435390.2018.1466932. Epub 2018 May 6.
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.
铋广泛应用于冶金、化妆品工业和医学诊断领域，最近，已制备出并证明铋纳米粒子（BiNP）是一种出色的 CT 成像剂。以前，我们曾为成像目的合成过基于牛血清白蛋白的 BiNP，但发现 BiNP 会造成暂时的肾脏损伤。由于铋对人类健康的不良事件已被报道，我们对 BiNP 诱导肾毒性的机制进行了扩展研究。血液生化分析表明，肌酐（CREA）和血尿素氮（BUN）增加，细胞凋亡/坏死导致管腔内铸型形成，在小鼠的近端曲管（PCT）中非常明显。BiNP 诱导的急性肾损伤（AKI）与 LC3II 的增加有关，而自噬流标志物 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，雷帕霉素进一步减轻了 BiNP 诱导的 AKI，而当应用氯喹时，AKI 变得更加严重。体外研究进一步证明，BiNP 在人胚肾细胞 293 中诱导自噬，表现为自噬小体（AV）形成，同时自噬相关蛋白水平升高，包括 LC3II、Beclin1 和 Atg12。具体来说，BiNP 产生的活性氧（ROS）可能是自噬的主要诱导剂，因为 ROS 阻断减轻了自噬。BiNP 诱导的自噬主要受 AMPK/mTOR 信号通路调节，部分受 Akt/mTOR 调节。我们的研究为更好地理解铋诱导的肾毒性提供了基础理论，从而为更好地临床应用铋相关化合物提供了依据。
