Black Phosphorus Quantum Dots Cause Nephrotoxicity in Organoids, Mice, and Human Cells
Corresponding Author
Chengyong He
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361005 China
E-mail: [email protected], [email protected], [email protected]
Search for more papers by this authorFengkai Ruan
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361005 China
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Xiamen University, Xiamen, Fujian, 361102 China
Search for more papers by this authorShengwei Jiang
Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, 518055 China
Search for more papers by this authorJie Zeng
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361005 China
Search for more papers by this authorHanying Yin
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361005 China
Search for more papers by this authorRong Liu
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Xiamen University, Xiamen, Fujian, 361102 China
Search for more papers by this authorYongxing Zhang
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Xiamen University, Xiamen, Fujian, 361102 China
Search for more papers by this authorLaiqiang Huang
Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, 518055 China
Search for more papers by this authorChonggang Wang
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361005 China
Search for more papers by this authorCorresponding Author
Shaohua Ma
Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, 518055 China
E-mail: [email protected], [email protected], [email protected]
Search for more papers by this authorCorresponding Author
Zhenghong Zuo
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361005 China
E-mail: [email protected], [email protected], [email protected]
Search for more papers by this authorCorresponding Author
Chengyong He
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361005 China
E-mail: [email protected], [email protected], [email protected]
Search for more papers by this authorFengkai Ruan
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361005 China
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Xiamen University, Xiamen, Fujian, 361102 China
Search for more papers by this authorShengwei Jiang
Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, 518055 China
Search for more papers by this authorJie Zeng
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361005 China
Search for more papers by this authorHanying Yin
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361005 China
Search for more papers by this authorRong Liu
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Xiamen University, Xiamen, Fujian, 361102 China
Search for more papers by this authorYongxing Zhang
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Xiamen University, Xiamen, Fujian, 361102 China
Search for more papers by this authorLaiqiang Huang
Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, 518055 China
Search for more papers by this authorChonggang Wang
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361005 China
Search for more papers by this authorCorresponding Author
Shaohua Ma
Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, 518055 China
E-mail: [email protected], [email protected], [email protected]
Search for more papers by this authorCorresponding Author
Zhenghong Zuo
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361005 China
E-mail: [email protected], [email protected], [email protected]
Search for more papers by this authorAbstract
Quantum dots (QDs) have numerous potential applications in lighting, engineering, and biomedicine. QDs are mainly excreted through the kidney due to their ultrasmall sizes; thus, the kidneys are target organs of QD toxicity. Here, an organoid screening platform is established and used to study the nephrotoxicity of QDs. Organoids are templated from monodisperse microfluidic Matrigel droplets and found to be homogeneous in both tissue structure and functional recapitulation within a population and suitable for the quantitative screening of toxic doses. Kidney organoids are proved displaying higher sensitivity than 2D-cultured cell lines. Similar to metal-containing QDs, black phosphorus (BP)-QDs are found to have moderate toxicity in the kidney organoids. The nephrotoxicity of BP-QDs are validated in both mice and human renal tubular epithelial cells. BP-QDs are also found to cause insulin insensitivity and endoplasmic reticulum (ER) stress in the kidney. Furthermore, ER stress-related IRE1α signaling is shown to mediate renal toxicity and insulin insensitivity caused by BP-QDs. In summary, this work demonstrates the use of constructed kidney organoids as 3D high-throughput screening tools to assess nanosafety and further illuminates the effects and molecular mechanisms of BP-QD nephrotoxicity. The findings will hopefully enable improvement of the safety of BP-QD applications.
Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
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References
- 1A. Nel, T. Xia, H. Meng, X. Wang, S. Lin, Z. Ji, H. Zhang, Acc. Chem. Res. 2013, 46, 607.
- 2X. Michalet, F. F. Pinaud, L. A. Bentolila, J. M. Tsay, S. Doose, J. J. Li, G. Sundaresan, A. M. Wu, S. S. Gambhir, S. Weiss, Science 2005, 307, 538.
- 3R. Leon, P. M. Petroff, D. Leonard, S. Fafard, Science 1995, 267, 1966.
- 4N. Lin, Z. Meng, G. W. Toh, Y. Zhen, Y. Diao, H. Xu, X. Y. Liu, Small 2015, 11, 1205.
- 5T. Guo, Y. Wu, Y. Lin, X. Xu, H. Lian, G. Huang, J. Z. Liu, X. Wu, H. H. Yang, Small 2018, 14, 1702815.
- 6S. Jiang, Y. Lin, H. Yao, C. Yang, L. Zhang, B. Luo, Z. Lei, L. Cao, N. Lin, X. Liu, Z. Lin, C. He, Arch. Toxicol. 2018, 92, 1421.
- 7H. S. Choi, W. Liu, P. Misra, E. Tanaka, J. P. Zimmer, B. Itty Ipe, M. G. Bawendi, J. V. Frangioni, Nat. Biotechnol. 2007, 25, 1165.
- 8J. Mo, Q. Xie, W. Wei, J. Zhao, Nat. Commun. 2018, 9, 2480.
- 9J. Shao, H. Xie, H. Huang, Z. Li, Z. Sun, Y. Xu, Q. Xiao, X. F. Yu, Y. Zhao, H. Zhang, H. Wang, P. K. Chu, Nat. Commun. 2016, 7, 12967.
- 10V. Wiwanitkit, Saudi J. Kidney Dis. Transplant. 2017, 28, 1203.
- 11A. I. Astashkina, B. K. Mann, G. D. Prestwich, D. W. Grainger, Biomaterials 2012, 33, 4712.
- 12H. Clevers, Cell 2016, 165, 1586.
- 13G. Vlachogiannis, S. Hedayat, A. Vatsiou, Y. Jamin, J. Fernandez-Mateos, K. Khan, A. Lampis, K. Eason, I. Huntingford, R. Burke, M. Rata, D. M. Koh, N. Tunariu, D. Collins, S. Hulkki-Wilson, C. Ragulan, I. Spiteri, S. Y. Moorcraft, I. Chau, S. Rao, D. Watkins, N. Fotiadis, M. Bali, M. Darvish-Damavandi, H. Lote, Z. Eltahir, E. C. Smyth, R. Begum, P. A. Clarke, J. C. Hahne, M. Dowsett, J. de Bono, P. Workman, A. Sadanandam, M. Fassan, O. J. Sansom, S. Eccles, N. Starling, C. Braconi, A. Sottoriva, S. P. Robinson, D. Cunningham, N. Valeri, Science 2018, 359, 920.
- 14S. Anju, J. Ashtami, P. V. Mohanan, Mater. Sci. Eng., C 2019, 97, 978.
- 15Z. Wang, Z. Liu, C. Su, B. Yang, X. Fei, Y. Li, Y. Hou, H. Zhao, Y. Guo, Z. Zhuang, H. Zhong, Z. Guo, Curr. Med. Chem. 2019, 26, 1788.
- 16X. Zhang, H. Xie, Z. Liu, C. Tan, Z. Luo, H. Li, J. Lin, L. Sun, W. Chen, Z. Xu, L. Xie, W. Huang, H. Zhang, Angew. Chem., Int. Ed. 2015, 54, 3653.
- 17Z. Sun, H. Xie, S. Tang, X. F. Yu, Z. Guo, J. Shao, H. Zhang, H. Huang, H. Wang, P. K. Chu, Angew. Chem., Int. Ed. 2015, 54, 11526.
- 18Z. Sun, Y. Zhao, Z. Li, H. Cui, Y. Zhou, W. Li, W. Tao, H. Zhang, H. Wang, P. K. Chu, X. F. Yu, Small 2017, 13, 1602896.
- 19L. J. Hale, S. E. Howden, B. Phipson, A. Lonsdale, P. X. Er, I. Ghobrial, S. Hosawi, S. Wilson, K. T. Lawlor, S. Khan, A. Oshlack, C. Quinlan, R. Lennon, M. H. Little, Nat. Commun. 2018, 9, 5167.
- 20N. M. Cruz, X. Song, S. M. Czerniecki, R. E. Gulieva, A. J. Churchill, Y. K. Kim, K. Winston, L. M. Tran, M. A. Diaz, H. Fu, L. S. Finn, Y. Pei, J. Himmelfarb, B. S. Freedman, Nat. Mater. 2017, 16, 1112.
- 21S. H. Ma, Soft Matter 2019, 15, 3848.
- 22N. Sachs, J. de Ligt, O. Kopper, E. Gogola, G. Bounova, F. Weeber, A. V. Balgobind, K. Wind, A. Gracanin, H. Begthel, J. Korving, R. van Boxtel, A. A. Duarte, D. Lelieveld, A. van Hoeck, R. F. Ernst, F. Blokzijl, I. J. Nijman, M. Hoogstraat, M. van de Ven, D. A. Egan, V. Zinzalla, J. Moll, S. F. Boj, E. E. Voest, L. Wessels, P. J. van Diest, S. Rottenberg, R. G. J. Vries, E. Cuppen, H. Clevers, Cell 2018, 172, 373.
- 23S. M. Czerniecki, N. M. Cruz, J. L. Harder, R. Menon, J. Annis, E. A. Otto, R. E. Gulieva, L. V. Islas, Y. K. Kim, L. M. Tran, T. J. Martins, J. W. Pippin, H. Fu, M. Kretzler, S. J. Shankland, J. Himmelfarb, R. T. Moon, N. Paragas, B. S. Freedman, Cell Stem Cell 2018, 22, 929.
- 24M. Takasato, P. X. Er, H. S. Chiu, M. H. Little, Nat. Protoc. 2016, 11, 1681.
- 25V. Madhu, A. S. Dighe, Q. Cui, D. N. Deal, Stem Cells Int. 2016, 2016, 1.
- 26Y. H. Tsai, R. Nattiv, P. H. Dedhia, M. S. Nagy, A. M. Chin, M. Thomson, O. D. Klein, J. R. Spence, Development 2017, 144, 1045.
- 27M. Takasato, M. H. Little, Methods Mol. Biol. 2017, 1597, 195.
- 28A. I. Astashkina, B. K. Mann, G. D. Prestwich, D. W. Grainger, Biomaterials 2012, 33, 4700.
- 29H. Wu, K. Uchimura, E. L. Donnelly, Y. Kirita, S. A. Morris, B. D. Humphreys, Cell Stem Cell 2018, 23, 869.
- 30M. Yan, Y. Zhang, H. Qin, K. Liu, M. Guo, Y. Ge, M. Xu, Y. Sun, X. Zheng, Int. J. Nanomed. 2016, 11, 529.
- 31A. I. Astashkina, C. F. Jones, G. Thiagarajan, K. Kurtzeborn, H. Ghandehari, B. D. Brooks, D. W. Grainger, Biomaterials 2014, 35, 6323.
- 32X. Mu, J. Y. Wang, X. Bai, F. Xu, H. Liu, J. Yang, Y. Jing, L. Liu, X. Xue, H. Dai, Q. Liu, Y. M. Sun, C. Liu, X. D. Zhang, ACS Appl. Mater. Interfaces 2017, 9, 20399.
- 33C. He, S. Jiang, H. Jin, S. Chen, G. Lin, H. Yao, X. Wang, P. Mi, Z. Ji, Y. Lin, Z. Lin, G. Liu, Biomaterials 2016, 83, 102.
- 34A. Skjesol, T. Liebe, D. B. Iliev, E. I. Thomassen, L. G. Tollersrud, M. Sobhkhez, L. Lindenskov Joensen, C. J. Secombes, J. B. Jorgensen, Dev. Comp. Immunol. 2014, 45, 177.
- 35Y. Jiao, S. Rieck, J. Le Lay, K. H. Kaestner, Diabetologia 2013, 56, 2435.
- 36D. Cao, S. Ouyang, Z. Liu, F. Ma, J. Wu, Endocr. J. 2014, 61, 437.
- 37A. I. S. Moretti, J. C. Pavanelli, P. Nolasco, M. S. Leisegang, L. Y. Tanaka, C. G. Fernandes, J. WosniakJr., D. Kajihara, M. H. Dias, D. C. Fernandes, H. Jo, N. V. Tran, I. Ebersberger, R. P. Brandes, D. Bonatto, F. R. M. Laurindo, Sci. Rep. 2017, 7, 17262.
- 38Y. Y. Shen, P. W. Peake, J. A. Charlesworth, Nephrology 2008, 13, 528.
- 39G. R. Soodini, Metab. Syndr. Relat. Disord. 2004, 2, 114.
- 40C. Zoccali, F. Mallamaci, G. Tripepi, F. A. Benedetto, S. Cutrupi, S. Parlongo, L. S. Malatino, G. Bonanno, G. Seminara, F. Rapisarda, P. Fatuzzo, M. Buemi, G. Nicocia, S. Tanaka, N. Ouchi, S. Kihara, T. Funahashi, Y. Matsuzawa, J. Am. Soc. Nephrol. 2002, 13, 179S.
- 41S. Mao, L. Fang, F. Liu, S. Jiang, L. Wu, J. Zhang, J. Recept. Signal Transduction 2018, 38, 89.
- 42C. Bravo, L. R. Cataldo, J. Galgani, J. Parada, J. L. Santos, J. Diabetes Res. 2017, 2017, 1.
- 43L. J. Hale, R. J. Coward, Curr. Opin. Nephrol. Hypertens. 2013, 22, 100.
- 44S. Horita, M. Nakamura, M. Suzuki, N. Satoh, A. Suzuki, G. Seki, Biomed Res. Int. 2016, 2016, 1.
- 45A. Berardi, D. J. Evans, F. Baldelli Bombelli, G. P. Lomonossoff, Nanoscale 2018, 10, 1667.
- 46R. Bravo, V. Parra, D. Gatica, A. E. Rodriguez, N. Torrealba, F. Paredes, Z. V. Wang, A. Zorzano, J. A. Hill, E. Jaimovich, A. F. Quest, S. Lavandero, Int. Rev. Cell Mol. Biol. 2013, 301, 215.
- 47A. Khaminets, T. Heinrich, M. Mari, P. Grumati, A. K. Huebner, M. Akutsu, L. Liebmann, A. Stolz, S. Nietzsche, N. Koch, M. Mauthe, I. Katona, B. Qualmann, J. Weis, F. Reggiori, I. Kurth, C. A. Hubner, I. Dikic, Nature 2015, 522, 354.
- 48V. Barquissau, F. Capel, D. Dardevet, C. Feillet-Coudray, A. Gallinier, M. A. Chauvin, J. Rieusset, B. Morio, Free Radicals Biol. Med. 2017, 113, 267.
- 49S. Munoz, S. Franckhauser, I. Elias, T. Ferre, A. Hidalgo, A. M. Monteys, M. Molas, S. Cerdan, A. Pujol, J. Ruberte, F. Bosch, Diabetologia 2010, 53, 2417.
- 50C. Zou, Y. Wang, Z. Shen, J. Biochem. Biophys. Methods 2005, 64, 207.
- 51H. Kato, S. Nakajima, Y. Saito, S. Takahashi, R. Katoh, M. Kitamura, Cell Death Differ. 2012, 19, 310.
- 52Q. Guo, L. Xu, H. Li, H. Sun, S. Wu, B. Zhou, Biochem. Biophys. Res. Commun. 2017, 484, 529.
- 53L. Qin, Z. Wang, L. Tao, Y. Wang, Autophagy 2010, 6, 239.
