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Proximal tubules eliminate endocytosed gold nanoparticles through an organelle-extrusion-mediated self-renewal mechanism

Nature Nanotechnology volume 18, pages 637–646 (2023)Cite this article

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Abstract

Proximal tubules energetically internalize and metabolize solutes filtered through glomeruli but are constantly challenged by foreign substances during the lifespan. Thus, it is critical to understand how proximal tubules stay healthy. Here we report a previously unrecognized mechanism of mitotically quiescent proximal tubular epithelial cells for eliminating gold nanoparticles that were endocytosed and even partially transformed into large nanoassemblies inside lysosomes/endosomes. By squeezing ~5 µm balloon-like extrusions through dense microvilli, transporting intact gold-containing endocytic vesicles into the extrusions along with mitochondria or other organelles and pinching the extrusions off the membranes into the lumen, proximal tubular epithelial cells re-eliminated >95% of endocytosed gold nanoparticles from the kidneys into the urine within a month. While this organelle-extrusion mechanism represents a new nanoparticle-elimination route, it is not activated by the gold nanoparticles but is an intrinsic ‘housekeeping’ function of normal proximal tubular epithelial cells, used to remove unwanted cytoplasmic contents and self-renew intracellular organelles without cell division to maintain homoeostasis.

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Fig. 1: Elimination process and interaction of renal-clearable engineered nanoparticles in the kidneys.
Fig. 2: Endocytosis and re-elimination of the PEGylated AuNPs by PTECs in vivo.
Fig. 3: Biotransformation and re-excretion of endocytosed (+)-AuNPs by PTs.
Fig. 4: Nanoparticle elimination by PTECs through an organelle-extrusion mechanism.
Fig. 5: Organelle extrusion is a native physiological function of PTs.
Fig. 6: Nanoparticle endocytosis and organelle extrusion significantly reduced in PTs with cisplatin-induced injury.

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All data from this work are available in the Article and its Supplementary Information. Source data are provided with this paper. Other relevant data are available from the corresponding authors upon reasonable request for research purposes.

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Acknowledgements

We acknowledge the financial support in part from the National Institute of Health (NIH; R01DK124881 (M.Y.), R01DK115986 (J.Z.), R01DK126140 (J.Z.) and R01DK103363 (J.Z.)), National Science Foundation (NSF; 2018188 (J.Z.)), Cancer Prevention Research Institute of Texas (CPRIT; RP200233 (J.Z.)), the University of Texas (UT) at Dallas Office of Research through the Core Facility Voucher Program (award number 11020 to M.Y.) and the Cecil H. and Ida Green Professorship in System Biology (to J.Z.) from the UT Dallas. We also acknowledge the assistance of the UT Southwestern Electron Microscopy Core and the Shared Instrumental Program of NIH (1S10OD021685 (K. Luby-Phelps)). We acknowledge the partial assistance of S. Ahrari at UT Dallas in the synthesis of (−)-AuNPs, and Q. Zhou and S. Li at UT Dallas on some ICP sample preparation. We thank late Dr. Hobson Wildenthal and internal funding support from UT Dallas and K. Luby-Phelps and her staff members at UT Southwestern (UTSW) Medical Center EM core facilities for EM sample preparation; J.-T. Hsieh and his staff members at the UTSW Medical Center for the tissue embedding and providing the HK-2 cell line; G. Meloni and his student R. L. Villones at UT Dallas for providing metallothionein; and Q. Cai at the UTSW Medical Center for her comments on H&E-stained tissue samples.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, TX, USA

    Yingyu Huang, Mengxiao Yu & Jie Zheng

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  1. Yingyu Huang
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  2. Mengxiao Yu
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Contributions

J.Z., Y.H. and M.Y. conceived the idea and designed the experiments. Y.H. performed most of the experimental studies and data collection. J.Z. recognized the unique organelle-extrusion process during EM imaging of the PTs with Y.H. and M.Y.; J.Z., Y.H. and M.Y. wrote the manuscript. All authors discussed and commented on the manuscript.

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Correspondence to Mengxiao Yu or Jie Zheng.

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Nature Nanotechnology thanks the anonymous reviewers for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 A schematic summary of substance transport processes carried by proximal tubular epithelial cells (PTECs).

PTECs can secrete substances from the blood into the tubular lumen and the urine through transporter-mediated influx- and efflux-processes (green arrow line), reabsorb substances from the lumen back into the bloodstream through transcytosis or transporter-mediated efflux after lysosomal degradation (yellow arrow line). In addition, this newly discovered organelle extrusion of PTECs represents another route to remove the endocytosed and even biotransformed substances back into the tubular lumen for further renal clearance (red arrow line), along with elimination of other intracellular organelles. Since organelle extrusion also happens in healthy proximal tubules without AuNP injection, the physiological function is believed to self-renew intracellular contents and remove wastes to maintain homeostasis without cell division.

Supplementary information

Supplementary Information

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Supplementary Data

Statistical source data for Supplementary Figs. 1, 3, 9–11, 13, 19, 23, 30 and 32–34.

Source data

Source Data Figs. 2 and 4–6

Statistical source data for Figs. 2 and 4–6.

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Huang, Y., Yu, M. & Zheng, J. Proximal tubules eliminate endocytosed gold nanoparticles through an organelle-extrusion-mediated self-renewal mechanism. Nat. Nanotechnol. 18, 637–646 (2023). https://doi.org/10.1038/s41565-023-01366-7

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