title: Characterizing the interactions of organic nanoparticles with renal epithelial cells in vivo.
abstract: Nanotechnology approaches are actively being pursued for drug delivery, novel diagnostics, implantable devices, and consumer products. While considerable research has been performed on the effects of these materials on targeted tumor or phagocytic cells, relatively little is known about their effects on renal cells. This becomes critical for supersmall nanoparticles (<10 nm), designed to be renally excreted. The active endocytic machinery of kidney proximal tubules avidly internalizes filtered proteins, which may also be the case for filtered nanoparticles. To test whether such interactions affect kidney function, we injected mice with either 5 nm dextran-based nanoparticles (DNP) that are similar in composition to FDA-approved materials or poly(amido amine) dendrimer nanoparticles (PNP) of comparable size. These fluorescently tagged nanoparticles were both filtered and internalized by renal tubular epithelial cells in a dose- and time-dependent fashion. The biological effects were quantitated by immunocytochemistry, measuring kidney injury markers and performing functional tests. DNP administration resulted in a dose-dependent increase in urinary output, while cellular albumin endocytosis was increased. The expression of megalin, a receptor involved in albumin uptake, was also increased, but AQP1 expression was unaffected. The effects after PNP administration were similar but additionally resulted in increased clathrin expression and increased endocytosis of dextran. We conclude that there are no major detrimental renal effects of DNP on overall kidney function, but changes in endocytosis-mediating protein expression do occur. These studies provide a framework for the testing of additional nanoparticle preparations as they become available.
authors: †Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, United States.|‡Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 United States.
authors: Anil V
authors: AV
authors: Nair
authors: †Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, United States.
authors: Edmund J
authors: EJ
authors: Keliher
authors: †Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, United States.|‡Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 United States.
authors: Amanda B
authors: AB
authors: Core
authors: †Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, United States.|‡Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 United States.
authors: Dennis
authors: D
authors: Brown
authors: †Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, United States.|§Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States.
authors: Ralph
authors: R
authors: Weissleder
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D051398:Aquaporin 1 / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D050091:Dendrimers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003911:Dextrans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D010316:Particle Size
chemical_list: D000418:Albumins; D002966:Clathrin; D050091:Dendrimers; D003911:Dextrans; C104700:PAMAM Starburst; D051398:Aquaporin 1
keywords: dextran; epithelial cells; kidney; nanoparticles; nanotechnology; toxicity