Local delivery of liposomal prednisolone leads to an anti-inflammatory profile in renal ischaemia-reperfusion injury in the rat

Carla M.A. Van Alem, Mark Boonstra, Jurriën Prins, Taisiya Bezhaeva, Mieke F. Van Essen, Jurjen M. Ruben, Alexander L. Vahrmeijer, Eric P. Van Der Veer, Johan W. De Fijter, Marlies E. Reinders, Onno Meijer, Josbert M. Metselaar, Cees Van Kooten, Joris I. Rotmans* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

Abstract

Background. Treatment of inflammatory kidney diseases with systemic high-dose glucocorticoids (GCs) has severe side effects. Liposomal encapsulation could facilitate local delivery of GCs to the inflamed kidney, as liposomes encapsulate their payload until extravasation at sites of inflammation, potentially resulting in local bioactivity. Our aim was to evaluate the ability of liposomes to accumulate locally after renal ischaemia-reperfusion injury in the rat and to study its effect on macrophages. Methods. In vitro, human macrophages were incubated with fluorescent liposomes, liposomal prednisolone, prednisolone, empty liposomes or saline. Uptake was studied microscopically and treatment effect was assessed by interkeukin 6 (IL-6) enzyme-linked immunosorbent assay. The mechanism of action was evaluated by analysing GC receptor activation by microscopy and quantitative polymerase chain reaction (qPCR). In vivo, rats were subjected to ischaemia-reperfusion injury and were injected intravenously with fluorescent liposomes, liposomal prednisolone, prednisolone, empty liposomes or saline. Uptake was measured by the FLARE camera and the treatment effect by immunohistochemistry for myeloid cells and qPCR for inflammatory markers. Results. In vitro, macrophages internalized liposomes after 8 hours. Prednisolone or liposomal prednisolone treatment reduced IL-6 production and both compounds induced translocation of the GC receptor to the nucleus and upregulation of PER1 messenger RNA (mRNA), indicating a similar mechanism of action. In vivo, fluorescent liposomes accumulated in the inflamed kidney. Liposomal prednisolone treatment increased the presence of ED2-positive anti-inflammatory macrophages and both prednisolone and liposomal prednisolone reduced monocyte chemoattractant protein-1 (MCP-1) mRNA production, indicating a reduced pro-inflammatory profile in the kidney. Conclusions. Liposomal encapsulation is a promising strategy for local delivery of glucocorticoids to the inflamed kidney.

Original languageEnglish
Pages (from-to)44-53
Number of pages10
JournalNephrology Dialysis Transplantation
Volume33
Issue number1
DOIs
Publication statusPublished - 1 Jan 2018
Externally publishedYes

Keywords

  • UT-Hybrid-D
  • Inflammatory kidney disease
  • Liposomal prednisolone
  • Local delivery
  • Macrophage
  • Acute kidney injury

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    Van Alem, C. M. A., Boonstra, M., Prins, J., Bezhaeva, T., Van Essen, M. F., Ruben, J. M., ... Rotmans, J. I. (2018). Local delivery of liposomal prednisolone leads to an anti-inflammatory profile in renal ischaemia-reperfusion injury in the rat. Nephrology Dialysis Transplantation, 33(1), 44-53. https://doi.org/10.1093/ndt/gfx204