PMID- 28992069 OWN - NLM STAT- MEDLINE DCOM- 20181127 LR - 20220316 IS - 1460-2385 (Electronic) IS - 0931-0509 (Linking) VI - 33 IP - 1 DP - 2018 Jan 1 TI - Local delivery of liposomal prednisolone leads to an anti-inflammatory profile in renal ischaemia-reperfusion injury in the rat. PG - 44-53 LID - 10.1093/ndt/gfx204 [doi] AB - 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. CI - (c) The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. FAU - van Alem, Carla M A AU - van Alem CMA AD - Department of Internal Medicine - Nephrology, Leiden University Medical Center, Leiden, The Netherlands. AD - Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. FAU - Boonstra, Mark AU - Boonstra M AD - Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. FAU - Prins, Jurrien AU - Prins J AD - Department of Internal Medicine - Nephrology, Leiden University Medical Center, Leiden, The Netherlands. AD - Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. FAU - Bezhaeva, Taisiya AU - Bezhaeva T AD - Department of Internal Medicine - Nephrology, Leiden University Medical Center, Leiden, The Netherlands. AD - Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. FAU - van Essen, Mieke F AU - van Essen MF AD - Department of Internal Medicine - Nephrology, Leiden University Medical Center, Leiden, The Netherlands. AD - Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. FAU - Ruben, Jurjen M AU - Ruben JM AD - Department of Internal Medicine - Nephrology, Leiden University Medical Center, Leiden, The Netherlands. AD - Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. FAU - Vahrmeijer, Alexander L AU - Vahrmeijer AL AD - Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. FAU - van der Veer, Eric P AU - van der Veer EP AD - Department of Internal Medicine - Nephrology, Leiden University Medical Center, Leiden, The Netherlands. AD - Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. FAU - de Fijter, Johan W AU - de Fijter JW AD - Department of Internal Medicine - Nephrology, Leiden University Medical Center, Leiden, The Netherlands. AD - Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. FAU - Reinders, Marlies E AU - Reinders ME AD - Department of Internal Medicine - Nephrology, Leiden University Medical Center, Leiden, The Netherlands. AD - Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. FAU - Meijer, Onno AU - Meijer O AD - Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. AD - Department of Internal Medicine - Endocrinology, Leiden University Medical Center, Leiden, The Netherlands. FAU - Metselaar, Josbert M AU - Metselaar JM AD - Management team, Enceladus Pharmaceuticals, Naarden, The Netherlands. AD - Department of Experimental Molecular Imaging, University Clinic, RWTH Aachen University, Aachen, Germany. FAU - van Kooten, Cees AU - van Kooten C AD - Department of Internal Medicine - Nephrology, Leiden University Medical Center, Leiden, The Netherlands. AD - Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. FAU - Rotmans, Joris I AU - Rotmans JI AD - Department of Internal Medicine - Nephrology, Leiden University Medical Center, Leiden, The Netherlands. AD - Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. LA - eng PT - Journal Article PL - England TA - Nephrol Dial Transplant JT - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association JID - 8706402 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Inflammation Mediators) RN - 0 (Liposomes) RN - 9PHQ9Y1OLM (Prednisolone) SB - IM MH - Animals MH - Anti-Inflammatory Agents/*therapeutic use MH - Cells, Cultured MH - *Drug Delivery Systems MH - Humans MH - Inflammation/metabolism/*prevention & control MH - Inflammation Mediators/*metabolism MH - Liposomes/*administration & dosage/chemistry MH - Macrophages/cytology/drug effects MH - Male MH - Prednisolone/*therapeutic use MH - Rats MH - Rats, Inbred Lew MH - Reperfusion Injury/*drug therapy/metabolism OTO - NOTNLM OT - acute kidney injury OT - inflammatory kidney disease OT - liposomal prednisolone OT - local delivery OT - macrophage EDAT- 2017/10/11 06:00 MHDA- 2018/11/28 06:00 CRDT- 2017/10/10 06:00 PHST- 2017/02/10 00:00 [received] PHST- 2017/05/03 00:00 [accepted] PHST- 2017/10/11 06:00 [pubmed] PHST- 2018/11/28 06:00 [medline] PHST- 2017/10/10 06:00 [entrez] AID - 3939815 [pii] AID - 10.1093/ndt/gfx204 [doi] PST - ppublish SO - Nephrol Dial Transplant. 2018 Jan 1;33(1):44-53. doi: 10.1093/ndt/gfx204.