Macrophage-secreted Lipocalin-2 Promotes Regeneration of Injured Primary Murine Renal Tubular Epithelial Cells

Lipocalin-2 (Lcn-2) is rapidly upregulated in macrophages after renal tubular injury and acts as renoprotective and pro-regenerative agent. Lcn-2 possesses the ability to bind and transport iron with high affinity. Therefore, the present study focuses on the decisive role of the Lcn-2 iron-load for...

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Published in:	International journal of molecular sciences 2020-03, Vol.21 (6), p.2038
Main Authors:	Urbschat, Anja, Thiemens, Anne-Kathrin, Mertens, Christina, Rehwald, Claudia, Meier, Julia K, Baer, Patrick C, Jung, Michaela
Format:	Article
Language:	eng
Subjects:	Animals Apoptosis Bone marrow Cell Proliferation Cisplatin Cisplatin - adverse effects Cytokines Epithelial cells Epithelial Cells - metabolism Genotype & phenotype Inflammation Injury prevention Interleukin 10 Iron Iron - metabolism Ischemia Kidney - drug effects Kidney - injuries Kidney - metabolism Kidneys Lipocalin lipocalin-2 Lipocalin-2 - genetics Lipocalin-2 - metabolism Macrophages Macrophages - metabolism Mice Mice, Inbred C57BL Mice, Knockout Phenotypes Protein expression Proteins Recombinant Proteins Regeneration renal tubular epithelial cells Tumor necrosis factor-TNF Up-Regulation
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Summary:	Lipocalin-2 (Lcn-2) is rapidly upregulated in macrophages after renal tubular injury and acts as renoprotective and pro-regenerative agent. Lcn-2 possesses the ability to bind and transport iron with high affinity. Therefore, the present study focuses on the decisive role of the Lcn-2 iron-load for its pro-regenerative function. Primary mouse tubular epithelial cells were isolated from kidney tissue of wildtype mice and incubated with 5μM Cisplatin for 24h to induce injury. Bone marrow-derived macrophages of wildtype and Lcn-2 mice were isolated and polarized with IL-10 towards an anti-inflammatory, iron-release phenotype. Their supernatants as well as recombinant iron-loaded holo-Lcn-2 was used for stimulation of Cisplatin-injured tubular epithelial cells. Incubation of tubular epithelial cells with wildtype supernatants resulted in less damage and induced cellular proliferation, whereas in absence of Lcn-2 no protective effect was observed. Epithelial integrity as well as cellular proliferation showed a clear protection upon rescue experiments applying holo-Lcn-2. Notably, we detected a positive correlation between total iron amounts in tubular epithelial cells and cellular proliferation, which, in turn, reinforced the assumed link between availability of Lcn-2-bound iron and recovery. We hypothesize that macrophage-released Lcn-2-bound iron is provided to tubular epithelial cells during toxic cell damage, whereby injury is limited and recovery is favored.
ISSN:	1422-0067 1661-6596 1422-0067