Macrophage-Derived Iron-Bound Lipocalin-2 Correlates with Renal Recovery Markers Following Sepsis-Induced Kidney Damage

• Published in: International journal of molecular sciences Vol. 21; no. 20; p. 7527
• Main Authors: Mertens, Christina, Kuchler, Laura, Sola, Anna, Guiteras, Roser, Grein, Stephan, Brüne, Bernhard, von Knethen, Andreas, Jung, Michaela
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13.10.2020; MDPI
• Subjects: Animals; Atomic absorption analysis; Atomic absorption spectroscopy; Biomarkers; Biomarkers - metabolism; Cecum; Cells, Cultured; CLP; Creatinine; Epithelial cells; Epithelial Cells - metabolism; Epithelium; Genotype & phenotype; Iron; Iron - metabolism; Ischemia; Kidney diseases; Kidney Tubules - cytology; Kidney Tubules - metabolism; Kidneys; Lipocalin; lipocalin-2; Lipocalin-2 - genetics; Lipocalin-2 - metabolism; Macrophages; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mortality; Protein Binding; Proteins; Renal failure; Renal function; Renal Insufficiency - etiology; Renal Insufficiency - metabolism; Renal Insufficiency - pathology; renal tubular epithelial cells; Sepsis; Sepsis - complications; iron; macrophages; lipocalin-2; renal tubular epithelial cells; CLP
• DOI: 10.3390/ijms21207527
• ISSN: 1422-0067; 1661-6596

During the course of sepsis in critically ill patients, kidney dysfunction and damage are among the first events of a complex scenario toward multi-organ failure and patient death. Acute kidney injury triggers the release of lipocalin-2 (Lcn-2), which is involved in both renal injury and recovery. Taking into account that Lcn-2 binds and transports iron with high affinity, we aimed at clarifying if Lcn-2 fulfills different biological functions according to its iron-loading status and its cellular source during sepsis-induced kidney failure. We assessed Lcn-2 levels both in serum and in the supernatant of short-term cultured renal macrophages (MΦ) as well as renal tubular epithelial cells (TEC) isolated from either Sham-operated or cecal ligation and puncture (CLP)-treated septic mice. Total kidney iron content was analyzed by Perls' staining, while Lcn-2-bound iron in the supernatants of short-term cultured cells was determined by atomic absorption spectroscopy. Lcn-2 protein in serum was rapidly up-regulated at 6 h after sepsis induction and subsequently increased up to 48 h. Lcn-2-levels in the supernatant of TEC peaked at 24 h and were low at 48 h with no change in its iron-loading. In contrast, in renal MΦ Lcn-2 was low at 24 h, but increased at 48 h, where it mainly appeared in its iron-bound form. Whereas TEC-secreted, iron-free Lcn-2 was associated with renal injury, increased MΦ-released iron-bound Lcn-2 was linked to renal recovery. Therefore, we hypothesized that both the cellular source of Lcn-2 as well as its iron-load crucially adds to its biological function during sepsis-induced renal injury.