Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany.
Department of Experimental Nephrology, IDIBELL, 08908 L'Hospitalet del Llobregat, Barcelona, Spain.
Int J Mol Sci. 2020 Oct 13;21(20):7527. doi: 10.3390/ijms21207527.
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.
在危重病患者脓毒症的病程中，肾功能障碍和损伤是导致多器官衰竭和患者死亡的复杂事件链中的最早事件之一。急性肾损伤会触发分泌素-2（Lcn-2）的释放，Lcn-2 既参与肾损伤也参与肾修复。鉴于 Lcn-2 具有高亲和力结合和转运铁的能力，我们旨在阐明 Lcn-2 是否根据其铁负荷状态及其在脓毒症诱导的肾功能衰竭期间的细胞来源来发挥不同的生物学功能。我们评估了血清中 Lcn-2 水平以及短期培养的肾巨噬细胞（MΦ）和从假手术或盲肠结扎穿刺（CLP）处理的脓毒症小鼠分离的肾小管上皮细胞（TEC）的上清液中的 Lcn-2 水平。通过 Perls 染色分析总肾铁含量，通过原子吸收光谱法测定短期培养细胞上清液中 Lcn-2 结合铁的含量。脓毒症诱导后 6 小时，血清中 Lcn-2 蛋白迅速上调，随后增加至 48 小时。TEC 上清液中 Lcn-2 水平在 24 小时达到峰值，48 小时时降低，其铁负荷无变化。相比之下，在肾 MΦ 中，Lcn-2 在 24 小时时水平较低，但在 48 小时时增加，主要以其结合铁的形式出现。尽管 TEC 分泌的无铁 Lcn-2 与肾损伤有关，但增加的 MΦ 释放的结合铁的 Lcn-2 与肾修复有关。因此，我们假设 Lcn-2 的细胞来源及其铁负荷对脓毒症诱导的肾损伤期间 Lcn-2 的生物学功能至关重要。
