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

Abstract

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.

A Mixture of Pure, Isolated Polyphenols Worsens the Insulin Resistance and Induces Kidney and Liver Fibrosis Markers in Diet-Induced Obese Mice

“…It has been documented that LCN2 is an iron-carrier protein, and its biological activity depends on its iron-load and on where it is produced (renal tubules or macrophages), which defines its dual role in the development of kidney damage [ 60 , 61 , 62 ]. Iron-free LCN2 secreted by renal tubular epithelial cells has been associated with renal injury, and the expression and release of macrophage-derived iron-bound LCN2 has been linked to renal recovery [ 63 ]. Similarly, it has also been shown that adipose-tissue-derived LCN2 plays a critical role in causing both chronic and acute renal injury, but it is also essential for the progression of CKD in rodent and human models [ 46 , 64 ].…”

The Macrophage Iron Signature in Health and Disease

“…It is widely accepted that the application of LCN-2 diminishes renal injury and enables renal regeneration [147,151,175,193,194]. Recently, we found that LCN-2 fulfills different biological functions according to its iron-loading status and its cellular source during sepsis-induced kidney failure [195]. Interestingly, LCN-2 was produced and secreted from renal tubular epithelial cells in its iron-free form, which was associated with renal damage.…”

Major signaling pathways and key mediators of macrophages in acute kidney injury (Review)

“…A study by Urbschat et al ( 91 ) showed that mouse tubular epithelial cells (TECs) promoted the proliferation of epithelial cells by taking macrophage-derived iron-loaded Lcn-2. Mertens et al ( 92 ) concluded that the cellular source of Lcn-2 (TECs or macrophages) and its iron loading determine the biological function of Lcn-2 in cecal ligation and puncture (CLP)-induced kidney injury. At 24 h after CLP-induced kidney injury, elevated levels of iron-free Lcn-2 in TECs are primarily considered as markers of kidney injury, whereas elevated levels of iron-loaded Lcn-2 from macrophage sources are associated with markers of recovery ( 92 ) ( Fig.…”