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

Urbschat, Anja; Thiemens, Anne-Kathrin; Mertens, Claudia; Rehwald, Claudia; Meier, Julia K.; Baer, Patrick C.; Jung, Michaela

doi:10.3390/ijms21062038

Cited by 15 publications

(18 citation statements)

References 52 publications

(82 reference statements)

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“…In addition, LCN2 secreted from SGCs might have stimulated macrophages infiltration into the DRG leading to their activation, release of inflammatory cytokines such TNF‐α, and potentiation of the inflammatory response. Previous studies have reported that macrophages produce LCN2 (Jung, Oren, et al, 2016; Jung, Brune, Hotter, & Sola, 2016; Urbschat et al, 2020), which might have contributed to increased expression of LCN2 in the DRG. However, in our study, expression of LCN2 in the DRG of diabetic mice did not colocalize with any cell types other than SGCs.…”

Section: Discussionmentioning

confidence: 95%

Satellite glia as a critical component of diabetic neuropathy: Role of lipocalin‐2 and pyruvate dehydrogenase kinase‐2 axis in the dorsal root ganglion

Bhusal

Rahman

Lee

et al. 2020

Glia

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Diabetic peripheral neuropathy (DPN) is a common complication of uncontrolled diabetes. The pathogenesis of DPN is associated with chronic inflammation in dorsal root ganglion (DRG), eventually causing structural and functional changes. Studies on DPN have primarily focused on neuronal component, and there is limited knowledge about the role of satellite glial cells (SGCs), although they completely enclose neuronal soma in DRG. Lipocalin‐2 (LCN2) is a pro‐inflammatory acute‐phase protein found in high levels in diverse neuroinflammatory and metabolic disorders. In diabetic DRG, the expression of LCN2 was increased exclusively in the SGCs. This upregulation of LCN2 in SGCs correlated with increased inflammatory responses in DRG and sciatic nerve. Furthermore, diabetes‐induced inflammation and morphological changes in DRG, as well as sciatic nerve, were attenuated in Lcn2 knockout (KO) mice. Lcn2 gene ablation also ameliorated neuropathy phenotype as determined by nerve conduction velocity and intraepidermal nerve fiber density. Mechanistically, studies using specific gene KO mice, adenovirus‐mediated gene overexpression strategy, and primary cultures of DRG SGCs and neurons have demonstrated that LCN2 enhances the expression of mitochondrial gate‐keeping regulator pyruvate dehydrogenase kinase‐2 (PDK2) through PPARβ/δ, thereby inhibiting pyruvate dehydrogenase activity and increasing production of glycolytic end product lactic acid in DRG SGCs and neurons of diabetic mice. Collectively, our findings reveal a crucial role of glial LCN2‐PPARβ/δ‐PDK2‐lactic acid axis in progression of DPN. Our results establish a link between pro‐inflammatory LCN2 and glycolytic PDK2 in DRG SGCs and neurons and propose a novel glia‐based mechanism and drug target for therapy of DPN. Main Points Diabetes upregulates LCN2 in satellite glia, which in turn increases pyruvate dehydrogenase kinase‐2 (PDK2) expression and lactic acid production in dorsal root ganglia (DRG). Glial LCN2‐PDK2‐lactic acid axis in DRG plays a crucial role in the pathogenesis of diabetic neuropathy.

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Section: Discussionmentioning

confidence: 95%

Satellite glia as a critical component of diabetic neuropathy: Role of lipocalin‐2 and pyruvate dehydrogenase kinase‐2 axis in the dorsal root ganglion

Bhusal

Rahman

Lee

et al. 2020

Glia

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“…With regard to Lcn-2, we found that iron-released MΦ also produces and secretes iron-loaded Lcn-2 as part of a complex network of iron-regulated genes in order to promote cellular proliferation [ 47 ]. In line, recent work from our group showed that TEC take up MΦ-secreted iron-loaded Lcn-2 in an in vitro cisplatin-induced injury model, whereby proliferation and epithelial cell polarity, as such recovery, was fostered [ 11 ].…”

Section: Discussionmentioning

confidence: 64%

“…Although the ability to transport and donate iron results as a pivotal mechanism of Lcn-2 to promote not only cell survival and proliferation, but also to limit tubular damage during acute renal injury [ 48 ], the decisive role of the iron-load of Lcn-2 has not been investigated so far in sepsis-induced kidney damage and subsequent recovery progression. Interestingly, results of the present study allow for the assumption that the cellular source of iron-loaded Lcn-2, which is crucial for renal repair [ 11 ], are kidney MΦ. We found neither changes in iron-loaded Lcn-2 levels in TEC nor any correlation to TEC-released Lcn-2 with renal regeneration markers PCNA and Stathmin.…”

Section: Discussionmentioning

confidence: 91%

“…These rather opposing functions might be explained by either the source of Lcn-2 during the early phases of kidney injury versus the later phases of renal recovery or its functional transporting activity. In this regard, we recently found that the biological activity of Lcn-2 depends on its iron-load, whereby iron-loaded Lcn-2 markedly enhanced renal regeneration in a cisplatin-model in vitro [ 11 ]. These observations are in line with other studies, proposing that the protective effects of Lcn-2 in renal ischemia/reperfusion injury might be due to its ability to serve as an iron transporter [ 12 , 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

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

Mertens

Kuchler

Solà

et al. 2020

IJMS

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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.

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“…2 ). 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.…”

Section: Macrophage-derived Mediators In Akimentioning

confidence: 99%

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

Chen

Wang³

et al. 2021

Mol Med Rep

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Acute kidney injury (AKI) has become a global public health problem with high morbidity and mortality rates, as well as high healthcare costs. Immune cells, particularly macrophages, which regulate tissue development, destroy pathogens, control homeostasis and repair wounds, play crucial and complex roles in AKI. In various types of AKI, numerous rapidly recruited monocytes and tissue-resident macrophages act in a coordinated manner. Thus, elucidating the phenotypic and functional characteristics of macrophages in AKI is essential for identifying potential therapeutic targets. Macrophage-sensing mediators and macrophage-derived mediators participate in the major macrophage-related signaling pathways in AKI, which regulate macrophage polarization and determine disease progression. In conclusion, macrophages change their roles and regulatory mechanisms during the occurrence and development of AKI. The aim of the present review was to contribute to an improved understanding of AKI and to the identification of novel therapeutic targets for this condition.

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

Cited by 15 publications

References 52 publications

Satellite glia as a critical component of diabetic neuropathy: Role of lipocalin‐2 and pyruvate dehydrogenase kinase‐2 axis in the dorsal root ganglion

Satellite glia as a critical component of diabetic neuropathy: Role of lipocalin‐2 and pyruvate dehydrogenase kinase‐2 axis in the dorsal root ganglion

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

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

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