The role of macrophages during acute kidney injury: destruction and repair

Han, Hwa In; Skvarca, Lauren Brilli; Espiritu, Eugenel B.; Davidson, Alan J.; Hukriede, Neil A.

doi:10.1007/s00467-017-3883-1

Cited by 69 publications

(62 citation statements)

References 78 publications

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“…The phenotypic changes and functions of macrophages are regulated by various signaling pathways. Transcription factors, including MAPK, JNK, and NF-κB, are involved in M1 programming ( 48 ). PPARγ-deficient macrophages are resistant to M2 polarization and promote insulin resistance ( 49 ).…”

Section: Discussionmentioning

confidence: 99%

Csf2 Attenuated Sepsis-Induced Acute Kidney Injury by Promoting Alternative Macrophage Transition

Zhai

Zhang

et al. 2020

Front. Immunol.

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Sepsis is a systemic inflammatory state that occurs in response to infection and significantly increases mortality in combination with acute kidney injury (AKI). Macrophages accumulate in the kidney after injury and undergo a transition from a proinflammatory (M1) phenotype to an alternatively activated (M2) phenotype that is required for normal repair. However, the specific signals that regulate the transition from the M1 to M2 phenotype in vivo are unknown. Here, we found an unexpected role of Colony stimulating factor 2 (Csf2) in controlling macrophage transition in vitro and in a mouse model of sepsis induced by cecal ligation and puncture (CLP). We first co-cultured human M1 macrophages with HK-2 cells and characterized cytokine/chemokine profiles via Luminex. Of the cytokines and chemokines that were overexpressed in medium from M1 macrophages cocultured with human kidney-2 (HK-2) cells compared with that from M1 macrophages cultured alone, Csf2 and IL6 showed the greatest increases. Csf2 was exclusively secreted by HK-2 cells but not by M1 macrophages. Furthermore, recombinant human Csf2 protein promoted transition of M1 macrophages to the M2 phenotype in a dose and time-dependent manner. The apoptosis and reactive oxygen species (ROS) release induced by M1 macrophages in HK-2 cells was attenuated after exposure to exogenous Csf2. In addition, the switch from the proinflammatory M1 phenotype to the M2 phenotype occurred via the p-Stat5 pathway, which was activated by Csf2. Importantly, we found that intraperitoneal injection of a Csf2-neutralizing antibody after CLP aggravated kidney injury and suppressed tubular proliferation, subsequently decreasing survival. However, administration of recombinant mouse Csf2 protein could rescue mice with sepsis. Together, our results indicate that Csf2 plays critical roles in regulating macrophage transition via activation of p-STAT5. These data form a foundation upon which new therapeutic strategies can be designed to improve the therapeutic efficacy of cytokine-based treatments for sepsis-induced AKI.

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Section: Discussionmentioning

confidence: 99%

Csf2 Attenuated Sepsis-Induced Acute Kidney Injury by Promoting Alternative Macrophage Transition

Zhai

Zhang

et al. 2020

Front. Immunol.

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“…As a member of the mononuclear phagocyte family, macrophages function as a key player in renal injury, inflammation and fibrosis. In addition, macrophages are pleiotropic inflammatory cells that participate in inflammatory reactions ( 8 ). With recruitment to the inflammatory milieu, macrophages interact with other cell types, such as fibroblasts, which transdifferentiate into matrix-secreting myofibroblasts, resulting in scar formation and structure destruction ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of allograft inflammatory factor‑1 expression and secretion by macrophages stimulated with aldosterone promotes renal fibroblasts to a profibrotic phenotype

Wang

Zhang

et al. 2018

Int J Mol Med

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Macrophages have been identified as a key cell type in the pathogenesis of renal interstitial fibrosis (RIF). However, the mechanism through which macrophages drive fibrosis remains unclear. The current study focuses on the effects and possible underlying mechanism of allograft inflammatory factor-1 (AIF-1), an inflammation-responsive scaffold protein expressed and secreted by macrophages, in promoting fibroblasts to a profibrotic phenotype. In vivo experiments indicated that AIF-1, CD68 and α-smooth muscle actin (α-SMA) were upregulated in kidney tissues of mice subjected to unilateral ureteric obstruction, while their expressions were inhibited by an aldosterone receptor antagonist, spironolactone. Double immunofluorescence staining revealed that AIF-1 expression co-localized with CD68-positive macrophages in the renal interstitium, indicating that AIF-1 expression in macrophages was increased in the RIF animal model. Furthermore, to identify the role of AIF-1 in promoting fibrosis, its expression and secretion by the RAW264.7 macrophage cell line were detected in vitro. The expression levels of α-SMA, phosphorylated p38 (p-p38) and fibronectin (FN) in fibroblasts were examined subsequent to co-culture with macrophages. The increase in AIF-1 expression and secretion was confirmed in RAW264.7 cells in response to aldosterone. After 72 h of co-culture between fibroblasts and macrophages stimulated with aldosterone, the α-SMA expression was induced in fibroblasts, with significantly increased expression levels of FN and p-p38 observed. In addition, AIF-1 expression was reduced by stable transfection of RAW264.7 cells with AIF-1 small interfering RNA, resulting in significantly reduced expression levels of α-SMA, p-p38 and FN in fibroblasts co-cultured with macrophages as compared with normal macrophages. These findings indicate that the expression of AIF-1 in macrophages is critical for the activation of renal fibroblasts to a profibrotic phenotype. AIF-1 expression was upregulated in macrophages, and may be a novel mechanism linking macrophages to the promotion of RIF via the p38 signaling pathway.

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“…CD68 and F4/80 expression indicated the infiltration of macrophages, a sign of inflammation. 18 TLR4 expression is an indicator of consistent inflammatory cell infiltration. Compared with the Con group, obvious increases in CD68 + and F4/80 + cells were found in the renal interstitia of DKD mice ( Figure 2A–C ).…”

Section: Resultsmentioning

confidence: 99%

Inhibitor of IGF1 receptor alleviates the inflammation process in the diabetic kidney mouse model without activating SOCS2

Dong

et al. 2018

DDDT

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ObjectiveTo explore the anti-inflammatory mechanism of IGF1R inhibitor in diabetic nephropathy.MethodsC57/BL6 mice were reared with high-fat diet for 8 weeks, then were injected 30 mg/kg streptozotocin intraperitoneally to induce type 2 diabetes. After 8 weeks, the type 2 diabetes nephropathy model was successfully set up the different drugs were administrated to mice with diabetes (insulin 1–2 U/day, benazepril 10 mg/kg per day intragastrically, IGF-1R inhibitor 30 mg/kg per day intragastrically). After 8 weeks drugs administration, all mice were collected the kidney tissue, measured levels of inflammatory factor (F4/80, TLR4and CD68) and fibrosis markers(αSMA, E-cadherin and SR) using immunohistochemistry and in situ hybridization.ResultsThe type 2 diabetes nephropathy model was built successfully, which along with increased urinary protein excretion rate and increased inflammatory infiltration, and the correlation was characterized by increased CD68+, F4/80+ cells and increased TLR4, αSMA, SR expression. IGF-1R inhibitors reversed this changes, but benazepril and insulin were without significant changes. The insulin decreased the expression level of IGF-1, and increased the levels of suppressor of cytokine signaling 2 (SOCS2). Benazepril and IGF-1R inhibitor were no significant changes like insulin.ConclusionInhibition of IGF1R was a more effective choice for inflammation treatment than Ben or Ins in diabetic kidney disease (DKD). The IGF1R inhibitor blocked pathological changes induced by the over-expression of IGF1 in DKD without up-regulating SOCS2 protein levels.

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The role of macrophages during acute kidney injury: destruction and repair

Cited by 69 publications

References 78 publications

Csf2 Attenuated Sepsis-Induced Acute Kidney Injury by Promoting Alternative Macrophage Transition

Csf2 Attenuated Sepsis-Induced Acute Kidney Injury by Promoting Alternative Macrophage Transition

Upregulation of allograft inflammatory factor‑1 expression and secretion by macrophages stimulated with aldosterone promotes renal fibroblasts to a profibrotic phenotype

Inhibitor of IGF1 receptor alleviates the inflammation process in the diabetic kidney mouse model without activating SOCS2

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