MIF-2/D-DT enhances proximal tubular cell regeneration through SLPI- and ATF4-dependent mechanisms

Ochi, Akinobu; Chen, Dong; Schulte, Wibke; Leng, Lin; Moeckel, Nickolas Gilbert; Piecychna, Marta; Averdunk, Luisa; Stoppe, Christian; Bucala, Richard; Moeckel, Gilbert

doi:10.1152/ajprenal.00683.2016

Cited by 40 publications

(33 citation statements)

References 77 publications

(73 reference statements)

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“…This was consistent with the pathogenic role of MIF in renal inflammatory diseases in which inhibition of MIF suppresses progressive renal injury in various forms of kidney diseases including anti‐GBM glomerulonephritis, septic shock, UUO and diabetic nephropathy . In contrast, a recent study reported that MIF is protective in AKI as high levels of plasma MIF in patients with cardiac surgery is associated with a reduced incidence of AKI and mice lacking MIF worsen AKI by inhibiting tubular epithelial cell proliferation in unilateral IRI‐induced AKI, which is also found in other two studies in which MIF or MIF‐2 inhibits AKI‐induced chronic renal injury by enhancing cell regeneration, although serum levels of creatinine are lower in MIF KO mice at 24 hours after AKI which is consistent with our finding. The reason for this discrepancy remains largely unknown.…”

Section: Disscussionsupporting

confidence: 87%

Macrophage migration inhibitory factor promotes renal injury induced by ischemic reperfusion

Tang

et al. 2019

J Cellular Molecular Medi

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Macrophage migration inhibitory factor (MIF) is pleiotropic cytokine that has multiple effects in many inflammatory and immune diseases. This study reveals a potential role of MIF in acute kidney injury (AKI) in patients and in kidney ischemic reperfusion injury (IRI) mouse model in MIF wild‐type (WT) and MIF knockout (KO) mice. Clinically, plasma and urinary MIF levels were largely elevated at the onset of AKI, declined to normal levels when AKI was resolved and correlated tightly with serum creatinine independent of disease causes. Experimentally, MIF levels in plasma and urine were rapidly elevated after IRI‐AKI and associated with the elevation of serum creatinine and the severity of tubular necrosis, which were suppressed in MIF KO mice. It was possible that MIF may mediate AKI via CD74/TLR4‐NF‐κB signalling as mice lacking MIF were protected from AKI by largely suppressing CD74/TLR‐4‐NF‐κB associated renal inflammation, including the expression of MCP‐1, TNF‐α, IL‐1β, IL‐6, iNOS, CXCL15(IL‐8 in human) and infiltration of macrophages, neutrophil, and T cells. In conclusion, our study suggests that MIF may be pathogenic in AKI and levels of plasma and urinary MIF may correlate with the progression and regression of AKI.

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Section: Disscussionsupporting

confidence: 87%

Macrophage migration inhibitory factor promotes renal injury induced by ischemic reperfusion

Tang

et al. 2019

J Cellular Molecular Medi

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“…Although, SLPI was suggested to exert kidney protection via promoting tubular cell regeneration, data on the functional role of SLPI in AKI and in critically ill patients are scarce 13 . Thus, experimental studies elucidating the pathophysiological effects of SLPI on oxidative stress and kidney injury are needed.…”

Section: Discussionmentioning

confidence: 99%

“…In the setting of oxidative stress, SLPI seems to have antioxidant and cytoprotective properties 11,12 . In a murine model of experimental ischemic AKI, Macrophage Migration Inhibitory Factor-2 (MIF-2) was suggested to exert kidney protection by upregulation of SLPI expression 13 .…”

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confidence: 99%

SLPI - a Biomarker of Acute Kidney Injury after Open and Endovascular Thoracoabdominal Aortic Aneurysm (TAAA) Repair

Averdunk

Rückbeil

Zarbock

et al. 2020

Sci Rep

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Acute kidney injury (AKi) is a relevant complication following thoracoabdominal aortic aneurysm repair (tAAA). Biomarkers, such as secretory leucocyte peptidase inhibitor (SLpi), may enable a more accurate diagnosis. in this study, we tested if SLpi measured in serum is an appropriate biomarker of AKi after TAAA repair. In a prospective observational single-center study including 33 patients (51.5% women, mean age 63.0 ± 16.2 years) undergoing open and endovascular aortic aneurysm repair in 2017, SLPI was measured peri-operatively (until 72 h after surgery). After surgery, the postoperative complications AKI, as defined according to the KDIGO diagnostic criteria, sepsis, death, MACE (major cardiovascular events) and, pneumonia were assessed. in a subgroup analysis, patients with preexisting kidney disease were excluded. Of 33 patients, 51.5% (n = 17) of patients developed AKI. Twelve hours after admission to the intensive care unit (ICU), SLPI serum levels were significantly increased in patients who developed AKI. Multivariable logistic regression revealed a significant association between SLPI 12 hours after admission to ICU and AKI (P = 0.0181, OR = 1.055, 95% CI = 1.009-1.103). The sensitivity of SLPI for AKI prediction was 76.47% (95% CI = 50.1-93.2) and the specificity was 87.5% (95% CI = 61.7-98.4) with an AUC = 0.838 (95% CI = 0.7-0.976) for an optimal cut-off 70.03 ng/ml 12 hours after surgery. in patients without pre-existing impaired renal function, an improved diagnostic quality of SLpi for AKI was observed (Sensitivities of 45.45-91.67%, Specificities of 77.7-100%, AUC = 0.716-0.932). there was no association between perioperative SLpi and the incidence of sepsis, death, MAce (major cardiovascular events), pneumonia. this study suggests that SLpi might be a post-operative biomarker of AKi after tAAA repair, with a superior diagnostic accuracy for patients without preexisting impaired renal function.Open and endovascular repair of thoracoabdominal aortic aneurysm (TAAA) is related to a high risk of postoperative complications. With an incidence ranging between 13 and 42%, acute kidney injury (AKI) is one of the most common complications and closely associated with increased mortality and cardiovascular morbidity 1-3 . The early detection of impaired kidney function and other organ dysfunctions may enable an immediate start of specific treatment bundles. The diagnosis of AKI is mainly based on patients' urine output and serum creatinine levels. Serum creatinine is an established, yet controversial biomarker due to its delayed increase and low sensitivity for the detection of an impaired kidney function 4-6 . In this context, the necessity of clinically available early and reliable biomarkers of AKI becomes evident.Secretory leucocyte peptidase inhibitor (SLPI) is a protease inhibitor and regulator of innate and adaptive immunity 7 . It is synthesized predominantly in immune and epithelial cells of mucosal surfaces, such as the pancreas and kidney 8 . Elevated serum SLPI levels have been observed in acu...

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“…It has also been reported that the proteome profile in IR kidneys at 48 h changed by CHBP treatment was mainly related to the oxidative stress [37]. There may be differentiations between (Table 3), was renoprotective in experimental ischemia AKI [38]. SLPI inhibits nuclear factor kappa beta (NF-κB) signaling pathway [39] and the maturation of IL-1β [40], and shown as a biomarker candidate in AKI [41,42].…”

Section: Discussionmentioning

confidence: 97%

Transcriptional Profiles in Ischemia/Reperfusion-Injured Murine Kidneys Synergistically Protected by Erythropoietin Derived Peptide CHBP and Caspase-3 siRNA

Chen

Zhang

et al. 2020

Preprint

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Background: Target-specific treatment is not available for acute kidney injury (AKI). A novel erythropoietin-derived cyclic helix B surface peptide (CHBP) protects kidneys against AKI subjected to different causes. Herein, we investigated the transcriptional profile of renoprotection induced by CHBP and its potential synergistic effects with caspase-3 siRNA (CASP3siRNA) on ischemia/reperfusion (IR) injury associated AKI. Methods: A mouse renal IR model was established by clamping bilateral pedicles for 30 min and reperfusion for 48 h. 0.03 mg/kg of CASP3siRNA/negative control (NCsiRNA) was injected via tail vein 2 h pre-surgery, with/without 24 nmol/kg of CHBP administered to peritoneal cavity at 15 min post reperfusion. The transcriptomic profile in kidneys was assessed by affymetrix gene chips, along with renal function, histology, active caspase-3 and HMGB1.Results: CHBP or CASP3siRNA significantly improved renal function and structure, with decreased caspase-3 and HMGB1 in IR kidneys. Combined treatment of CHBP and CASP3siRNA further preserved kidney structure, and reduced active caspase-3 and HMGB1. Furthermore, fold change > 1.414 and P < 0.05 were used to identify differentially expressed genes (DEGs). In IR kidneys, 281 DEGs induced by CHBP were mainly involved in promoting cell division and improving cellular function and metabolism (up-regulated STAT5B and SLC22A7). The additional administration of CASP3siRNA caused 504 and 418 DEGs in IR + CHBP kidneys with or without NCsiRNA, with 37 genes in common. These DEGs were associated with modulated apoptosis and inflammation (up-regulated BCL6，SLPI and SERPINA3M), and immunity, injury and microvascular homeostasis (up-regulated CFH and GREM1, and down-regulated ANGPTL2). Conclusions: This proof-of-effect study indicated that the synergistic renoprotection of CHBP and CASP3siRNA at the early stage of IR-induced AKI. Underlying genes, BCL6, SLPI, SERPINA3M, GREM1 and ANGPTL2, might be potential new biomarkers for clinical applications.

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MIF-2/D-DT enhances proximal tubular cell regeneration through SLPI- and ATF4-dependent mechanisms

Cited by 40 publications

References 77 publications

Macrophage migration inhibitory factor promotes renal injury induced by ischemic reperfusion

Macrophage migration inhibitory factor promotes renal injury induced by ischemic reperfusion

SLPI - a Biomarker of Acute Kidney Injury after Open and Endovascular Thoracoabdominal Aortic Aneurysm (TAAA) Repair

Transcriptional Profiles in Ischemia/Reperfusion-Injured Murine Kidneys Synergistically Protected by Erythropoietin Derived Peptide CHBP and Caspase-3 siRNA

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