The protective role of macrophage migration inhibitory factor in acute kidney injury after cardiac surgery

Abstract

Acute kidney injury (AKI) represents the most frequent complication after cardiac surgery. Macrophage migration inhibitory factor (MIF) is a stress-regulating cytokine that was shown to protect the heart from myocardial ischemia-reperfusion injury, but its role in the pathogenesis of AKI remains unknown. In an observational study, serum and urinary MIF was quantified in 60 patients scheduled for elective conventional cardiac surgery with the use of cardiopulmonary bypass. Cardiac surgery triggered an increase in MIF serum concentrations, and patients with high circulating MIF (>median) 12 hours after surgery had a significantly reduced risk of developing AKI (relative risk reduction, 72.7%; 95% confidence interval, 12 to 91.5%; = 0.03). Experimental AKI was induced in wild-type and mice by 30 min of ischemia followed by 6 or 24 hours of reperfusion, or by rhabdomyolysis. -deficient mice exhibited increased tubular cell injury, increased regulated cell death (necroptosis and ferroptosis), and enhanced oxidative stress. Therapeutic administration of recombinant MIF after ischemia-reperfusion in mice ameliorated AKI. In vitro treatment of tubular epithelial cells with recombinant MIF reduced cell death and oxidative stress as measured by glutathione and thiobarbituric acid reactive substances in the setting of hypoxia. Our data provide evidence of a renoprotective role of MIF in experimental ischemia-reperfusion injury by protecting renal tubular epithelial cells, consistent with our observation that high MIF in cardiac surgery patients is associated with a reduced incidence of AKI.

Macrophage migration inhibitory factor promotes renal injury induced by ischemic reperfusion

“…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.…”

“…Macrophage migration inhibitory factor was a stress molecular that release quickly under disease conditions including surgery, sepsis, acute massive gastrointestinal bleeding or kidney diseases. It is reported that MIF is rapidly released and peaks within one hour during operation . Here, we reported that plasma MIF was closely correlated with the progression and regression in patients with AKI.…”

Contribution of the macrophage migration inhibitory factor superfamily of cytokines in the pathogenesis of preclinical and human multiple sclerosis: In silico and in vivo evidences

“…The anti-inflammatory action of both endogenous and exogenous MIF has also been recently demonstrated in a model of acute kidney injury, in spite of the apparently paradox that this model is prevented by glucocorticoids (GC) and that MIF is a known antagonist of GC (Choi et al, 2013;Stoppe et al, 2018).…”

Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair

“…CD74 is expressed on the surface of renal tubular epithelial cells. Also, these cells express low levels of MIF which is increased following AKI to ensure adequate supplies at the site of damage (80,81). A spontaneous pathological renal phenotype is absent MIF knock-out mice, suggesting little to no effect on healthy organs (82).…”

“…A spontaneous pathological renal phenotype is absent MIF knock-out mice, suggesting little to no effect on healthy organs (82). However, high MIF levels can be found in the serum of patients following cardiac surgery and correlates with protection from AKI (81). In a murine model of experimental ischemia-reperfusion injury, MIF, MIF-2, and CD74 knock-out mice had worse tubular injury compared to wild type control mice.…”