Macrophage Migration Inhibitory Factor in Clinical Kidney Disease

Abstract

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine implicated in acute and chronic inflammatory conditions, including sepsis, autoimmune disease, atherogenesis, plaque instability, and pulmonary arterial hypertension. MIF in plasma and urine is significantly elevated in patients with acute kidney injury (AKI) and elevated MIF in serum is associated with markers of oxidative stress, endothelial dysfunction, arterial stiffness, and markers of myocardial damage in chronic kidney disease (CKD). Furthermore, MIF seems to be involved in vascular processes and cardiovascular disease associated with CKD, glomerulonephritis, autosomal dominant polycystic kidney disease, and possibly also in progression to renal failure. Moreover, in active anti-neutrophil cytoplasmatic antibody-associated vasculitis, plasma MIF levels have been shown to be significantly elevated as compared with samples from patients in remission. A significant difference in the genotype frequency of high production MIF -173 G/C genotype has been found in end-stage renal disease, compared to controls. Inhibition of MIF in a diabetic nephropathy model ameliorated blood glucose and albuminuria and in a model of adult polycystic kidney disease cyst growth was delayed. Preclinical studies support a potential therapeutic role for MIF in AKI and in a number of CKDs, whereas these data in human disease are still observational. Future interventional studies are needed to delineate the role of MIF as a treatment target in clinical kidney disease.

Role of the Renin-Angiotensin-Aldosterone System beyond Blood Pressure Regulation: Molecular and Cellular Mechanisms Involved in End-Organ Damage during Arterial Hypertension

“…Of these, TGF-β mediates the processes of proliferation, apoptosis, and collagen synthesis and is one of the most ubiquitous profibrotic factors. This factor has been widely studied in the amelioration of chronic kidney disease due to the action of its upstream regulator, the macrophage migration inhibitory factor [ 79 , 80 ]. A recently reported novel interaction of TGF-β through the NOTCH signaling pathway indicates that this factor can positively regulate the hepatocyte growth factor, which could have a reparative effect in chronic kidney disease [ 81 ].…”

Predictive potential of macrophage migration inhibitory factor (MIF) in patients with heart failure with preserved ejection fraction (HFpEF)

“…Beyond this background, MIF seems to be a good candidate marker to be evaluated in HFpEF since it was shown to be a marker for oxidative stress, organ fibrosis, cell damage, atherosclerosis, lung disease, rheumatic diseases, sepsis [ 21 ], severe illness, and chronic kidney disease [ 12 , 13 , 18 , 19 , 22 – 25 ]. MIF is a pleiotropic upstream pro-inflammatory integral mediator of the innate immune system, stimulating the release of multiple cytokines, including tumor necrosis factor (TNF)-α which has been shown to activate matrix metalloproteinases and to be responsible for collagen degradation and progressive left ventricular dilation [ 26 ].…”

Pharmacokinetics, disease-modifying activity, and safety of an experimental therapeutic targeting an immunological isoform of macrophage migration inhibitory factor, in rat glomerulonephritis

“…Kidney cells show marked de novo expression of MIF during development of rat anti-GBM nephritis, including endothelium and glomerular and tubular epithelial cells, which correlates with macrophage accumulation within the glomerulus and tubulointerstitium (Lan et al, 1996;Lang et al, 2015). Upregulation of MIF expression by parietal epithelial cells is associated with macrophage accumulation within Bowman's space and crescent formation; however, MIF is also expressed by macrophages, T cells, and fibroblast-like cells within renal lesions (Lan et al, 1997;Lang et al, 2015;Bruchfeld et al, 2016). A recent report studying GN in mice further suggests that MIF and its receptor complex CD74/CD44 mediate glomerular injury and are crucially involved in the pathologic proliferation of glomerular cells (Djudjaj et al 2016).…”

“…Macrophage Migration Inhibitory Factor (MIF) is a regulatory cytokine of the innate and adaptive immune response and is produced, stored, and secreted by macrophages and other cells of the immune system (Lolis and Bucala, 2003). MIF is therefore considered a promising and rational therapeutic target across inflammatory conditions (Hoi et al, 2007;Leng et al 2011;Lang et al, 2015;Bruchfeld et al, 2016). Anti-MIF treatment has previously been shown to prevent loss of renal function and to inhibit renal leukocyte infiltration and activation in an experimental model of rat GN (Yang et al, 1997) induced by administration of nephrotoxic serum (NTS).…”