Elevated macrophage migration inhibitory factor (MIF) levels in the urine of patients with focal glomerular sclerosis

Department of Internal Medicine, Division of Nephrology and Endocrinology, Nihon University School of Medicine, Tokyo, Japan.
Clinical & Experimental Immunology (Impact Factor: 3.28). 03/2005; 139(2):338-47. DOI: 10.1111/j.1365-2249.2004.02670.x
Source: PubMed

ABSTRACT The pathogenesis of focal glomerular sclerosis (FGS) is poorly understood. Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine released from T cells and macrophages, and is a key molecule in inflammation. To examine further the possible role of MIF in FGS, we measured MIF levels in the urine. The purpose of the present study was to evaluate the involvement of MIF in FGS. Urine samples were obtained from 20 FGS patients. The disease controls included 40 patients with minimal-change nephrotic syndrome (MCNS) and membranous nephropathy (MN). A group of healthy subjects also served as controls. Biopsies were performed in all patients prior to entry to the study. The samples were assayed for MIF protein by a sandwich enzyme-linked immunosorbent assay (ELISA). The levels of MIF in the urine of FGS patients were significantly higher than those of the normal controls and patients with MCNS and MN. In contrast, the levels of urinary MIF (uMIF) in patients with MCNS and MN did not differ significantly from normal values. In the present study, attention also focused on the relationship between uMIF levels and pathological features. Among the patients with FGS, uMIF levels were significantly correlated with the grade of mesangial matrix increase and that of interstitial fibrosis. There was also a significant correlation between uMIF levels and the number of both intraglomerular and interstitial macrophages. Although the underlying mechanisms remain to be determined, our study presents evidence that urinary excretion of MIF is increased in FGS patients with active renal lesions.

1 Follower
  • Source
    • "Therefore, its deleterious effects, including podocyte apoptosis (Tejada et al., 2008) may be exerted in these cells also in an autocrine manner. Macrophage migration inhibitory factor (MIF) is another cytokine which may promote cell injury and which is synthesized by podocytes (Sasaki et al., 2004; Matsumoto et al., 2005). Possibility of an autocrine response to MIF has been proven by recent finding that podocytes from diabetic Pima Indians show an increased expression of the functional MIF receptor CD74, which was further confirmed in cultured human podocytes exposed to high glucose (Sanchez-Nino et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hyperglycemia and deriving from glomerular hypertension mechanical stress are the key factors underlying pathogenesis of diabetic nephropathy (DN). Multiple direct and secondary effects of both these factors are mediated by complex signaling pathways with extensive interactions. The common signaling pathways stimulated by high glucose and mechanical insult may act in an additive manner, thereby accelerating the cell damage. Podocytes, the cells covering the outer aspect of glomerular basement membrane (GBM), are subjected not only to the load of filtered glucose but also to diverse mechanical forces. Bulging into the Bowman's space, they have no support from the apical side, which makes them particularly susceptible to the effects of mechanical strain. Both high glucose and mechanical stress may impair the protein systems anchoring the podocyte foot processes in GBM, therefore blunting resistance of these cells to mechanical forces. Modulation by these factors of expression and activity of numerous structural and functional proteins results in the (auto)inflammatory responses, dysfunction, apoptosis or necrosis of the podocytes. Loss of the podocytes is irreversible due to their inability to proliferate and to replenish damaged cells. Podocytes are injured early in the course of DN, which, most likely, underlies further glomerular and renal damage in diabetes. This review summarizes the effects of elevated glucose and mechanical stress that seem to be involved in podocyte impairment in diabetes, with particular focus on the possible interactions between these factors.
    Journal of Cellular Physiology 11/2009; 221(2):288-95. DOI:10.1002/jcp.21856 · 3.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: MIF is a proinflammatory cytokine present in preformed stores in human urothelium. In animal models of bladder inflammation, including bacterial cystitis, MIF is up-regulated in the bladder and released from the bladder as a high molecular weight complex. We compared urine MIF amounts in patients with UTI to that in patients without UTI, and we examined and identified MIF-protein complexes in urine. Using enzyme-linked immunosorbent assay we compared MIF levels in the urine of 14 patients with UTI to levels in 16 controls with no UTI. Western blotting under native, denaturing and reducing conditions was done to examine MIF complexes found in urine. Mass spectrometry identified MIF associated proteins in urine, while co-immunoprecipitation confirmed the associations. Mean urine MIF amounts +/- SEM determined by enzyme-linked immunosorbent assay were significantly greater in 14 patients with UTI compared to that in 16 controls (1.96 +/- 0.40 vs 0.59 +/- 0.09 ng/mg creatinine, p <0.01). Western blotting under denaturing conditions showed several high molecular weight complexes (100 to 165 kDa) that increased in UTI urine as well as typical, monomeric MIF (12 kDa). Mass spectrometry identified associated MIF proteins, including ceruloplasmin, albumin and uromodulin. Co-immunoprecipitation confirmed mass spectrometry findings and also identified MIF interaction with alpha-2-macroglobulin. Increased urine MIF amounts in patients with bacterial cystitis support our experimental evidence showing a role for MIF in pelvic visceral inflammation. The novel finding of an association of MIF with other urine proteins suggest that the physiologically relevant form of MIF may be an MIF-protein complex.
    The Journal of Urology 04/2006; 175(4):1523-8. DOI:10.1016/S0022-5347(05)00650-6 · 3.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Macrophage migration inhibitory factor (MIF) may play an important role in the pathogenesis of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). We examined whether MIF has an influence on the development of aGVHD and survival using BALB/c-based MIF knock-out (MIF KO) mice. Although MIF expression was observed in lymphocytes that had infiltrated the liver during aGVHD in both wild-type (WT) and MIF KO mice that received bone marrow cells (BM) and spleen cells (SP) from C57BL/6N mice, no significant difference was found in severity of aGVHD or survival rate between the two groups of mice. However, MIF level had decreased at 1 week after HSCT when MIF KO mice were used as the recipients. In the experiment using MIF KO mice as the donors, the recipient mice transplanted with BM and SP from MIF KO mice had significantly lower aGVHD scores on days 14, 21, and 35 than those in the recipient mice transplanted with BM and SP from WT-BALB/c mice. Histopathological findings supported these observations, showing that the bile ducts and lobules in the liver were destroyed by infiltrating MIF-expressing lymphocytes in the recipients of BM and SP from WT-BALB/c mice, while the bile ducts were not destroyed even by infiltrating MIF-deficient lymphocytes in the recipients of BM and SP from MIF KO mice. Therefore, these findings suggest that MIF has an effect on the development of aGVHD in a murine model of allogeneic stem cell transplantation.
    Transplant Immunology 09/2006; 16(2):117-24. DOI:10.1016/j.trim.2006.05.001 · 1.83 Impact Factor
Show more


1 Download
Available from

Similar Publications