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      Differential Effects of FMLP-Activated Neutrophils from Patients with IgA Nephropathy Enhanced Endothelin 1 Production of Glomerular Mesangial Cells

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      S. Karger AG

      Reactive oxygen species, FMLP, Neutrophil, Mesangial cell, Endothelin 1

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          Background: Neutrophil infiltration in the glomeruli is common in patients with IgA nephropathy (IgAN). The pathogenetic roles of the infiltrated neutrophils and their relationship with glomerular mesangial cells, however, are not clear. Methods: We examined the effects of coculture with N-formyl-methionyl-leucyl-phenylalanine (FMLP) activated neutrophils on the viability, endothelin 1 (ET-1) production, and ET-1 mRNA expression of rat glomerular mesangial cells. Neutrophils were isolated from 15 IgAN patients, from 13 patients with non-IgA mesangial proliferative glomerulonephritis (MsPGN), and from 10 normal controls. Results: The ET-1 production by mesangial cells was significantly higher after stimulation with FMLP-activated neutrophils from IgAN patients than that of MsPGN patients and normal controls, and this effect was significantly abolished by pretreating mesangial cells with superoxide dismutase and partly abolished by catalase. The ET-I mRNA expression of mesangial cells showed a parallel increase with ET-1 protein. The trypan blue exclusion test showed significant mesangial cell death after stimulation with FMLP-activated neutrophils as compared with quiescent neutrophils, and the cell death was also prevented by superoxide dismutase but not catalase. The FMLP-activated neutrophils from IgAN patients produced more superoxide than those of MsPGN patients and normal controls. Conclusion: The FMLP-activated neutrophils from patients with IgAN have differential effects in enhancing the cell death and the ET-1 production of glomerular mesangial cells through the release of superoxide.

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          Plasma alpha 2 macroglobulin is increased in nephrotic patients as a result of increased synthesis alone.

          alpha 2 Macroglobulin (alpha 2M), a protease inhibitor, is often increased in plasma of patients with the nephrotic syndrome. Although it has been speculated that synthesis is increased, no direct measurements have been performed. alpha 2M synthesis in both normal subjects (N = 4) and nephrotic patients (N = 7) were measured using endogenous labeling with 13C valine in order to establish the mechanism of increased plasma level in the nephrotic syndrome and the relationship between alpha 2M synthesis rate and plasma concentration over a wide range of plasma concentration values. A primed (15 mumol/kg)/continuous (15 mumol/kg/hr) infusion was administered for six hours. Blood samples were collected at different intervals and at each time point alpha 2M was isolated from EDTA plasma using immunoprecipitation and SDS-polyacrylamide gel electrophoresis (PAGE). Care was taken to ensure that the alpha 2M used for combustion had not been subjected to proteolysis. The rate of appearance of 13C valine derived from the isolated alpha 2M was measured by gas chromatography combustion isotope ratio mass spectrometry. Plasma alpha 2M was significantly elevated in nephrotic subjects (3.13 +/- 0.33 g/liter) versus controls (1.64 +/- 0.15 g/liter; P = 0.012). The alpha 2M fractional synthesis rate [(FSR), which is equal to fractional catabolic rate (FCR) in steady state] was the same in the two groups: 2.70 +/- 0.18%/day for the nephrotic patients versus controls 2.74 +/- 0.21%/day. However, the alpha 2M absolute synthesis rate (ASR) was significantly (P = 0.012) increased in the patients (3.69 +/- 0.33 mg/kg/day) versus controls (2.06 +/- 0.35 mg/kg/day). Plasma alpha 2M concentration correlated directly to its ASR (r2 = 0.821; P = 0.0001; N = 11). Increased plasma alpha 2M concentration in nephrotic patients is therefore a result of increased synthesis alone.

            Author and article information

            S. Karger AG
            10 October 2001
            : 89
            : 3
            : 274-279
            Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
            46085 Nephron 2001;89:274–279
            © 2001 S. Karger AG, Basel

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            Page count
            Figures: 2, Tables: 3, References: 21, Pages: 6
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            Original Paper

            Cardiovascular Medicine, Nephrology

            Endothelin 1, Reactive oxygen species, FMLP, Neutrophil, Mesangial cell


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