We evaluated the expression of inflammatory cytokines in renal tissues obtained from 45 patients with several types of glomerulonephritis. Immunofluorescence studies with specific antibodies to interleukin (IL)-1 alpha, IL-1 beta, IL-6, tumour necrosis factor (TNF)-alpha, and TNF-beta showed intense cytoplasmic staining in the glomeruli and interstitium. Cells positive for these cytokines were found frequently in tissue from patients with lupus nephritis (WHO Class IV) and membranoproliferative glomerulonephritis, and, to a lesser extent, in tissue from patients with mesangial proliferative glomerulonephritis, Henoch-Schönlein purpura nephritis, and minimal change nephrotic syndrome. Most of these cells were dual-stained with a monoclonal antibody to monocytes-macrophages. In situ hybridization for cytokine mRNA, combined with immunoperoxidase staining for monocytes-macrophages, detected IL-1 alpha, IL-6, and TNF-alpha mRNA in monocytes-macrophages infiltrating the glomeruli and interstitium. Occasionally, there was weak or moderate immunostaining for IL-1 alpha, IL-6, and TNF-alpha in the glomerular mesangial and epithelial cells, but in situ hybridization signals were rarely found in these loci. These findings suggest that infiltrating monocytes-macrophages, rather than resident glomerular cells, are the major source of inflammatory cytokines in human glomerulonephritis.
To understand the regulatory mechanism of apoptosis in human glomerulonephritis, we examined the expression of Fas antigen (CD95) and Bcl-2 in five normal human kidney specimens and 80 tissues from patients with several types of glomerular diseases. These proteins were detected in glomeruli by immunofluorescence. The number of intraglomerular cells positive for Fas antigen was high in Henoch-Schönlein purpura nephritis and lupus nephritis, and that of Bcl-2-positive intraglomerular cells was high in lupus nephritis, focal glomerular sclerosis, and IgA nephritis. Dual-labeling and staining on serial sections indicated that mesangial cells and occasionally infiltrating leukocytes expressed Fas antigen and Bcl-2. In situ hybridization detected Bcl-2 mRNA in glomerular cells. Electron microscopy revealed apoptotic cells and apoptotic bodies in proliferated mesangial areas and within the glomerular capillaries. Fragmented DNA was detected in glomeruli by in situ nick end labeling, the data of which paralleled the number of Fas antigen-positive intraglomerular cells. In mesangial proliferative types of glomerulonephritis, the population of Bcl-2-positive intraglomerular cells, but not that of Fas antigen-positive cells, was significantly correlated with the number of proliferating cell nuclear antigen-positive glomerular cells, the grade of mesangial cell increase, and the magnitude of proteinuria. This study showed that Fas antigen and Bcl-2 are up-regulated in the glomeruli of several types of human renal diseases. Bcl-2 overexpression might play a role in the prolonged proliferation of mesangial cells and glomerular hypercellularity in glomerulonephritis.
We studied mRNA and protein expression of interleukins (IL) and tumor necrosis factor (TNF) in renal tissues biopsied from 40 patients with IgA nephritis. Immunofluorescent staining with antibodies to IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF-alpha, and TNF-beta was intense in the cytoplasm of cells in glomeruli, which were dual-stained with an anti-monocyte-macrophage antibody. In addition, moderate immunofluorescence for TNF-alpha, and weak staining for IL-1 alpha and IL-6 were occasionally found in resident glomerular cells. Immunoperoxidase-in situ hybridization dual-labeling revealed that IL-1 alpha, IL-6, and TNF-alpha mRNA signals were present in intraglomerular cells reactive with anti-monocyte-macrophage antibody, which further supported the immunofluorescent findings. Cells expressing IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF-alpha, and TNF-beta were also observed in the interstitium. Most of these cells were also labeled with the anti-monocyte-macrophage antibody. The number of IL-1 alpha, IL-6, and TNF-alpha-positive cells infiltrating the glomerulus significantly correlated with mesangial hypercellularity. IL-8 and TNF-alpha-positive intraglomerular cells were correlated with the magnitude of proteinuria. The population of interstitial cells positive for IL-1 alpha, IL-6, IL-8, and TNF-alpha was associated with the grade of tubulointerstitial changes and proteinuria. There was no correlation between local IL-1 alpha, IL-6, and TNF-alpha expression in glomeruli or interstitium and serum or urinary levels of the respective cytokines.(ABSTRACT TRUNCATED AT 250 WORDS)
This study offers morphological evidence of the involvement of lipid abnormalities in human glomerular injury. Renal biopsy tissues from patients with several types of glomerular diseases were immunocytochemically examined using antibodies to apolipoproteins (apo) A-I, B-100, and E, and antibodies to low density lipoprotein (LDL) receptors and scavenger receptors. Immunofluorescent staining showed the predominant deposition of apo B and apo E in the mesangial area in mesangial proliferative types of glomerulonephritis; the distribution and staining intensity of these apolipoproteins correlated with the grade of mesangial proliferation and proteinuria, but were independent of plasma lipid levels. Immunoelectron microscopy revealed that apo B and apo E were distributed in droplets within glomerular epithelial and mesangial cells or in a granular pattern in the expanded mesangial matrix. Apo A-I was mainly localized in the visceral epithelial cells of normal human kidneys. Staining for apo A-I was increased in the glomerular epithelial cells of nephritic kidneys, compared to the pattern in normal human kidneys, and was decreased in the sclerosed areas of glomeruli. An immunogold technique revealed the expression of LDL receptors on the surface membranes of glomerular mesangial and epithelial cells. Dual immunofluorescent staining showed that apo B and LDL receptors were occasionally co-localized in nephritic glomeruli. Scavenger receptor was detected on the plasma membranes of mesangial and visceral epithelial cells. The glomerular expression of scavenger receptor was increased in glomeruli with marked mesangial proliferation. In addition, the expression of this receptor was intense in monocytes/macrophages occasionally infiltrating the glomeruli. Our present findings indicate that in human nephritic kidneys, glomerular epithelial and mesangial cells express both LDL receptors and scavenger receptors. The accumulation of apolipoproteins, whether receptor-mediated or mediated by other mechanisms, can occur independently of plasma lipid levels, and may be associated with mesangial expansion and proteinuria.
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