ABSTRACT
Lupus nephritis is associated with thickening of the glomerular extracellular membranes. Distribution of collagen IV alpha-chains in the glomerular basement membrane in kidneys of lupus-prone B/W mice has been examined in this study. The results are indicative of a qualitative change in the collagen IV matrix occurring around the time of development of proteinuria, with an embryonic alpha1/alpha2 isoform replacing the normal glomerular basement membrane (GBM). These changes mimic alterations seen in Alport syndrome and coincide with an increase in collagenolytic activity within the glomerulus. It has been hypothesized that alterations in collagen matrix synthesis represent compensatory responses to an increase in GBM proteolysis and could represent an important step in the pathogenesis of nephritis through the formation of a dysfunctional glomerular filter. Also, aberrations in the collagen matrix composition could contribute to the deposition of autoantibodies within the glomerulus.
Subject(s)
Collagen Type IV/metabolism , Glomerular Basement Membrane/metabolism , Lupus Nephritis/physiopathology , Animals , Disease Models, Animal , Female , Glomerular Basement Membrane/physiopathology , Kidney Glomerulus/metabolism , Kidney Glomerulus/physiopathology , Lupus Nephritis/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred NZB , Protein Isoforms , Proteinuria/etiologyABSTRACT
Impaired course of inflammation is a likely mechanism behind a number of diabetic complications. The present study was undertaken to investigate lipopolysaccharide-induced production of tumour necrosis factor (TNF)-alpha in monocytes from patients with type 2 diabetes and to assess its relationship with diabetes-associated metabolic abnormalities. Monocytic TNF-alpha mRNA production was lower in the diabetic participants compared to their corresponding controls. Diabetic subjects who had been receiving simvastatin treatment had TNF-alpha mRNA production similar to that of the healthy participants. The release of TNF-alpha from diabetic cells correlated negatively with serum levels of apolipoprotein B (apoB) (R = -0.755, P = 0.001), total plasma cholesterol (R = - 0.702, P = 0.002) and the presence of retinopathy (R = -0.572, P = 0.021). No such associations were found in the control subjects. In a multiple linear regression model, only the level of apoB and diabetes duration demonstrated significant effects on the release of TNF-alpha, with apoB alone accounting for 57% of the variation. We conclude that production of TNF-alpha mRNA in response to the bacterial stimulant is compromised in poorly controlled type 2 diabetes. Lipid abnormalities are associated with the observed defect. Impaired cytokine production represents a significant defect in the functioning of the immune system and may contribute to aberrations in the course of inflammation in the diabetic state.
Subject(s)
Apolipoproteins B/blood , Diabetes Mellitus, Type 2/metabolism , Monocytes/metabolism , Tumor Necrosis Factor-alpha/metabolism , Female , Humans , In Vitro Techniques , Linear Models , Male , Middle Aged , RNA, Messenger/genetics , RNA, Messenger/metabolism , Tumor Necrosis Factor-alpha/geneticsABSTRACT
Macrophage dysfunction is a likely mechanism underlying common diabetic complications such as increased susceptibility to infection, accelerated atherosclerosis, and disturbed wound healing. There are no available studies on the function of tissue macrophages in diabetes in humans. We have therefore studied peritoneal macrophages from diabetic type 2-like db/db mice. We found that the release of tumor necrosis factor-alpha and interleukin-1beta from lipopolysaccharide plus interferon-gamma-stimulated macrophages and vascular endothelial growth factor from both stimulated and nonstimulated macrophages was significantly reduced in diabetic animals compared with nondiabetic controls. Nitric oxide production from the stimulated db/db macrophages was significantly higher than that in the db/+ cultures, whereas there was no difference in their ability to generate reactive oxygen species. When studied both at light and electron microscopic levels, macrophages in diabetic animals had an altered morphological appearance compared with those of normal controls. We conclude that the function and morphology of the macrophages are disturbed in db/db mice and that this disturbance is related to the mechanisms underlying common inflammatory and degenerative manifestations in diabetes.
