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Background/aim: Evidence from ex vivo glomerular analysis has implicated overexpression of transforming growth factor (TGF) beta 1 in progressive renal disease. The roles of TGF-beta2 and TGF-beta3 are less clear. The purpose of this study was to define the temporal expression and abundance of TGF-beta isoforms in both acute and progressive Thy-1 glomerulonephritis during the crucial initiation phase of these models., Methods: Acute Thy-1 glomerulonephritis was induced by a single injection of OX7, while the progressive model was induced by two injections, 7 days apart., Results: Cellular infiltration of glomeruli consisted of transient increases of neutrophils and ED1+ macrophages. The distribution of TGF-beta1, TGF-beta2, and TGF-beta3 revealed distinct differences in normal and nephritic rats. No changes in TGF-beta1 staining were observed within glomeruli of either model. In marked contrast, in the one-shot model, TGF-beta2 and TGF-beta3 stainings increased rapidly, yet transiently, throughout affected glomeruli, followed by more sustained staining in glomerular epithelial cells. Diffuse, transient staining was absent in two-shot glomerulonephritis, but an increase in epithelial cell staining mirrored that seen in the one-shot model., Conclusion: Based on these results, we propose that the effects, formerly thought of as solely due to a single entity, TGF-beta1, may be the result of an interplay between individual TGF-beta isoforms., (Copyright 2004 S. Karger AG, Basel)

Macrophages have a central role in the control of inflammation because, depending on the local microenvironment, they can develop into cells that cause further injury or facilitate tissue repair. Understanding what signals determine whether macrophages develop into cells that promote injury or facilitate repair is one of the most important issues in inflammatory cell biology, not least because of the opportunities for developing novel therapies. This is highly relevant to glomerulonephritis because of the prominence of the macrophage infiltrate in all types of severe or progressive nephritis, and the present unsatisfactory nature of treatments for these diseases. This review will focuses on how macrophages are activated in vitro and in normal and inflamed glomeruli. The new concept of 'macrophage programming' is introduced and novel strategies to alter macrophage function within nephritic glomeruli that could be used for the treatment of glomerular inflammation are highlighted.

In proliferative glomerulonephritis glomeruli are the target of an inflammatory reaction involving macrophage recruitment and activation. We examined the role of mesangial cells in this process. Supernatants from basal, IL-1, IFN-tau or LPS-stimulated rat mesangial cells (MCS) were tested for chemotactic, colony-stimulating and activation effects on macrophages in vitro. IL-1-stimulated MCS produced a macrophage chemoattractant (p = 0.007 compared with basal MCS) and MCP-1 mRNA was detected in IL-1-stimulated mesangial cells. LPS or IL-1-stimulated MCS produced colony-stimulating activity (LPS p < 0.05, IL-1 p < 0.01, compared with basal MCS or control supernatant, CS). Macrophage activation, assessed by nitric oxide generation, was suppressed. This evidence from functional bioassays supports a selective role for mesangial cells in the control of macrophage-induced glomerular injury, whereby activated mesangial cells participate in the recruitment and proliferation of infiltrating macrophages, and suppresses at least one field of macrophage activation, namely nitric oxide generation.

The mechanisms by which intercurrent bacterial infections are associated with increased tissue injury in some forms of glomerulonephritis may include complement activation by bacteria and subsequent increased glomerular neutrophil (PMN) infiltration. We have studied the effect of complement activation after cobra venom factor (CVF) in anti-glomerular basement membrane (GBM) antibody-mediated disease. A single injection of CVF 24 h before the administration of heterologous nephrotoxic globulin (NTG) to Sprague-Dawley rats resulted in greatly increased albuminuria in some animals on the second day of this model. This phenomenon was reproducible and depended on the presence of circulating PMN and complement. We have previously shown that the administration of CVF on days 9 and 11 of the HgCl2 model in inbred Brown Norway rats, resulted in increased albuminuria in all animals at day 17 (p less than 0.05). The administration of small amounts of CVF with consequent complement activation in antibody-mediated disease represents a model for the increased injury seen after infection in human disease.