Search

The inflammation that is involved in the development of glomerulonephritis is tightly regulated by the expression of anti-inflammatory factors. These include circulating hormones, such as glucocorticoids, and mediators that are produced by intrinsic cells and infiltrating leucocytes. The present review focuses on these anti-inflammatory factors, summarizing in particular their activities in existing models of glomerulonephritis. In addition, experimental evidence is presented that anti-inflammatory mediators are able to increase glucocorticoid binding or signalling in target cells. These data help to explain the in-vivo efficacy of anti-inflammatory mediators, and offer a promising new avenue for therapeutic intervention.

Among other neuropeptides and neurohormones, growth hormone (GH) and somatostatin (SRIF) have been shown to modulate the development of glomerular injury in various renal diseases. In particular, GH is implicated in the induction of glomerular hypertrophy and sclerosis in partial nephrectomy and diabetic nephropathy. While GH effects on glomerular hypertrophy are likely mediated by insulin-like growth factor I (IGF-I), GH effects on glomerular sclerosis are independent of IGF-I. Those effects rather require multiple signaling pathways functioning in series, e.g. angiotensin II binding preceding transforming growth factor beta (TGF-beta) release, or pro-inflammatory factor release preceding repair/scarring processes. In contrast with GH, SRIF administration prevents the development of glomerular lesions in experimental diabetes, partial nephrectomy and immune glomerulonephritis. Inhibitory effects of SRIF on glomerular hypotrophy may be through a decrease in GH secretion and/or IGF-I expression or through a direct blockade of glomerular cell proliferation. The mechanisms underlying the anti-inflammatory effects of SRIF are most likely a deactivation of inflammatory cells related in part to an upregulated response of these cells to glucocorticoids. Additional studies will be required to further define the role of GH and SRIF in the development of glomerular injury and, hence, to identify new targets for a therapeutic approach in glomerular diseases.

Studies of glomerulonephritis models have shown that inflammatory reaction is responsible for the development of glomerulosclerosis and tubulo-interstitial sclerosis and, hence, for the progression to end stage renal failure. That macrophage accumulation and fibrosis extension are frequently not closely related events suggests that macrophages are not involved in progression process. Glomerular sclerosis is rather associated with the release of mediators from resident cells-mainly growth factors such as platelet-derived growth factor and transforming growth factor-beta--the synthesis and bioactivity of which are enhanced by inflammatory mediators. Tubulo-interstitial sclerosis is induced by inflammatory lesions of the glomerulus that lead to proteinuria. Indeed, reabsorption of proteins in proximal tubule triggers epithelial cells to release proinflammatory and prosclerotic mediators into the interstitium. New therapeutic approaches including gene transfer strategies are directed at suppressing the efficiency of such mediators.

Inflammatory processes within the glomerulus are switched off by the local generation of anti-inflammatory mediators. These mediators include eicosanoids (e.g., lipoxins), anti-inflammatory cytokines (interleukins 4 and 13), antagonists of proinflammatory cytokines (interleukin 1 receptor antagonist), neuropoietic cytokines (leukemia inhibitory factor and interleukin 6), as well as deactivators of inflammatory macrophages (transforming growth factor beta and interleukin 10). They limit the effects of proinflammatory mediators by inhibiting their production, stability, or function. Recent attempts to reduce inflammatory lesions in experimental glomerulonephritis have focused on upregulating the expression of these anti-inflammatory mediators by using protein or gene transfer. In particular administration of interleukin 4, interleukin 1 receptor antagonist, leukemia inhibitory factor, or interleukin 10 has been shown to be effective in the treatment of nephrotoxic nephritis. Of all the mediators already tested, interleukin 10 has the greatest potential because of its strong anti-inflammatory effects and weak adverse effects.

In this review the authors describe the physiopathological mechanisms responsible for inflammatory lesions in primary glomerulonephritis. Primary glomerular nephropathies can be reproduced experimentally: models have been set up for non-proliferative kidney diseases such as minimal change disease or membranous glomerulopathies, and for proliferative kidney diseases such as Berger's disease. Studies performed with these models have resulted in the identification of inflammatory mechanisms creating glomerular lesions which may be acute (proteinuria) or progressive (glomerular sclerosis). These mechanisms include activation of resident cells, notably mesangial cells, and recruitment of circulating cells such as neutrophils, monocytes/macrophages and platelets. These cells participate in the local inflammatory reaction by releasing soluble mediators including biologically active lipids, such as eicosanoids, reactive oxygen and nitrogen derivatives, proteases, cytokines and vasoactive polypeptides. The importance of these mediators has been deduced from the fact that they are produced locally in excess, their introduction produces lesions and, above all, their suppression by inhibitory or antagonistic pharmacological agents reduces the severity of the lesions. Several observations have shown that the development of all the lesions can be prevented simply by blocking the activity of only one of these mediators. It is therefore possible to consider replacing the conventional glucocorticoid treatment, which has multiple pharmacological actions, by a more specific treatment directed against a single mediator.