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Pathogenesis of glomerulonephritis. Animal models suggest that autoimmunity underlies pathogenesis of most GN. Disease initiation requires loss of tolerance and activation of self-reactive lymphocytes. Activated B and T cells interact to promote autoantibody and cytokine production, immune complex formation, antibody deposition, macrophage and neutrophil recruitment, renal infl ammation, and activation of renal endothelial, mesangial, epithelial and tubular cells. Glomerular and tubulointerstitial antigens may be specifi cally targeted by autoantibodies and self-reactive CD4 and CD8 TCR alpha/beta effector T cells, gamma/delta T cells and NKT cells. Numerous soluble and cellular mediators participate in subsequent tissue infl ammation, injury and repair, and modulate local renal immune responses. The predominant cells and molecules engaged vary depending on the etiology and site of glomerular injury.
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Glomerulonephritis is a common cause of chronic kidney disease and end stage renal failure. Current therapy relies on variably effective, nonspecific and toxic immunosuppression. Recent insights into underlying biology and disease pathogenesis in human glomerulonephritis combined with advances in the fields of inflammation and autoimmunity promise...
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Context 1
... models have been particularly informative, both in highlighting the role of autoimmunity in the development of most GN and in providing in vivo tools with which to dissect the complex cell interactions that perpetuate disease and specifi c effector mechanisms that mediate tissue injury and infl ammation. These models have revealed multiple targets for interven- tion, with disease specifi city determined by the initiating antigen, the specific receptors on responding B and T lymphocytes, the glomerular antigen targeted locally, and the subset of downstream effectors recruited in a particular disease or individual ( Figure 1). Three of the most extensively studied animal models of nephritis involve antibody interactions with intrinsic glomerular protein. ...
Context 2
... large number of cellular and soluble mediators and modu- lators of immunity and infl ammation and cell activation are implicated in immune activation, tissue destruction, remod- eling and repair in GN (Fig. 1). Each of these is a potential target for therapeutic intervention (Table 3). The discussion below focuses on two modulators, IgG Fc gamma receptors (FcγR) and complement, that are particularly amenable to therapeutic manipulation and for which a variety of thera- peutic modulators are already in preclinical or early clinical ...
Citations
... Anti-GBM glomerulonephropathy is characterized by deposition of immune complexes along the GBM. These immune complexes contain autoantibodies against GBM proteins, such as collagen type IV and neutral endopeptidase (Foster 2008;Hudson et al. 2003). Binding of anti-GBM autoantibodies to the GBM leads to autoimmune damage characterized by strong activation of the complement (evidenced by deposits of C3), infiltration of leukocytes into the inflamed tissue, and proteinuria. ...
... All this leads to the deterioration and loss of renal function. The research shows that the complement system plays a role in renal injury due to Goodpasture's syndrome by the proinflammatory effect of classical pathway activated C5a and/or cell lysis effect of C5b-9 (Foster 2008;Ma et al. 2013;Turnberg and Cook 2005). ...
Serum complement cascade, a part of innate immunity required for host protection against invading pathogens, is also a mediator of various forms of disease and injury. It is activated by classical, lectin, and alternative pathways that lead to activation of C3 component by C3 convertases, release of C3b opsonin, C5 conversion and eventually membrane attack complex formation. The tightly regulated activation process yields also C3a and C5a anaphylatoxins, which target a broad spectrum of immune and non-immune cells. The review discusses the involvement of the complement cascade in kidney disease pathogenesis and injury. The role of the complement pathways in autoantibody-mediated forms of glomerulonephritis (lupus nephritis, anti-glomerular basement membrane disease, anti-neutrophil cytoplasmic autoantibody-induced or membranoproliferative glomerulonephritis, membranous nephropathy), C3 glomerulopathy, atypical forms of hemolytic uremic syndrome, ischemic-reperfusion injury of transplanted kidney, and antibody-mediated renal allograft rejection are discussed. The disturbances in complement activation and regulation with underlying genetics are presented and related to observed pathology. Also promising strategies targeting the complement system in complement-related disorders are mentioned.
... Complement activation and FcRg contribute to tissue injury in various forms of glomerulopathy. 31,32 We recently reported that C3 caused mesangial cells to convert to the synthetic phenotype and aggravated a glomerular injury. 33 Finally, synaptotagmins represent a family of putative vesicular trafficking proteins. ...
Pyrrole-imidazole (PI) polyamides are small synthetic molecules that recognize and attach to the minor groove of DNA, thereby inhibiting gene transcription by blocking transcription factor binding. These derivatives can act as gene silencers inhibiting target gene expression under stimulatory conditions such as disease. To evaluate PI polyamides as treatments for the progression of renal diseases, we examined morphological effects, pharmacological properties, and the specificity of PI polyamides targeted to the transforming growth factor (TGF)-β1 promoter during salt-induced hypertensive nephrosclerosis in Dahl salt-sensitive rats. The targeted PI polyamide markedly reduced glomerulosclerosis and interstitial fibrosis without side effects. PI polyamide significantly decreased expression of TGF-β1 and extracellular matrix in the renal cortex. Microarray analysis found that only 3% of the transcripts were affected by PI polyamide, but this included decreased expression of extracellular matrix, TGF-β1-related cytokines, angiogenic, and cell stabilizing factors, proteinases, and renal injury-related factors. Thus, targeted PI polyamides are potential gene silencers for diseases not treatable by current remedies.
... Glomerulonephritis is one of the most common causes of chronic kidney disease and end-stage renal failure in the world. 57 It does not describe a single disease but rather a general phenotype, characterized by glomerular inflammation and cellular proliferation, that produces a number of clinical consequences such as haematuria, proteinuria and reduced glomerular filtration. 57 The disease can manifest as a symptom of systemic disorders such as lupus, Goodpasture's syndrome (anti-glomerular basement membrane (GBM) glomerulonephritis) and anti-neutrophil cytoplasmic autoantibody (ANCA)-induced glomerulonephritis, or a kidney-specific condition as in membranoproliferative glomerulonephritis (MPGN). ...
... 57 It does not describe a single disease but rather a general phenotype, characterized by glomerular inflammation and cellular proliferation, that produces a number of clinical consequences such as haematuria, proteinuria and reduced glomerular filtration. 57 The disease can manifest as a symptom of systemic disorders such as lupus, Goodpasture's syndrome (anti-glomerular basement membrane (GBM) glomerulonephritis) and anti-neutrophil cytoplasmic autoantibody (ANCA)-induced glomerulonephritis, or a kidney-specific condition as in membranoproliferative glomerulonephritis (MPGN). 58 Anti-GBM-induced glomerulonephritis is characterized by immune complex deposition along the GBM. ...
... Often, these immune complexes contain autoantibodies against basement membrane proteins such as type IV collagen and neutral endopeptidase. 57 Depending on the antigen, these autoantibodies can cause damage outside the kidney, such as lung damage in Goodpasture's syndrome, or trigger relapses posttransplantation as seen in Alport's syndrome. 57 Many studies have shown that the complement system affects anti-GBM glomerulonephritis in human patients by amplifying antibody-mediated injury through the classical pathway and enhancing the inflammatory response through C5 activation. ...
Complement is a part of the body's innate immune system that helps defend the host from microbial infection. It is tightly controlled by a number of cell surface and fluid-phase proteins so that under normal circumstances injury to autologous tissues is avoided. In many pathological settings, such as when the complement regulatory mechanisms are dysfunctional or overwhelmed, complement attack of autologous tissues can occur with severe, sometimes life-threatening consequences. The kidney appears to be particularly vulnerable to complement-mediated inflammatory injury and many kidney pathologies have been linked to abnormal complement activation. Clinical and experimental studies have shown that complement attack can be a primary cause in rare, genetically predisposed kidney diseases or a significant contributor to kidney injury caused by other etiological factors. Here we provide a brief review of recent advances on the activation and regulation of the complement system in kidney disease, with a particular emphasis on the relevance of complement regulatory proteins.
In the present study, we examined the effects of IL-10 after 24 h in a model of acute glomerulonephritis (GN). One hour after the anti-Thy 1 antibody administration, a single i.v. dose of IL-10 was administered to rats. Normal rats, control nephritic rats and nephritic rats treated with IL-10, were sacrificed 24 h after administration of antibody. Samples of urine, blood and organs were subsequently collected. The effects of IL-10 were studied by quantification of various inflammatory parameters at the protein level after immunohistochemical staining and at the mRNA level by a quantitative real time PCR technique. Nitric oxide and protein content were determined in serum and in 24 h-excreted urine, respectively. The inflammatory parameters were reduced in the IL-10-treated group: in increment in glomerular CD14, ICAM-1 and MMP-13 staining induced by anti-Thy 1 injection was significantly attenuated by IL-10 In contrast, mRNA levels for CD14, IL-1β, TNF-α and MCP-1 were not different between IL-10-treated and control GN groups. In conclusion, a single i.v. dose of IL-10 suppresses the expression of several inflammatory parameters, 24 h after inducing of acute GN but at this time point mRNA levels of all parameters examined were not affected. Although its therapeutic efficacy needs further evaluation, anti-inflammatory effects of this short-lived cytokine can be found one day after its administration.
This study was to evaluate the therapeutic effect of baicalein, extracted from Scutellaria baicalensis , on lipopolysaccharide (LPS)-induced glomerulonephritis in mice. For this purpose, bacterial LPS (2.5 mg/kg/day) was injected intraperitoneally (i.p.) for 14 days to induce glomerulonephritis; then mice were treated with baicalein (150 mg/kg/day) by oral gavage for 14 days. In comparison to samples from mice receiving only LPS injection, oral administration of baicalein significantly attenuated the rise of serum levels of blood urea nitrogen and creatinine, prtoeinuria, kidney wet-to-dry weight ratio as well as renal glomerular cell proliferation induced by LPS. Moreover, treatment with baicalein decreased the urine NOx (nitrite+nitrate) concentration and serum levels of proinflammatory cytokine including tumor necrosis factor-α, interleukin-1β and interleukin-6 accompanied by suppression of inducible nitric oxide synthase and cyclooxygenase-2 expression and prostaglandin E<SUB>2 </SUB>production in renal tissue relative to LPS-injected alone mice. Similarly, the LPS-induced increase of urine 8-iso-prostaglandin F<SUB>2</SUB>α, a marker of reactive oxygen species, was also markedly inhibited by baicalein. The present results demonstrate that baicalein possesses antiinflammatory and antioxidant properties that may be of benefit against the deleterious actions of LPS in glomerulonephritis.
