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Are you currently facing challenges in developing effective treatments for glomerulonephritis, including difficulties in targeting specific complement pathways, optimizing drug delivery to the kidney, and navigating the complexities of clinical trials? Creative Biolabs' innovative complement-targeted therapeutics platform helps you accelerate your drug discovery process and develop highly effective treatments for glomerulonephritis.
Immunopathology of Glomerulonephritis
Glomerulonephritis (GN) encompasses various kidney diseases, predominantly marked by inflammation of the glomeruli or renal microvasculature. Mesangial proliferative glomerulonephritis (MPGN) specifically affects the mesangium, and though rare, significantly impacts kidney function. This distinct condition can manifest with nephrotic syndrome symptoms, such as proteinuria, hypoalbuminemia, hypercholesterolemia, edema, and hematuria, and is classified by the WHO as type II lupus nephritis. Emerging evidence suggests that interleukin-10, known for its robust anti-inflammatory properties, may offer therapeutic inhibition of MPGN.
Fig 1. Mesangial proliferative glomerulonephritis.1
Causes
MPGN is frequently associated with IgA nephropathy (IgAN), a prevalent global form of GN characterized by glomerular inflammation. Mesangial cell proliferation, central to MPGN, is common across numerous glomerular diseases, including IgAN, IgMN, lupus nephritis, Alport syndrome, and postinfectious GN. MPGN is linked to several renal disorders, some with familial patterns, yet no specific genes have been pinpointed as causative. Genetic predisposition may increase MPGN risk. Complement proteins C2 and C3 are implicated in GN pathogenesis, with IgAN also exhibiting autoimmune features.
Diagnosis
In MPGN patients, peripheral capillary walls appear thin and fragile without detectable deposits, duplication, focal breaks, or cellular necrosis. While visceral and parietal epithelial cells remain non-proliferative, they may occasionally be enlarged. Crescents and segmental sclerosis are typically absent. The tubulointerstitium and vasculature generally appear normal unless reduced renal function, hypertension, or advanced age are factors. Electron microscopy reveals increased mesangial cells and sometimes infiltrating monocytes or leukocytes. Mesangial matrix volume is typically diffusely elevated. Electron-dense mesangial deposits are common, especially with immunoglobulin (IgG, IgM, IgA) deposits. Large paramesangial dense deposits suggest IgA nephropathy. The absence of subendothelial/subepithelial deposits differentiates MPGN from post-infectious causes or lupus nephritis, with the latter characterized by multiple immunoglobulin deposits and abundant tubuloreticular bodies on electron microscopy.
Complement Activation Pathways and Glomerulonephritis Pathogenesis
In GN, all three complement activation pathways can be implicated in the pathogenesis, though their relative contributions vary depending on the specific type of GN. These pathways are interconnected, and activation of one pathway can amplify the activation of others. This complex interplay contributes to the overall complement dysregulation observed in GN.
Table 1 GN-related complement activation pathways.
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Complement Activation Pathways
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Description
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Classical Pathway
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This pathway is typically activated by antigen-antibody complexes. In certain forms of GN, such as anti-GBM disease and some types of immune complex-mediated GN, the classical pathway plays a significant role.
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Alternative Pathway
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This pathway can be activated by various triggers, including microbial surfaces and altered host cells. It often plays a crucial role in GN, particularly in conditions like IgA nephropathy and C3 glomerulopathy, where there is dysregulation of complement control.
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Lectin Pathway
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While its role in GN is still being investigated, evidence suggests it can contribute to inflammation and injury in some forms of the disease.
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Complement Molecular Mechanisms in GN
Table 2 Molecular mechanisms of complement-mediated.
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Key Complement Components
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Functions
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C3a
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Contributes to inflammation by recruiting and activating leukocytes.
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C5a
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A potent inflammatory mediator that attracts immune cells to the glomerulus, promoting inflammation and the release of other inflammatory molecules.
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MAC
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A complex formed by terminal complement pathway activation. Inserts into cell membranes, forming pores that disrupt cell integrity, leading to cell lysis or sublethal injury of glomerular cells (podocytes, endothelial cells, and mesangial cells).
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TGF-β
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Its release is stimulated by chronic complement activation, promoting the production of extracellular matrix proteins and contributing to glomerulosclerosis and fibrosis.
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Related Hot Products
Our extensive complement platform provides a wide and economical selection of complement-related products. Please feel free to contact us for additional information.
Table 3 Featured products.
Related Hot Services
Table 4 Complement test services for SS-related complement studies.
Resources
Creative Biolabs has established advanced Complement Therapeutics platform including antibody engineering platform, protease inhibitor platform, and drug discovery platform, and is equipped to offer a full range of biotherapeutics development services regarding drug discovery and validation for glomerulonephritis.
Reference
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From Wikipedia: Nephron - Own work, CC BY-SA 3.0 https://commons.wikimedia.org/wiki/File:Membranoproliferative_glomerulonephritis_-_very_high_mag.jpg.
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