heparitin-sulfate and Anti-Glomerular-Basement-Membrane-Disease

Topics: Animals; Anti-Glomerular Basement Membrane Disease; Basement Membrane; Chondroitin Sulfate Proteoglycans; Collagen; Diabetes Mellitus; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Laminin; Nephritis, Hereditary; Protein Conformation; Skin Diseases, Vesiculobullous

The GBM is an important structure for the development of immunologic renal disease. It may serve as the primary antigen or as the site of deposition of immune complexes. The GBM is recognized as the major protein filtration barrier of the glomerulus. The composition of the GBM includes collagen, predominantly but not exclusively type IV, which is present as procollagen. Two glycoproteins, laminin and fibronectin, are either intrinsic components of the GBM or intimately associated with the membrane. Heparan sulfate, a glycosaminoglycan, is contained within the substance of the GBM and seems to comprise the primary anion of the structure. Antibodies to these individual GBM components are being recognized with increasing frequency in patients with glomerulonephritis. The recognition of these antibodies may serve to expand our definition of both immunologic and degenerative diseases of basement membrane.

Topics: Anti-Glomerular Basement Membrane Disease; Antibodies; Antigen-Antibody Complex; Antigens; Basement Membrane; Collagen; Fibronectins; Glomerulonephritis; Glycoproteins; Heparitin Sulfate; Humans; Immune Complex Diseases; Kidney Glomerulus; Laminin

The glomerular endothelial glycocalyx is postulated to be an important modulator of permeability and inflammation. The glycocalyx consists of complex polysaccharides, the main functional constituent of which, heparan sulfate (HS), is synthesized and modified by multiple enzymes. The N-deacetylase-N-sulfotransferase (Ndst) enzymes initiate and dictate the modification process. Here we evaluated the effects of modulation of HS in the endothelial glycocalyx on albuminuria and glomerular leukocyte influx using mice deficient in endothelial and leukocyte Ndst1 (TEKCre+/Ndst1flox/flox). In these mice, glomerular expression of a specific HS domain was significantly decreased, whereas the expression of other HS domains was normal. In the endothelial glycocalyx, this specific HS structure was not associated with albuminuria or with changes in renal function. However, glomerular leukocyte influx was significantly reduced during antiglomerular basement membrane nephritis, which was associated with less glomerular injury and better renal function. In vitro decreased adhesion of wild-type and Ndst1-deficient granulocytes to Ndst1-silenced glomerular endothelial cells was found, accompanied by a decreased binding of chemokines and L-selectin. Thus, modulation of HS in the glomerular endothelial glycocalyx significantly reduced the inflammatory response in antiglomerular basement membrane nephritis.

Topics: Animals; Anti-Glomerular Basement Membrane Disease; Autoantibodies; Cell Adhesion; Cell Line; Chemokines; Chemotaxis, Leukocyte; Coculture Techniques; Disease Models, Animal; Down-Regulation; Endothelial Cells; Female; Glycocalyx; Heparitin Sulfate; Kidney Glomerulus; L-Selectin; Leukocytes; Male; Mice, Inbred C57BL; Mice, Knockout; RNA Interference; Signal Transduction; Sulfotransferases; Time Factors; Transfection

The case of a 21-year old man who died due to an intracranial thrombosis just after diagnosis of Goodpasture's disease, is reported. Discussion deals with the putative mechanisms, which could be responsible for the thrombosis.

Topics: Anti-Glomerular Basement Membrane Disease; Anticoagulants; Chondroitin Sulfates; Combined Modality Therapy; Dermatan Sulfate; Diabetes Insipidus, Neurogenic; Disseminated Intravascular Coagulation; Enoxaparin; Fatal Outcome; Headache; Heparin; Heparitin Sulfate; Humans; Immunosuppressive Agents; Male; Methylprednisolone; Plasma Exchange; Platelet Factor 4; Sinus Thrombosis, Intracranial; Thrombocytopenia; Young Adult

Sera from patients with poststreptococcal glomerulonephritis (PSGN) known to have antibodies to proteoglycans were studied for the presence of antibodies against other basement membrane (BM) components. BM collagen (type IV) was isolated in the native state by extracting bovine anterior lens capsule (ALC) with 0.5 M acetic acid. The 7-S (collagenous) domain and the NC-1 (noncollagenous) domain of type IV collagen were obtained after bacterial collagenase digestion of ALC followed by gel filtration. Laminin was isolated from the mouse EHS tumor and fibronectin from human plasma. Immunologic studies, using an ELISA and electroimmunoblot, revealed the presence of antibodies that reacted with intact, native type IV collagen and the 7-S collagenous domain of this molecule. Reaction with the NC-1 (noncollagenous) domain was minimal, and not higher than that obtained with control sera. Laminin reaction strongly with the patients' sera, but fibronectin did not. Unlike sera from patients with Goodpasture syndrome, which contain antibodies primarily against the NC-1 (noncollagenous) domain of type IV collagen, sera from patients with acute PSGN contain antibodies against all the major macromolecular components of BM. This difference in immunologic reactivity may account for the observed differences in the pathologic picture at the glomerular level.

Topics: Anti-Glomerular Basement Membrane Disease; Autoimmune Diseases; Basement Membrane; Collagen; Extracellular Matrix; Fibronectins; Glomerulonephritis; Heparitin Sulfate; Humans; Laminin; Proteoglycans; Streptococcal Infections