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2.
Pediatr Nephrol ; 24(8): 1439-44, 2009 Aug.
Article in English | MEDLINE | ID: mdl-18958500

ABSTRACT

The human complement system is vital for host defense and plays a role in a number of inflammatory disorders. Inherited deficiency or dysfunction of most of the individual complement components occurs uncommonly. The phenotype displayed by such patients varies with the specific component deficiency and ranges from recurrent infections to autoimmune diseases. Most of the latter are associated with glomerulonephritis. The onset of severe lupus erythematosus in a young child, with prominent cutaneous and renal manifestations, especially if a similar disorder is present in another family member, is a clue to the presence of a complement component deficiency. The distinguishing of acquired deficiencies from inherited deficiencies in complement components is sometimes difficult and may require sophisticated laboratory testing.


Subject(s)
Complement System Proteins , Immune System Diseases/complications , Immune System Diseases/genetics , Kidney Diseases/immunology , Child , Complement Pathway, Classical , Humans
3.
PLoS One ; 3(10): e3334, 2008 Oct 06.
Article in English | MEDLINE | ID: mdl-18836527

ABSTRACT

BACKGROUND: The role of circulating complement in host defense and immune disease is well established. Although a number of cells and tissues are capable of synthesizing complement components locally, the importance of such local synthesis in immune disease has been difficult to establish. METHODOLOGY/PRINCIPAL FINDINGS: We used bone marrow transplantation (BMT) between C3 knockout (C3KO) and wild type (WT) mice to construct animals that were discordant for systemic (hepatic) and local (monocytic) C3 synthetic capacity. An immune complex glomerulonephritis (GN) was then induced using intraperitoneal injections of horse spleen apoferritin (HSA) with a lipopolysaccharide (LPS) adjuvant. All HSA/LPS animals developed a proliferative GN with glomerular infiltration by monocytes. By sensitive ELISA, monocyte C3 synthesis could be detected in C3KO animals transplanted with WT bone marrow cells. Despite this, there were no significant differences among groups of mice in measures of clinical (proteinuria, renal function) or histologic (glomerular cellularity, crescents) disease severity. CONCLUSIONS/SIGNIFICANCE: In this model of GN, local synthesis of C3 by infiltrating cells does not appear to be of pathologic importance.


Subject(s)
Bone Marrow Transplantation/immunology , Complement C3/deficiency , Glomerulonephritis/immunology , Animals , Apoferritins/toxicity , Complement C3/analysis , Complement C3/biosynthesis , Complement C3/genetics , Disease Models, Animal , Glomerulonephritis/chemically induced , Glomerulonephritis/pathology , Homozygote , Horses , Immunohistochemistry , Kidney Glomerulus/immunology , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Lipopolysaccharide Receptors/metabolism , Lipopolysaccharides/toxicity , Mice , Mice, Inbred C57BL , Mice, Knockout , Spleen/chemistry
4.
J Biol Chem ; 280(50): 41421-8, 2005 Dec 16.
Article in English | MEDLINE | ID: mdl-16223730

ABSTRACT

The DNA-binding ETS transcription factor Spi-1/PU.1 is of central importance in determining the myeloid-erythroid developmental switch and is required for monocyte and osteoclast differentiation. Many monocyte genes are dependent upon this factor, including the gene that codes for interleukin-1beta. It has long been known that the conserved ETS DNA-binding domain of Spi-1/PU.1 functionally cooperates via direct association with a diverse collection of DNA-binding proteins, including members of the basic leucine zipper domain (bZIP) family. However, the molecular basis for this interaction has long been elusive. Using a combination of approaches, we have mapped a single residue on the surface of the ETS domain critical for protein tethering by the C/EBPbeta carboxyl-terminal bZIP domain. This residue is also important for nuclear localization and DNA binding. In addition, dependence upon the leucine zipper suggests a novel mode for both protein-DNA interaction and functional cooperativity.


Subject(s)
Basic-Leucine Zipper Transcription Factors/chemistry , DNA/chemistry , Escherichia coli/metabolism , Arginine/chemistry , Blotting, Western , CCAAT-Enhancer-Binding Protein-beta/chemistry , Cations , Cell Nucleus/metabolism , Dose-Response Relationship, Drug , Genetic Vectors , Glutathione Transferase/metabolism , HeLa Cells , Humans , Interleukin-1/metabolism , Luciferases/metabolism , Models, Biological , Models, Genetic , Models, Molecular , Monocytes/metabolism , Plasmids/metabolism , Promoter Regions, Genetic , Protein Binding , Protein Conformation , Protein Structure, Secondary , Protein Structure, Tertiary , Proteins/chemistry , Proto-Oncogene Proteins/chemistry , Trans-Activators/chemistry , Transcriptional Activation
5.
J Lab Clin Med ; 146(3): 174-8, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16131456

ABSTRACT

Skeletal demineralization is a frequent accompaniment of chronic renal disease and is likely multifactorial. We studied the role of inflammation in stimulating bone resorption in a rat model of glomerulonephritis (GN). Three-week-old Sprague-Dawley rats received either saline (n = 8) or horse spleen apoferritin and lipopolysaccharide (HSA/LPS, n = 8) by intraperitoneal injection, for 6 weeks; afterward, they were observed for either an additional 3 weeks (9 weeks total; n = 4 from each group) or 14 weeks (20 weeks total; n = 4 from each group). Kidneys were analyzed by histomorphometry, and blood and urine samples were obtained to assess bone resorption. Whole-body and isolated femur Dual-Energy X-ray Absorptiometry (DEXA) scans were performed at the end of each study. HSA/LPS-treated animals developed a proliferative GN by 9 weeks, which is associated with proteinuria but no change in renal function. Between 9 and 20 weeks, there was evidence of an increasing interstitial inflammation (1381 +/- 67 interstitial cells/mm(2) at 9 weeks and 1818 +/- 28 interstitial cells/mm(2) at 20 weeks.) There was also evidence of bone resorbing activity as assessed by experimental/control (E/C) < 1.0 at 9 (E/C plasma = 0.66 +/- 0.05) and 20 (E/C plasma = 0.52 +/- 0.04) weeks. Parathyroid hormone (PTH) levels were normal at all time points, and no differences in bone mineral density were found. This model produces not only an immune glomerular/tubular injury, but also a stimulus for bone resorption that is related to objective measures of inflammation severity. The bone resorption is not caused by renal insufficiency, hyperparathyroidism, or steroid therapy. This model will prove useful in other studies of the role of renal inflammation in skeletal disorders.


Subject(s)
Calcium/metabolism , Glomerulonephritis/physiopathology , Animals , Bone Density , Bone Resorption/physiopathology , Disease Models, Animal , Glomerulonephritis/immunology , Glomerulonephritis/metabolism , Glomerulonephritis/pathology , Kidney Glomerulus/pathology , Rats , Rats, Sprague-Dawley
6.
Clin Immunol ; 115(1): 80-4, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15870025

ABSTRACT

We have suggested that renal tubular synthesis of C3 and its activation in the cortical interstitium is a mechanism for the progression of glomerulonephritis to interstitial injury. To test this hypothesis, immune complex glomerulonephritis was induced in C57BL/6 mice by intraperitoneal injections of horse spleen apoferritin and lipopolysaccharide (HSA/LPS). When compared to wild-type (WT) animals, C3 knockout (C3KO) mice had glomerular changes that were identical. Morphometric analysis of the cortical interstitium, however, showed marked differences. WT mice had more interstitial inflammation, edema, and tubular atrophy, when compared to C3KO mice. At the end of the experiment, WT animals also had significantly more proteinuria than did C3KOs. These experiments provide further evidence of a role of locally synthesized complement in the progression of glomerular disease.


Subject(s)
Complement C3/immunology , Glomerulonephritis/immunology , Kidney Tubules/immunology , Albuminuria/pathology , Animals , Apoferritins/administration & dosage , Glomerulonephritis/pathology , Histocytochemistry , Kidney Tubules/pathology , Lipopolysaccharides/administration & dosage , Mice , Mice, Inbred C57BL , Mice, Knockout
7.
Cell Commun Adhes ; 10(2): 59-67, 2003.
Article in English | MEDLINE | ID: mdl-14681057

ABSTRACT

Heparin is known to influence the growth, proliferation, and migration of vascular cells, but the precise mechanisms are unknown. We previously demonstrated that unfractionated heparin (UH) binds to the platelet integrin alpha(IIb)beta(3), and enhances ligand binding. To help define the specificity and site(s) of heparin-integrin interactions, we employed the erythroleukemic K562 cell line, transfected to express specific integrins (alpha(v)beta(3), alpha(v)beta(5), and alpha(IIb)beta(3)). By comparing K562 cells expressing a common alpha subunit (Kalpha(v)beta(3), Kalpha(v)beta(5)) with cells expressing a common beta subunit (Kalpha(v)beta(3), Kalpha(IIb)beta(3)), we observed that heparin differentially modulated integrin-mediated adhesion to vitronectin. UH at 0.5-7.5 microg/ml consistently enhanced the adhesion of beta(3) expressing cells (Kalpha(v)beta(3),Kalpha(IIb)beta(3)). In contrast, UH at 0.5-7.5 microg/ml inhibited Kalpha(v)beta(5) adhesion. Experiments using integrin-blocking antibodies, appropriate control ligands, and nontransfected native K562 cells revealed that heparin's actions were mediated by the specific integrins under study. Preincubation of heparin with Kalpha(v)beta(3) cells enhanced adhesion, while preincubation of heparin with the adhesive substrate (vitronectin) had minimal effect. There was a structural specificity to heparin's effect, in that a low molecular weight heparin and chondroitin sulfate showed significantly less enhancement of adhesion. These findings suggest that heparin's modulation of integrin-ligand interactions occurs through its action on the integrin. The inhibitory or stimulatory effects of heparin depend on the beta subunit type, and the potency is dictated by structural characteristics of the glycosaminoglycan.


Subject(s)
Blood Cells/drug effects , Cell Membrane/drug effects , Heparin/pharmacology , Integrin alpha Chains/drug effects , Integrin beta Chains/drug effects , Antibodies/pharmacology , Anticoagulants/pharmacology , Blood Cells/metabolism , Cell Adhesion/drug effects , Cell Adhesion/physiology , Cell Line, Tumor , Cell Membrane/metabolism , Chondroitin Sulfates/pharmacology , Dose-Response Relationship, Drug , Glycosaminoglycans/chemistry , Glycosaminoglycans/metabolism , Humans , Integrin alpha Chains/genetics , Integrin alpha Chains/metabolism , Integrin beta Chains/genetics , Integrin beta Chains/metabolism , Molecular Weight , Protein Subunits/drug effects , Protein Subunits/genetics , Protein Subunits/metabolism , Transfection , Vitronectin/metabolism
8.
Bioorg Med Chem ; 11(22): 4769-77, 2003 Nov 03.
Article in English | MEDLINE | ID: mdl-14556792

ABSTRACT

The human immunodeficiency virus (HIV) has been shown to be the causative agent for AIDS. The HIV virus encodes for a unique aspartyl protease that is essential for the production of enzymes and proteins in the final stages of maturation. Protease inhibitors have been useful in combating the disease. The inhibitors incorporate a variety of isosteres including the hydroxyethylurea at the protease cleavage site. We have shown that the replacement of t-butylurea moiety by benzothiazolesulfonamide provided inhibitors with improved potency and antiviral activities. Some of the compounds have shown good oral bioavailability and half-life in rats. The synthesis of benzothiazole derivatives led us to explore other heterocycles. During the course of our studies, we also developed an efficient synthesis of benzothiazole-6-sulfonic acid via a two-step procedure starting from sulfanilamide.


Subject(s)
HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , HIV Protease/metabolism , Sulfonamides/chemistry , Sulfonamides/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology , Urea/analogs & derivatives , Administration, Oral , Animals , Biological Availability , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacokinetics , Humans , Inhibitory Concentration 50 , Rats , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokinetics , Thiazoles/chemical synthesis , Thiazoles/pharmacokinetics , Urea/chemistry , Urea/pharmacology
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