| 1. |
- Garsen, Marjolein, et al.
(författare)
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Heparanase Is Essential for the Development of Acute Experimental Glomerulonephritis
- 2016
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 186:4, s. 805-815
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Tidskriftsartikel (refereegranskat)abstract
- Heparanase, a heparan sulfate (HS)-specific endoglucuronidase, mediates the onset of proteinuria and renal damage during experimental diabetic nephropathy. Glomerular heparanase expression is increased in most proteinuric diseases. Herein, we evaluated the role of heparanase in two models of experimental glomerulonephritis, being anti-glomerular basement membrane and lipopolysaccharide-induced glomerulonephritis, in wild-type and heparanase-deficient mice. Induction of experimental glomerulonephritis Led to an increased heparanase expression in wild-type mice, which was associated with a decreased glomerular expression of a highly sulfated HS domain, and albuminuria. Albuminuria was reduced in the heparanase-deficient mice in both models of experimental glomerulonephritis, which was accompanied by a better renal function and less renal damage. Notably, glomerular HS expression was preserved in the heparanase-deficient mice. Glomerular leukocyte and macrophage influx was reduced in the heparanase-deficient mice, which was accompanied by a reduced expression of both types 1 and 2 helper T-cell cytokines. In vitro, tumor necrosis factor-alpha and Lipopolysaccharide directly induced heparanase expression and increased transendothelial albumin passage. Our study shows that heparanase contributes to proteinuria and renal damage in experimental glomerulonephritis by decreasing glomerular HS expression, enhancing renal leukocyte and macrophage influx, and affecting the Local cytokine milieu.
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| 2. |
- Gil, Natali, et al.
(författare)
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Heparanase Is Essential for the Development of Diabetic Nephropathy in Mice
- 2012
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 61:1, s. 208-216
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic nephropathy (DN) is the major life-threatening complication of diabetes. Abnormal permselectivity of glomerular basement membrane (GBM) plays an important role in DN pathogenesis. Heparanase is the predominant enzyme that degrades heparan sulfate (HS), the main polysaccharide of the GBM. Loss of GBM HS in diabetic kidney was associated with increased glomerular expression of heparanase; however, the causal involvement of heparanase in the pathogenesis of DN has not been demonstrated. We report for the first time the essential involvement of heparanase in DN. With the use of Hpse-KO mice, we found that deletion of the heparanase gene protects diabetic mice from DN. Furthermore, by investigating the molecular mechanism underlying induction of the enzyme in DN, we found that transcription factor early growth response 1 (Egr1) is responsible for activation of heparanase promoter under diabetic conditions. The specific heparanase inhibitor SST0001 markedly decreased the extent of albuminuria and renal damage in mouse models of DN. Our results collectively underscore the crucial role of heparanase in the pathogenesis of DN and its potential as a highly relevant target for interventions in patients with DN.
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| 3. |
- Smits, Nicole C., et al.
(författare)
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The heparan sulfate motif (GlcNS6S-IdoA2S)3, common in heparin, has a strict topography and is involved in cell behavior and disease
- 2010
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 285:52, s. 41143-41151
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Tidskriftsartikel (refereegranskat)abstract
- Heparan sulfate (HS) is a structurally complex polysaccharide that interacts with a broad spectrum of extracellular effector ligands and thereby is thought to regulate a diverse array of biologic processes. The specificity of HS-ligand interactions is determined by the arrangement of sulfate groups on HS, which creates distinct binding motifs. Biologically important HS motifs are expected to exhibit regulated expression. Yet, there is a profound lack of tools to identify such motifs; consequently, little is known of their structures and functions. We have identified a novel phage display-derived antibody (NS4F5) that recognizes a highly regulated HS motif (HS(NS4F5)), which we have rigorously identified as (GlcNS6S-IdoA2S)(3). HS(NS4F5) exhibits a restricted expression in healthy adult tissues. Blocking HS(NS4F5) on cells in culture resulted in reduced proliferation and enhanced sensitivity to apoptosis. HS(NS4F5) is upregulated in tumor endothelial cells, consistent with a role in endothelial cell activation. Indeed, TNF-α stimulated endothelial expression of HS(NS4F5), which contributed to leukocyte adhesion. In a mouse model of severe systemic AA amyloidosis, HS(NS4F5) was expressed within amyloid deposits, which were successfully detected by microSPECT imaging using NS4F5 as a molecularly targeted probe. Combined, our results demonstrate that NS4F5 is a powerful tool for elucidating the biological function of HS(NS4F5) and can be exploited as a probe to detect novel polysaccharide biomarkers of disease processes.
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| 4. |
- Dieker, Jurgen, et al.
(författare)
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Autoantibodies against Modified Histone Peptides in SLE Patients Are Associated with Disease Activity and Lupus Nephritis
- 2016
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 11:10
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Tidskriftsartikel (refereegranskat)abstract
- Persistent exposure of the immune system to death cell debris leads to autoantibodies against chromatin in patients with systemic lupus erythematosus (SLE). Deposition of antichromatin/ chromatin complexes can instigate inflammation in multiple organs including the kidney. Previously we identified specific cell death-associated histone modifications as targets of autoantibodies in SLE. In this study we addressed, in a large cohort of SLE patients and controls, the question whether plasma reactivities with specific histone peptides associated with serology and clinical features. Plasma from SLE patients with and without lupus nephritis, disease controls, and healthy controls, were tested in ELISA with histone H4 peptide acetylated at lysines 8, 12 and 16 (H4p(ac)), H2B peptide acetylated at lysine 12 (H2Bp(ac)), H3 peptide trimethylated at lysine 27 (H3p(me)), and their unmodified equivalents. SLE patients displayed a higher reactivity with the modified equivalent of each peptide. Reactivity with H4p(ac) showed both a high sensitivity (89%) and specificity (91%) for SLE, while H2Bp(ac) exhibited a high specificity (96%) but lower sensitivity (69%). Reactivity with H3p(me) appeared not specific for SLE. Anti-H4p(ac) and anti-H2Bp(ac) reactivity demonstrated a high correlation with disease activity. Moreover, patients reacting with multiple modified histone peptides exhibited higher SLEDAI and lower C3 levels. SLE patients with renal involvement showed higher reactivity with H2B/H2Bp(ac) and a more pronounced reactivity with the modified equivalent of H3p(me) and H2Bp(ac). In conclusion, reactivity with H4p(ac) and H2Bp(ac) is specific for SLE patients and correlates with disease activity, whereas reactivity with H2Bp(ac) is in particular associated with lupus nephritis.
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| 5. |
- Goldberg, Rachel, et al.
(författare)
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Role of Heparanase-Driven Inflammatory Cascade in Pathogenesis of Diabetic Nephropathy
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 63:12, s. 4302-4313
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Tidskriftsartikel (refereegranskat)abstract
- Renal involvement is a major medical concern in the diabetic population, and with the global epidemic of diabetes, diabetic nephropathy (DN) became the leading cause of end-stage renal failure in the Western world. Heparanase (the only known mammalian endoglycosidase that cleaves heparan sulfate) is essentially involved in DN pathogenesis. Nevertheless, the exact mode of heparanase action in sustaining the pathology of DN remains unclear. Here we describe a previously unrecognized combinatorial circuit of heparanase-driven molecular events promoting chronic inflammation and renal injury in individuals with DN. These events are fueled by heterotypic interactions among glomerular, tubular, and immune cell compartments, as well as diabetic milieu (DM) components. We found that under diabetic conditions latent heparanase, overexpressed by glomerular cells and posttranslationally activated by cathepsin L of tubular origin, sustains continuous activation of kidney-damaging macrophages by DM components, thus creating chronic inflammatory conditions and fostering macrophage-mediated renal injury. Elucidation of the mechanism underlying the enzyme action in diabetic kidney damage is critically important for the proper design and future implementation of heparanase-targeting therapeutic interventions (which are currently under intensive development and clinical testing) in individuals with DN and perhaps other complications of diabetes.
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| 6. |
- Hermano, Esther, et al.
(författare)
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Heparanase Accelerates Obesity-Associated Breast Cancer Progression
- 2019
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 79:20, s. 5342-5354
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Tidskriftsartikel (refereegranskat)abstract
- Obese women have higher risk of bearing breast tumors that are highly aggressive and resistant to therapies. Tumor-promoting effects of obesity occur locally via adipose inflammation and related alterations to the extracellular matrix (ECM) as well as systemically via circulating metabolic mediators (e.g., free fatty acids, FFA) associated with excess adiposity and implicated in toll-like receptor-mediated activation of macrophages-key cellular players in obesity-related cancer progression. Although the contribution of macrophages to proneoplastic effects of obesity is well documented, the role of ECM components and their enzymatic degradation is less appreciated. We show that heparanase, the sole mammalian endoglucuronidase that cleaves heparan sulfate in ECM, is preferentially expressed in clinical/experimental obesity-associated breast tumors. Heparanase deficiency abolished obesity-accelerated tumor progression in vivo. Heparanase orchestrated a complex molecular program that occurred concurrently in adipose and tumor tissue and sustained the cancer-promoting action of obesity. Heparanase was required for adipose tissue macrophages to produce inflammatory mediators responsible for local induction of aromatase, a rate-limiting enzyme in estrogen biosynthesis. Estrogen upregulated heparanase in hormone-responsive breast tumors. In subsequent stages, elevated levels of heparanase induced acquisition of procancerous phenotype by tumor-associated macrophages, resulting in activation of tumor-promoting signaling and acceleration of breast tumor growth under obese conditions. As techniques to screen for heparanase expression in tumors become available, these findings provide rational and a mechanistic basis for designing antiheparanase approaches to uncouple obesity and breast cancer in a rapidly growing population of obese patients. Significance: This study reveals the role of heparanase in promoting obesity-associated breast cancer and provides a mechanistically informed approach to uncouple obesity and breast cancer in a rapidly growing population of obese patients.
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| 7. |
- Smith, Richard J.H., et al.
(författare)
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C3 glomerulopathy — understanding a rare complement-driven renal disease
- 2019
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Ingår i: Nature Reviews Nephrology. - : Springer Science and Business Media LLC. - 1759-5061 .- 1759-507X.
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Forskningsöversikt (refereegranskat)abstract
- The C3 glomerulopathies are a group of rare kidney diseases characterized by complement dysregulation occurring in the fluid phase and in the glomerular microenvironment, which results in prominent complement C3 deposition in kidney biopsy samples. The two major subgroups of C3 glomerulopathy — dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) — have overlapping clinical and pathological features suggestive of a disease continuum. Dysregulation of the complement alternative pathway is fundamental to the manifestations of C3 glomerulopathy, although terminal pathway dysregulation is also common. Disease is driven by acquired factors in most patients — namely, autoantibodies that target the C3 or C5 convertases. These autoantibodies drive complement dysregulation by increasing the half-life of these vital but normally short-lived enzymes. Genetic variation in complement-related genes is a less frequent cause. No disease-specific treatments are available, although immunosuppressive agents and terminal complement pathway blockers are helpful in some patients. Unfortunately, no treatment is universally effective or curative. In aggregate, the limited data on renal transplantation point to a high risk of disease recurrence (both DDD and C3GN) in allograft recipients. Clinical trials are underway to test the efficacy of several first-generation drugs that target the alternative complement pathway.
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