Matrix metalloproteinase-9 mediated shedding of syndecan-4 in glomerular endothelial cells

Background - Diabetic nephropathy is the most common cause of end‐stage renal failure in the western world and Asia. The mechanisms are not fully elucidated, but disruption of glomerular endothelial glycocalyx and shedding of its components including syndecans has been implicated. Aims - We hypothesize that reduced glomerular filtration in diabetes is caused by disruption of endothelial glycocalyx in glomeruli, including increased shedding of syndecan‐4. The aim of this study was to determine the effects of experimental diabetic conditions by means of hyperglycemia and IL‐1β exposure on syndecan‐4 shedding in GEnC, and to investigate regulation of shedding by sheddases. Results - We found that in GEnC the expression of syndecan‐4 is higher than that of the other syndecans. In polarized GEnC, apical shedding of syndecan‐4 and syndecan‐4 gene expression was increased by 60% after IL‐1β‐stimulation, but not affected by hyperglycemic conditions. This was accompanied by a 50% increase in MMP9 gene expression in IL‐1β‐stimulated cells but not hyperglycemia. MMP9 knockdown reduced syndecan‐4 shedding by 50%. Conclusion - IL‐1β but not hyperglycemia increases the shedding of syndecan‐4 from GEnC in an MMP9‐dependent manner. This provides a potential mechanism of GEnC damage in diabetes and other inflammatory conditions

Matrix metalloproteinase-9 mediated shedding of syndecan-4 in glomerular endothelial cells

Background - Diabetic nephropathy is the most common cause of end‐stage renal failure in the western world and Asia. The mechanisms are not fully elucidated, but disruption of glomerular endothelial glycocalyx and shedding of its components including syndecans has been implicated. Aims - We hypothesize that reduced glomerular filtration in diabetes is caused by disruption of endothelial glycocalyx in glomeruli, including increased shedding of syndecan‐4. The aim of this study was to determine the effects of experimental diabetic conditions by means of hyperglycemia and IL‐1β exposure on syndecan‐4 shedding in GEnC, and to investigate regulation of shedding by sheddases. Results - We found that in GEnC the expression of syndecan‐4 is higher than that of the other syndecans. In polarized GEnC, apical shedding of syndecan‐4 and syndecan‐4 gene expression was increased by 60% after IL‐1β‐stimulation, but not affected by hyperglycemic conditions. This was accompanied by a 50% increase in MMP9 gene expression in IL‐1β‐stimulated cells but not hyperglycemia. MMP9 knockdown reduced syndecan‐4 shedding by 50%. Conclusion - IL‐1β but not hyperglycemia increases the shedding of syndecan‐4 from GEnC in an MMP9‐dependent manner. This provides a potential mechanism of GEnC damage in diabetes and other inflammatory conditions

Matrix metalloproteinases in subjects with type 1 diabetes

<p>Abstract</p> <p>Background</p> <p>Nephropathy is serious complication of diabetes. We have previously shown that level of the proteoglycan syndecan-1 in blood is associated with ultrastructural kidney changes in young persons with type 1 diabetes. Dysregulation of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) may contribute to the development of nephropathy. The aim of this study was to investigate if the levels of MMPs in blood samples are potential markers of early nephropathy in type 1 diabetes.</p> <p>Methods</p> <p>Blood samples were collected from type 1 diabetes patients after 11 years of diabetes (n = 15) and healthy volunteers (n = 12) and stored at ÷80°C until measurement. Levels and activities of serum MMP-2, MMP-9, TIMP-1 and TIMP- 2 were analyzed and compared to those of control individuals using ELISA, SDS-PAGE gelatin zymography, and Western blot analysis.</p> <p>Results</p> <p>The serum levels of both MMP-9 and MMP-2 were significantly higher in subjects with type 1 diabetes, compared to controls (p = 0.016 and p = 0.008 respectively). Western blotting revealed no differences between the two groups in the levels of TIMP-1 or TIMP-2, respectively.</p> <p>Conclusion</p> <p>Our MMP analysis of serum from a limited number of patients with type 1 diabetes suggest that such analysis is potentially useful as markers in studies of people at risk of progression to chronic kidney disease.</p

Intellectual disability and nutrition‐related health

Intellectual disability (ID) is a condition that affects approximately 1% of the population (Maulik et al, 2011). The numbers may differ across nations, owing to different systems and diagnosis entries or lack of such, but usually range between 0.6 and 3% (Stromme & Valvatne, 1998). Persons with ID are a heterogeneous group with different diagnoses and different levels of intellectual ability. These range from profound (IQ < 20) and serious ID (IQ 20–34) to moderate (IQ 35–49) and light ID (IQ 50–69); this roughly translates into the intellectual capacity of children between 3–12 years of age. More than 75% of persons with ID have the mild form and their intellectual capacity and potential may be underestimated in some cases if IQ is the only diagnostic criteria. However, the range in itself is an important factor to take into account when addressing nutrition and health issues. It is further important to recognize that ID is also a feature of several rare disorders, and many disorders not yet identified, adding to the complexity of this group

Internalization and stepwise degradation of heparan sulfate proteoglycans in rat hepatocytes

AbstractIntracellular transport and degradation of membrane anchored heparan sulfate proteoglycans (HSPGs) were studied in cultured rat hepatocytes labeled with [35S]sulfate and [3H]glucosamine. Pulse chase experiments showed that membrane anchored HSPGs were constitutively transported to the cell surface after completion of polymerization and modification of the glycosaminoglycan chains in the Golgi apparatus. The intact HSPGs had a relatively short residence time at the cell surface and in non-degrading compartments (T1/2 ∼2–3 h), while [35S]sulfate labeled degradation products were found in lysosomes, and to a lesser extent in late endosomes. These degradation products which were free heparan sulfate chains with little or no protein covalently attached, were approximately half the size of the original glycosaminoglycan chains and were the only degradation intermediate found in the course of HSPG catabolism in these cells. In cells incubated in the presence of the microtubule perturbant vinblastine, or in the presence of the vacuolar ATPase inhibitor bafilomycin A1, and in cells incubated at 19°C, the endocytosed HSPGs were retained in endosomes and no degradation products were detected. Disruption of lysosomes with glycyl-phenylalanine 2-naphthylamide (GPN) revealed a GPN resistant degradative compartment with both intact and partially degraded HSPGs. This compartment probably corresponds to late endosomes. Treatment of hepatocytes with the thiol protease inhibitor leupeptin inhibited the final degradation of the protein moiety of the HSPGs. The protein portion seems to be degraded completely before the glycosaminoglycan chains are cleaved. The degradation of the glycosaminoglycan chains is rapid and complete with one observable intermediate