BACKGROUND: Decreased heparan sulfate proteoglycan content of the glomerular basement membrane has been described in proteinuric patients with diabetic nephropathy. Heparanase is an endo-beta-D-glucuronidase that cleaves negatively charged heparan sulfate side chains in the basement membrane and extracellular matrix. OBJECTIVES: To investigate whether urine from type I diabetic patients differs in heparanase activity from control subjects and whether resident glomerular cells could be the source of urinary heparanase. METHODS: Using soluble 35S-HSPG and sulfate-labeled extracellular matrix we assessed heparanase activity in human glomerular epithelial cells, rat mesangial cells, and urine from 73 type I diabetic patients. Heparanase activity resulted in the conversion of a high molecular weight sulfate-labeled HSPG into heparan sulfate degradation fragments as determined by gel filtration analysis. RESULTS: High heparanase activity was found in lysates of both epithelial and mesangial cells. Immunohistochemical staining localized the heparanase protein to both glomeruli capillaries and tubular epithelium. Heparanase activity was detected in the urine of 16% and 25% of the normoalbuminuric and microalbuminuric diabetic patients, respectively. Urine from 40 healthy individuals did not possess detectable heparanase. Urinary heparanase activity was associated with worse glycemic control. CONCLUSION: We suggest that heparanase enzyme participates in the tunover of glomerular HSPG. Hyperglycemia enhances heparanase activity and/or secretion in some diabetic patients, resulting in the loss of albumin permselective properties of the GBM.
BACKGROUND: Decreased heparan sulfate proteoglycan content of the glomerular basement membrane has been described in proteinuric patients with diabetic nephropathy. Heparanase is an endo-beta-D-glucuronidase that cleaves negatively charged heparan sulfate side chains in the basement membrane and extracellular matrix. OBJECTIVES: To investigate whether urine from type I diabeticpatients differs in heparanase activity from control subjects and whether resident glomerular cells could be the source of urinary heparanase. METHODS: Using soluble 35S-HSPG and sulfate-labeled extracellular matrix we assessed heparanase activity in human glomerular epithelial cells, rat mesangial cells, and urine from 73 type I diabeticpatients. Heparanase activity resulted in the conversion of a high molecular weight sulfate-labeled HSPG into heparan sulfate degradation fragments as determined by gel filtration analysis. RESULTS: High heparanase activity was found in lysates of both epithelial and mesangial cells. Immunohistochemical staining localized the heparanase protein to both glomeruli capillaries and tubular epithelium. Heparanase activity was detected in the urine of 16% and 25% of the normoalbuminuric and microalbuminuric diabeticpatients, respectively. Urine from 40 healthy individuals did not possess detectable heparanase. Urinary heparanase activity was associated with worse glycemic control. CONCLUSION: We suggest that heparanase enzyme participates in the tunover of glomerular HSPG. Hyperglycemia enhances heparanase activity and/or secretion in some diabeticpatients, resulting in the loss of albumin permselective properties of the GBM.
Authors: Aaron B Baker; William J Gibson; Vijaya B Kolachalama; Mordechai Golomb; Laura Indolfi; Christopher Spruell; Eyal Zcharia; Israel Vlodavsky; Elazer R Edelman Journal: J Am Coll Cardiol Date: 2012-04-24 Impact factor: 24.094
Authors: T J M Wijnhoven; M J W van den Hoven; H Ding; T H van Kuppevelt; J van der Vlag; J H M Berden; R A Prinz; E J Lewis; M Schwartz; X Xu Journal: Diabetologia Date: 2007-12-06 Impact factor: 10.122
Authors: Partha S Bhattacharjee; Tashfin S Huq; Valencia Potter; Anna Young; Ian R Davenport; Richard Graves; Tarun K Mandal; Christian Clement; Harris E McFerrin; Syed Muniruzzaman; Shubha K Ireland; James M Hill Journal: PLoS One Date: 2012-12-19 Impact factor: 3.240