title: Involvement of human heparanase in the pathogenesis of diabetic nephropathy.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departments of Pediatrics and Nephrology, Bikur Holim Hospital, Jerusalem, Israel.
authors.forename: Avi
authors.initials: A
authors.lastname: Katz
authors.forename: David J
authors.initials: DJ
authors.lastname: Van-Dijk
authors.forename: Helena
authors.initials: H
authors.lastname: Aingorn
authors.forename: Arie
authors.initials: A
authors.lastname: Erman
authors.forename: Malcolm
authors.initials: M
authors.lastname: Davies
authors.forename: David
authors.initials: D
authors.lastname: Darmon
authors.forename: Hagit
authors.initials: H
authors.lastname: Hurvitz
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
mesh_terms: D000328:Adult; D000419:Albuminuria / Q000378:metabolism; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000652:urine; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000209:etiology; D005260:Female; D005966:Glucuronidase / Q000378:metabolism* / Q000652:urine; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D008297:Male; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D019812:Heparan Sulfate Proteoglycans; D000099175:Heparanase