Involvement of human heparanase in the pathogenesis of diabetic nephropathy.
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.
Katz
Avi
A
Departments of Pediatrics and Nephrology, Bikur Holim Hospital, Jerusalem, Israel.
Van-Dijk
David J
DJ
Aingorn
Helena
H
Erman
Arie
A
Davies
Malcolm
M
Darmon
David
D
Hurvitz
Hagit
H
Vlodavsky
Israel
I
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
D005966:Glucuronidase; D019812:Heparan Sulfate Proteoglycans; D000099175:Heparanase