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Diabetes 54:2172-2178, 2005
© 2005 by the American Diabetes Association, Inc.

Heparanase-1 Gene Expression and Regulation by High Glucose in Renal Epithelial Cells

A Potential Role in the Pathogenesis of Proteinuria in Diabetic Patients

Justin B. Maxhimer1, Michael Somenek1, Geetha Rao1, Catherine E. Pesce1, David Baldwin, Jr.2, Paolo Gattuso3, Melvin M. Schwartz3, Edmund J. Lewis4, Richard A. Prinz1, and Xiulong Xu1

1 Department of General Surgery, Rush University Medical Center, Chicago, Illinois
2 Section of Endocrinology, Department of Medicine, Rush University Medical Center, Chicago, Illinois
3 Department of Pathology, Rush University Medical Center, Chicago, Illinois
4 Section of Nephrology, Rush University Medical Center, Chicago, Illinois

The molecular mechanisms of heparan sulfate proteoglycan downregulation in the glomerular basement membrane (GBM) of the kidneys with diabetic nephropathy remain controversial. In the present study, we showed that the expression of heparanase-1 (HPR1), a heparan sulfate–degrading endoglycosidase, was upregulated in the renal epithelial cells in the kidney with diabetic nephropathy. Urinary HPR1 levels were elevated in patients with diabetic nephropathy. In vitro cell culture studies revealed that HPR1 promoter–driven luciferase reporter gene expression, HPR1 mRNA, and protein were upregulated in renal epithelial cells under high glucose conditions. Induction of HPR1 expression by high glucose led to decreased cell surface heparan sulfate expression. HPR1 inhibitors were able to restore cell surface heparan sulfate expression. Functional analysis revealed that renal epithelial cells grown under high glucose conditions resulted in an increase of basement membrane permeability to albumin. Our studies suggest that loss of heparan sulfate in the GBM with diabetic nephropathy is attributable to accelerated heparan sulfate degradation by increased HPR1 expression.

Address correspondence and reprint requests to Xiulong Xu, Department of General Surgery, Rush University Medical Center, 1653 W. Congress Parkway, Chicago, IL 60612. E-mail: xiulong_xu{at}rush.edu

Abbreviations: DMEM, Dulbecco’s modified Eagle’s medium; FBS, fetal bovine serum; GBM, glomerular basement membrane; HSPG, heparan sulfate proteoglycan; HPR1, heparanase-1


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