Heparanase Is Essential for the Development of Diabetic Nephropathy in Mice
- Natali Gil1,
- Rachel Goldberg1,
- Tzahi Neuman2,
- Marjolein Garsen3,
- Eyal Zcharia4,
- Ariel M. Rubinstein1,
- Toin van Kuppevelt5,
- Amichay Meirovitz1,
- Claudio Pisano6,
- Jin-Ping Li7,
- Johan van der Vlag3,
- Israel Vlodavsky4⇓ and
- Michael Elkin1⇓
- 1Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
- 2Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
- 3Nephrology Research Laboratory, Department of Nephrology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
- 4Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine, Technion, Haifa, Israel
- 5Department of Matrix Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
- 6Oncology Area Research and Development, Sigma-Tau S.p.A., Rome, Italy
- 7Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
- Corresponding author: Michael Elkin, , or Israel Vlodavsky, .
N.G. and R.G. contributed equally to this work.
Diabetic nephropathy (DN) is the major life-threatening complication of diabetes. Abnormal permselectivity of glomerular basement membrane (GBM) plays an important role in DN pathogenesis. Heparanase is the predominant enzyme that degrades heparan sulfate (HS), the main polysaccharide of the GBM. Loss of GBM HS in diabetic kidney was associated with increased glomerular expression of heparanase; however, the causal involvement of heparanase in the pathogenesis of DN has not been demonstrated. We report for the first time the essential involvement of heparanase in DN. With the use of Hpse-KO mice, we found that deletion of the heparanase gene protects diabetic mice from DN. Furthermore, by investigating the molecular mechanism underlying induction of the enzyme in DN, we found that transcription factor early growth response 1 (Egr1) is responsible for activation of heparanase promoter under diabetic conditions. The specific heparanase inhibitor SST0001 markedly decreased the extent of albuminuria and renal damage in mouse models of DN. Our results collectively underscore the crucial role of heparanase in the pathogenesis of DN and its potential as a highly relevant target for therapeutic interventions in patients with DN.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1024/-/DC1.
- Received July 31, 2011.
- Accepted October 5, 2011.
- © 2012 by the American Diabetes Association.
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