Heparanase is essential for the development of diabetic nephropathy in mice

Natali Gil; Rachel Goldberg; Tzahi Neuman; Marjolein Garsen; Eyal Zcharia; Ariel M. Rubinstein; Toin Van Kuppevelt; Amichay Meirovitz; Claudio Pisano; Jin Ping Li; Johan Van Der Vlag; Israel Vlodavsky; Michael Elkin

doi:10.2337/db11-1024

Heparanase is essential for the development of diabetic nephropathy in mice

Natali Gil, Rachel Goldberg, Tzahi Neuman, Marjolein Garsen, Eyal Zcharia, Ariel M. Rubinstein, Toin Van Kuppevelt, Amichay Meirovitz, Claudio Pisano, Jin Ping Li, Johan Van Der Vlag, Israel Vlodavsky, Michael Elkin

Research output: Contribution to journal › Article › peer-review

163 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	208-216
Number of pages	9
Journal	Diabetes
Volume	61
Issue number	1
DOIs	https://doi.org/10.2337/db11-1024
State	Published - 1 Jan 2012
Externally published	Yes

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

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10.2337/db11-1024

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@article{22b90eca8ad246b88ed34048c3d2bb29,

title = "Heparanase is essential for the development of diabetic nephropathy in mice",

abstract = "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.",

author = "Natali Gil and Rachel Goldberg and Tzahi Neuman and Marjolein Garsen and Eyal Zcharia and Rubinstein, {Ariel M.} and {Van Kuppevelt}, Toin and Amichay Meirovitz and Claudio Pisano and Li, {Jin Ping} and {Van Der Vlag}, Johan and Israel Vlodavsky and Michael Elkin",

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doi = "10.2337/db11-1024",

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AU - Gil, Natali

AU - Goldberg, Rachel

AU - Neuman, Tzahi

AU - Garsen, Marjolein

AU - Zcharia, Eyal

AU - Rubinstein, Ariel M.

AU - Van Kuppevelt, Toin

AU - Meirovitz, Amichay

AU - Pisano, Claudio

AU - Li, Jin Ping

AU - Van Der Vlag, Johan

AU - Vlodavsky, Israel

AU - Elkin, Michael

PY - 2012/1/1

Y1 - 2012/1/1

N2 - 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.

AB - 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.

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SP - 208

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JO - Diabetes

JF - Diabetes

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Heparanase is essential for the development of diabetic nephropathy in mice

Abstract

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