Heparanase Is Essential for the Development of Diabetic Nephropathy in Mice

Gil, Natali; Goldberg, Rachel; Neuman, Tzahi; Garsen, Marjolein; Zcharia, Eyal; Rubinstein, Ariel M.; Kuppevelt, Toin van; Meirovitz, Amichay; Pisano, Claudio; Li, Jinping; Vlag, Johan van der; Vlodavsky, Israël; Elkin, Michael

doi:10.2337/db11-1024

Cited by 172 publications

(200 citation statements)

References 48 publications

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“…Taken together, mAbs 9E8 and H1023 are expected to exert high specificity, enabling solely the targeting of heparanase enzymatic activity, and hence revealing its involvement and therapeutic significance in tumor progression, inflammation (43), type 1 diabetes (44), and diabetic nephropathy (45), as a single agent or in combination with approved therapies.…”

Section: Discussionmentioning

confidence: 99%

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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140

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Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of proteoglycans, resulting in disassembly of the extracellular matrix underlying endothelial and epithelial cells and associating with enhanced cell invasion and metastasis. Heparanase expression is induced in carcinomas and sarcomas, often associating with enhanced tumor metastasis and poor prognosis. In contrast, the function of heparanase in hematological malignancies (except myeloma) was not investigated in depth. Here, we provide evidence that heparanase is expressed by human follicular and diffused non-Hodgkin's B-lymphomas, and that heparanase inhibitors restrain the growth of tumor xenografts produced by lymphoma cell lines. Furthermore, we describe, for the first time to our knowledge, the development and characterization of heparanaseneutralizing monoclonal antibodies that inhibit cell invasion and tumor metastasis, the hallmark of heparanase activity. Using luciferase-labeled Raji lymphoma cells, we show that the heparanase-neutralizing monoclonal antibodies profoundly inhibit tumor load in the mouse bones, associating with reduced cell proliferation and angiogenesis. Notably, we found that Raji cells lack intrinsic heparanase activity, but tumor xenografts produced by this cell line exhibit typical heparanase activity, likely contributed by host cells composing the tumor microenvironment. Thus, the neutralizing monoclonal antibodies attenuate lymphoma growth by targeting heparanase in the tumor microenvironment.heparanase | lymphoma | neutralizing antibody | tumor growth | metastasis H eparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, releasing saccharide products with appreciable size (4-7 kDa) and biological potency. Enzymatic degradation of HS leads to disassembly of the extracellular matrix (ECM) and correlates with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the ECM and basement membrane underlying epithelial and endothelial cells (1, 2). Heparanase expression is induced in human cancer, most often associating with reduced patients' survival postoperation, increased tumor metastasis, and higher vessel density (3-5). In addition, heparanase up-regulation is associated with tumors larger in size (3, 5). Likewise, heparanase over-expression enhanced (6, 7), whereas local delivery of anti-heparanase siRNA inhibited (8), the growth of tumor xenografts. These results imply that heparanase function is not limited to tumor metastasis but is engaged in progression of the primary lesion, thus critically supporting the intimate involvement of heparanase in tumor progression and encouraging the development of heparanase inhibitors as anticancer therapeutics (9-12). As a consequence, heparanase inhibitors are currently evaluated in phase 1 clinical trials (13).Heparanase activity is similarly implicated in the progression of multiple myeloma (14-16), but its significan...

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Section: Discussionmentioning

confidence: 99%

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

140

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“…Increases in heparanase levels correlate inversely with GBM HS content and can be responsible for glycocalyx changes, supporting the impression that heparanase plays an active part in the onset of proteinuria [10]. This impression is confirmed by the finding in a mouse model of diabetic nephropathy that inhibiting heparanase with SST0001 prompts a reduction in albuminuria, fibrosis and TGFβ expression [11]. Heparanase also has a physiological role in maintaining cellular and ECM homeostasis, and its dysregulation contributes to the epithelial-mesenchymal transition (EMT) of tubular cells and the onset of fibrosis [12].…”

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confidence: 58%

“…Several conditions associated with renal damage can up-regulate heparanase in the kidney, including albuminuria, high glucose concentrations, advanced glycosylation end-products (AGE), TGFβ and FGF-2 [11]. Increases in heparanase levels correlate inversely with GBM HS content and can be responsible for glycocalyx changes, supporting the impression that heparanase plays an active part in the onset of proteinuria [10].…”

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confidence: 99%

“…[10]. Heparanase thus has multifaceted activities, which may be structural or involved in cell-cell and cell-ECM crosstalk, remodelling of the ECM and basement membranes by degrading HS, controlling the ECM storage of growth factors and cytokines bound to HS, tuning intracellular signalling pathways (Src, Akt and p38 MAPK) through interaction with transmembrane proteins, and modulating FGF-2 and TGFβ intracellular signalling [11].…”

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confidence: 99%

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Heparanase: another renal player controlled by vitamin D

Masola

Zaza

Onisto

et al. 2015

The Journal of Pathology

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To take effect, 1,25-D 3 needs to bind to vitamin D receptor (VDR), a nuclear receptor expressed in various organs (including the kidney) that acts as a transcription factor, regulating the gene expression of proteins implicated in calcium and phosphate transportation [2]. Finding that VDR is also expressed in cells uninvolved in mineral metabolism suggests, however, that vitamin D has a much broader range of activities. In fact, VDR can bind to genes involved in cell proliferation and differentiation. Vitamin D has a modulating effect on inflammation and on the immune and endocrine systems, including the renin-angiotensin-aldosterone (RAA) axis and insulin resistance [3]. The conviction that these general activities of vitamin D may be of paramount importance is supported by epidemiological studies showing a strong association between low vitamin D levels and a higher risk of cardiovascular, infectious, autoimmune and neurodegenerative disorders, diabetes and cancer, both in healthy people and in patients with chronic kidney disease (CKD) [4,5]. Interventional studies also support this impression, and supplementation with vitamin D and its analogues seems to be associated with a lower mortality [5].Interestingly, supplementation with vitamin D and its analogues may have kidney-protecting effects too, as suggested by a decrease in urinary protein levels [6]. Proteinuria is the most powerful predictor of unfavourable outcome in most forms of CKD, and its reduction is considered to be a surrogate endpoint in trials investigating the effects of experimental drugs on the progression of CKD to end-stage renal disease (ESRD) [7]. Vitamin D may exert its nephroprotective action by modulating the RAA system, which plays a vital part in regulating blood pressure and volume, electrolyte homeostasis and the intraglomerular pressure that drives proteinuria. Drugs targeting the RAA system -the angiotensin-converting enzyme inhibitors (ACEi) and the angiotensin receptor blockers (ARB) -are believed to reduce glomerular filtration, and consequently also proteinuria, by reducing the intraglomerular pressure, and the reduction in proteinuria

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“…33 Furthermore, Gil et al reported that the deletion of the heparanase gene, the predominant enzyme that degrades heparan sulfate, protects diabetic mice from diabetic nephropathy. 34 Production of heparanase has been shown to be regulated by oxidative stress. 35 It is considered that the improvement of glomerular permeability by preservation of glomerular glycocalyx in GCHtg/Ins2 +/Akita mice results from inhibiting ROS production via eNOS recoupling.…”

Section: Discussionmentioning

confidence: 99%

Maintenance of Endothelial Guanosine Triphosphate Cyclohydrolase I Ameliorates Diabetic Nephropathy

Kidokoro

Satoh²,

Channon

et al. 2013

Journal of the American Society of Nephrology

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In diabetes, endothelial nitric oxide synthase (eNOS) produces superoxide anion rather than nitric oxide, referred to as "eNOS uncoupling," which may contribute to endothelial dysfunction, albuminuria, and diabetic nephropathy. Reduced levels of endothelium-derived tetrahydrobiopterin (BH4), an essential cofactor for eNOS, promote eNOS uncoupling. Accelerated degradation of guanosine triphosphate cyclohydrolase I (GTPCH I), the rate-limiting enzyme in BH4 biosynthesis, also occurs in diabetes, suggesting that GTPCH I may have a role in diabetic microvascular disease. Here, we crossed endothelium-dominant GTPCH I transgenic mice with Ins2 +/Akita diabetic mice and found that endothelial overexpression of GTPCH I led to higher levels of intrarenal BH4 and lower levels of urinary albumin and reactive oxygen species compared with diabetic control mice. Furthermore, GTPCH I overexpression attenuated the hyperpermeability of macromolecules observed in diabetic control mice. In addition, we treated Ins2 +/Akita mice with metformin, which activates AMP-activated protein kinase (AMPK) and thereby slows the degradation of GTPCH I; despite blood glucose levels that were similar to untreated mice, those treated with metformin had significantly less albuminuria. Similarly, in vitro, treating human glomerular endothelial cells with AMPK activators attenuated glucose-induced reductions in phospho-AMPK, GTPCH I, and coupled eNOS. Taken together, these data suggest that maintenance of endothelial GTPCH I expression and the resulting improvement in BH4 biosynthesis ameliorate diabetic nephropathy.

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Heparanase Is Essential for the Development of Diabetic Nephropathy in Mice

Cited by 172 publications

References 48 publications

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Heparanase: another renal player controlled by vitamin D

Maintenance of Endothelial Guanosine Triphosphate Cyclohydrolase I Ameliorates Diabetic Nephropathy

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