Impact of heparanase on renal fibrosis

Masola, Valentina; Zaza, Gianluigi; Onisto, Maurizio; Lupo, Antonio; Gambaro, Giovanni

doi:10.1186/s12967-015-0538-5

Cited by 52 publications

(49 citation statements)

References 55 publications

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“…93,96 Much of the preclinical work has focused on heparanase’s role in tumor growth and metastasis, however it has been reported to play role in other pathologic disease states such as inflammation, vascular disease, and kidney disease are currently being explored. 4,154 …”

Section: Discussionmentioning

confidence: 99%

Mechanisms of heparanase inhibitors in cancer therapy

Heyman

Yang

2016

Experimental Hematology

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Heparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains contributing to break down of the extracellular matrix. Increased expression of heparanase has been found in numerous malignancies, and is associated with a poor prognosis. It has generated significant interest as a potential anti-neoplastic target because of the multiple roles it plays in tumor growth and metastasis. The pro-tumorigenic effects of heparanase are enhanced by the release of HS side chains, with subsequent increase in bioactive fragments and increased cytokine levels; both promoting tumor invasion, angiogenesis and metastasis. Preclinical experiments have shown heparanase inhibitors to substantially reduce tumor growth and metastasis leading to clinical trials with heparan sulfate mimetics. In this review we will examine heparanase’s role in tumor biology, its interaction with heparan surface proteoglycans, specifically syndecan-1; as well as the mechanism of action for heparanase inhibitors developed as anti-neoplastic therapeutics.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of heparanase inhibitors in cancer therapy

Heyman

Yang

2016

Experimental Hematology

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“…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: 86%

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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“…The role of heparanase in kidney morphogenesis has not been explored, however its over-expression has been implicated in renal fibrosis (reviewed in (93). This may be due to the regulation of TGFβ function by heparanase.…”

Section: Introductionmentioning

confidence: 99%

The function of heparan sulfate during branching morphogenesis

2017

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Branching morphogenesis is a fundamental process in the development of diverse epithelial organs such as the lung, kidney, liver, pancreas, prostate, salivary, lacrimal and mammary glands. A unifying theme during organogenesis is the importance of epithelial cell interactions with the extracellular matrix (ECM) and growth factors (GFs). The diverse developmental mechanisms giving rise to these epithelial organs involve many organ-specific GFs, but a unifying paradigm during organogenesis is the regulation of GF activity by heparan sulfates (HS) on the cell surface and in the ECM. This primarily involves the interactions of GFs with the sulfated side-chains of HS proteoglycans. HS is one of the most diverse biopolymers and modulates GF binding and signaling at the cell surface and in the ECM of all tissues. Here, we review what is known about how HS regulates branching morphogenesis of epithelial organs with emphasis on the developing salivary gland, which is a classic model to investigate epithelial-ECM interactions. We also address the structure, biosynthesis, turnover and function of HS during organogenesis. Understanding the regulatory mechanisms that control HS dynamics may aid in the development of therapeutic interventions for diseases and novel strategies for tissue engineering and regenerative medicine.

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Impact of heparanase on renal fibrosis

Cited by 52 publications

References 55 publications

Mechanisms of heparanase inhibitors in cancer therapy

Mechanisms of heparanase inhibitors in cancer therapy

Heparanase: another renal player controlled by vitamin D

The function of heparan sulfate during branching morphogenesis

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