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  • Review Article
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Heparanase: roles in cell survival, extracellular matrix remodelling and the development of kidney disease

Nature Reviews Nephrology volume 13, pages 201–212 (2017)Cite this article

Subjects

Key Points

  • Heparanase is the only known mammalian endoglycosidase capable of degrading heparan sulfate (HS); it is involved in intracellular processes such as gene transcription and autophagy, but can be released into the extracellular matrix where it degrades HS

  • Immunocytes and podocytes can secrete proheparanase as well as the lysosomal cysteine protease cathepsin L, which cleaves proheparanase, to produce active heparanase

  • Activated extracellular heparanase alters the glycocalyx surfaces of glomerular endothelium and infiltrating immunocytes, and alters interactions between podocytes and the glomerular basement membrane, thereby facilitating the development of albuminuria and further glomerular inflammation

  • Increased renal heparanase activity is also involved in epithelial–mesenchymal transition and fibrosis during acute kidney injury, as well as loss of renal microvascular stability

  • Heparanase deficiency in animals, and pharmacological inhibition of heparanase, protects against the development of glomerular injury and diabetic nephropathy

  • Urinary excretion of heparanase might identify patients at risk of progressive kidney disease; elucidation of the crystal structure of heparanase has facilitated the development of new therapies to interfere with heparanase activity

Abstract

Heparanase has regulatory roles in various processes, including cell communication, gene transcription and autophagy. In addition, it is the only known mammalian endoglycosidase that is capable of degrading heparan sulfate (HS). HS chains are important constituents and organizers of the extracellular matrix (ECM), and have a key role in maintaining the integrity and function of the glomerular filtration barrier. In addition, HS chains regulate the activity of numerous bioactive molecules, such as cytokines and growth factors, at the cell surface and in the ECM. Given the functional diversity of HS, its degradation by heparanase profoundly affects important pathophysiological processes, including tumour development, neovascularization and inflammation, as well as progression of kidney disease. Heparanase-mediated degradation and subsequent remodelling of HS in the ECM of the glomerulus is a key mechanism in the development of glomerular disease, as exemplified by the complete resistance of heparanase-deficient animals to diabetes and immune-mediated kidney disease. This Review summarizes the role of heparanase in the development of kidney disease, and its potential as a therapeutic target.

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Figure 1: Heparanase structure and binding of heparan sulfate to its cleavage site.
Figure 2: Cellular metabolism of heparanase.
Figure 3: Targeting immunocytes to reduce heparanase activation.
Figure 4: Podocyte–endothelial cross talk and activation of heparanase.

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Acknowledgements

The work of the authors is supported by the Dutch Kidney Foundation through a collaborative GLYCOREN grant (CP 0903).

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Nephrology, The Einthoven Laboratory for Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands

    Ton J. Rabelink, Bernard M. van den Berg & Ganqi Wang

  2. Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 10, Nijmegen, 6525 GA, The Netherlands

    Marjolein Garsen & Johan van der Vlag

  3. Department of Oncology, Tumor Biology Research Unit, Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel

    Michael Elkin

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Contributions

All authors researched data for the article. T.J.R., B.M.v.d.B. and J.v.d.V. wrote the manuscript. T.J.R., B.M.v.d.B., M.G., G.W., M.E. and J.v.d.V. contributed to discussions of the content and reviewed or edited the manuscript before submission.

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Correspondence to Ton J. Rabelink.

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DATABASES

Protein Data Bank

UCSF Chimera software

Glossary

β-Linked glucuronides

Any substance produced by linking glucuronic acid to another substance via a glycosidic bond.

Non-reducing end

The terminal carbon of the polysaccharide, which has no free aldehyde or ketone group, and is not able to oxidize other molecules.

Heparinoid

A substance with activity similar to that of the anticoagulant heparin.

Spiegelmer

Trade name for an artificial RNA-like oligonucleotide built from l-ribose units, which are highly resistant to degradation by nucleases.

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Rabelink, T., van den Berg, B., Garsen, M. et al. Heparanase: roles in cell survival, extracellular matrix remodelling and the development of kidney disease. Nat Rev Nephrol 13, 201–212 (2017). https://doi.org/10.1038/nrneph.2017.6

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