Key Points
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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
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Immunocytes and podocytes can secrete proheparanase as well as the lysosomal cysteine protease cathepsin L, which cleaves proheparanase, to produce active heparanase
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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
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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
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Heparanase deficiency in animals, and pharmacological inhibition of heparanase, protects against the development of glomerular injury and diabetic nephropathy
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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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The work of the authors is supported by the Dutch Kidney Foundation through a collaborative GLYCOREN grant (CP 0903).
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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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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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DOI: https://doi.org/10.1038/nrneph.2017.6
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