Heparanase: roles in cell survival, extracellular matrix remodelling and the development of kidney disease.
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.
The Einthoven Laboratory for Vascular Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Ton J
TJ
Rabelink
The Einthoven Laboratory for Vascular Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Bernard M
BM
van den Berg
Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands.
Marjolein
M
Garsen
The Einthoven Laboratory for Vascular Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Ganqi
G
Wang
Tumor Biology Research Unit, Department of Oncology, Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, 91120 Israel.
Michael
M
Elkin
Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands.
Johan
J
van der Vlag
D000818:Animals; D002470:Cell Survival / Q000502:physiology*; D005109:Extracellular Matrix / Q000201:enzymology / Q000502:physiology*; D005966:Glucuronidase / Q000502:physiology*; D006801:Humans; D007674:Kidney Diseases / Q000201:enzymology / Q000209:etiology*; D000099175:Heparanase
D005966:Glucuronidase; D000099175:Heparanase