Anti-proteinuric effects of glycosaminoglycan-based drugs.
Heparan sulfate (HS) is a member of the family of glycosaminoglycans (GAGs) that is generally bound to a core protein to form a proteoglycan (PG). HSPGs may be cell-membrane associated (glypicans and syndecans) or located within the extracellular matrix (agrin, perlecan and type XVIII collagen). The sulfate and carboxylic groups in HS are responsible for the negative charge of the sugar chain. HS is abundantly present in the filter unit of the kidney, especially in the glomerular basement membrane (GBM), and is assumed to repel negatively charged proteins, including albumin, thereby preventing their filtration. Alterations in HS expression in the GBM have been reported in a number of renal pathologies, including diabetic nephropathy, minimal change nephropathy and membranous glomerulopathy.A decreased HS expression in the GBM generally correlates with an increase in the level of proteinuria. Progressive proteinuria may result in end-stage renal failure when untreated. Based on these findings, GAG-based drugs have been used to treat proteinuria and some, notably sulodexide, have shown beneficial effects. The biosynthesis of HS and its possible role in renal filtration are discussed, an overview of GAG-based drugs and their effect on proteinuria is provided, and possible mechanisms by which GAG-based drugs ameliorate proteinuria are discussed.
Wijnhoven
Tessa  J M
T
Nijmegen Centre for Molecular Life Sciences, Department of Matrix Biochemistry and Nephrology Research Laboratory, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
Lensen
Joost F M
JF
Rops
Angelique L
AL
McCarthy
Kevin J
KJ
van der Vlag
Johan
J
Berden
Jo H M
JH
van den Heuvel
Lambert P W J
LP
van Kuppevelt
Toin H
TH
D000818:Animals; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D016207:Cytokines / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D005966:Glucuronidase / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000627:therapeutic use*; D006493:Heparin / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000033:anatomy & histology / Q000378:metabolism / Q000502:physiology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000648:ultrastructure; D008969:Molecular Sequence Data; D011507:Proteinuria / Q000188:drug therapy / Q000503:physiopathology; D000099175:Heparanase
D016207:Cytokines; D005343:Fibrinolytic Agents; D005966:Glucuronidase; D017127:Glycation End Products, Advanced; D019812:Heparan Sulfate Proteoglycans; D006493:Heparin; D036341:Intercellular Signaling Peptides and Proteins; D000099175:Heparanase