Proteoglycans in primary human endothelial cells and in the mouse kidney
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AbstractIn this study we investigate the role of proteoglycans (PGs) in primary human endothelial cells (HUVECs) and in mouse kidney. The PGs exhibit multiple functions by interactions of their glycosaminoglycan (GAG) chains with other partner molecules. Posttranslational modifications of these GAGs, including sulfation, are critical for their binding properties. Such changes may play an important role in the development of diabetic complications. In particular, the role of heparan sulfate (HS) PGs has received much attention in earlier studies.
Our studies demonstrated changes in HSPG expression and structure in HUVECs cultured in diabetic conditions. Additionally, we identified serglycin, a chondroitin sulfate (CS) / dermatan sulfate (DS) PG, as a prominent PG in these cells. We found serglycin located in intracellular vesicles colocalized with the chemokine CXCL-1, suggesting a role in endothelial storage and secretion of partner molecules. Both inflammatory stimuli and proliferative status affected serglycin expression and cellular localization, which may have impact on endothelial cells in inflammation and angiogenesis.
It has been suggested that reduced sulfation of HSPGs is implicated in the impaired renal filtration of diabetic nephropathy. We compared kidneys from diabetic db/db mice to healthy db/+ controls and found no effect on HSPG expression nor structure. A novel finding however, was a reduced sulfation and altered structure of CS/DS PGs, suggesting a role for CS/DS in the development of diabetic complications.
Taken together, our results show an alteration in PG expression and structure both in the vasculature and the kidneys. These findings may prove relevant to studies on diabetes and its complications.
List of papers. Papers I-III are removed from the thesis due to publisher restrictions.
Paper I: Reine TM, Kusche-Gullberg M, Feta A, Jenssen T, Kolset SO. Heparan sulfate expression is affected by inflammatory stimuli in primary human endothelial cells. Glycoconj J. 2012 Jan;29(1):67-76. Epub 2011 Dec 22 doi:10.1007/s10719-011-9365-y
Paper II: Meen AJ, Øynebråten I, Reine TM, Duelli A, Svennevig K, Pejler G, Jenssen T, Kolset SO. Serglycin is a major proteoglycan in polarized human endothelial cells and is implicated in the secretion of the chemokine GROalpha/CXCL1. J Biol Chem. 2011 Jan 28;286(4):2636-47. Epub 2010 Nov 12 doi:10.1074/jbc.M110.151944
Paper III: Reine TM, Vuong TT, Meen AJ, Jenssen T, Kolset SO. Serglycin expression is reduced in quiescent primary endothelial cells Submitted manuscript.
Paper IV: Reine TM, Grøndahl F, Jenssen T, Hadler-Olsen E, Prydz K, Kolset SO. Reduced sulfation of chondroitin sulfate but not heparan sulfate in kidneys of diabetic db/db mice. Manuscript, published as: J Histochem Cytochem. 2013 Aug;61(8):606-16. Epub 2013 Jun 11. doi:10.1369/0022155413494392