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Elevated level of ambient glucose stimulates the synthesis of high-molecular-weight hyaluronic acid by human mesangial cells. The involvement of transforming growth factor beta1 and its activation by thrombospondin-1

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Yevdokimova N. Y.

Acta Biochimica Polonica

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2006

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tom 53

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nr 2

The dysregulation of the metabolism of glycosaminoglycan and protein components of extracellular matrix (ECM) is a typical feature of diabetic complications. High glucose-induced enrichment of ECM with hyaluronan (HA) not only affects tissue structural integrity, but influences cell metabolic response due to the variety of effects depending on the HA polymer molecular weight. TSP-1-dependent activation of TGFβ1 axis is known to mediate numerous matrix disorders in diabetes, but its role concerning HA has not been studied so far. In this work we demonstrated that 30 mM d-glucose increased the incorporation of [3H]glucosamine in high-molecular-weight ( > 2000 kDa) HA of medium and matrix compartments of human mesangial cultures. Simultaneously, the synthesis of HA with lower molecular weight and HA degradation were not altered. The cause of the increased high-molecular-weight HA synthesis consisted in the up-regulation of hyaluronan synthase (HAS) 2 mRNA without alterations of the expression of HAS3, which generates HA of lower molecular weight. d-Glucose at 30 mM also stimulated the production of transforming growth factor β1 (TGFβ1), the excessive activation of which was determined by the up-regulation of thrombospondin-1 (TSP-1). The blockage of TGFβ1 action either by neutralizing anti-TGFβ1 antibodies or by quenching the TGFβ1 activation (with TSP-1-derived synthetic GGWSHW peptide) abolished the effect of high glucose on HAS2 mRNA expression and normalized the synthesis of HA. Exogenous human TGFβ1 had the same effect on HAS2 expression and HA synthesis as high glucose treatment. Therefore, we supposed that TSP-1-dependent TGFβ1 activation is involved in the observed high glucose effect on HA metabolism. Since high-molecular-weight HA polymers, unlike middle- and low-molecular weight HA oligosaccharides, are known to possess anti-inflammatory and anti-fibrotic functions, we suppose that the enrichment of mesangial matrix with high-molecular-weight HA may represent an endogenous mechanism to limit renal injury in diabetes.

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Effects of wheat germ agglutinin and concanavalin A on the accumulation of glycosaminoglycans in pericellular matrix of human dermal fibroblasts. A comparison with insulin

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Yevdokimova N. Y., Yefimov A. S.

Acta Biochimica Polonica

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2001

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tom 48

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nr 2

The ef fect of in su lin, wheat aerm ag glu ti nin (WGA), pea nut ag glu ti nin (PNA) and concanavalin A (ConA) on [ 3H]glucosamine incorporation into pericellular glycosaminoglycans (GAGs) was investigated in two lines of cultured human dermal fibroblasts. Insulin and WGA stimulated [3H]glucosamine incorporation into hyaluronic acid (HA) and heparan sul phate (HS) with out any al ter ation of chondroitin sulphate (CS) and dermatan sul phate (DS) con tents. ConA in creased [ 3H]glucosamine in- cor po ra tion into HS, CS and DS, but had no ef fect on [ 3H]glucosamine in cor po ra tion into HA. PNA af fected nei ther the con tent, nor the com po si tion of GAGs. In con trast to PNA, ConA and WGA stimulated glycolysis and demonstrated an evident antiproliferative ef fect on der mal fibroblasts. Thus, both the in su lin-like ac tion of WGA and ConA on cul tured der mal fibroblasts and the dif fer ences be tween the ef fects of lectins on mod u la tion of GAGs syn the sis ap pear to be de ter mined by their chem i cal structure.

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Fibrin D-dimer impairs the accumulation and anticoagulant properties of heparan sulphate and stimulates secretion of plasminogen activator inhibitor-1 by rabbit coronary endothelial cells

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Yevdokimova N. Y., Veselovska L. D., Gogolinska G. K., Buchanevich O. M., Kosyakova G. V., Gritsenko P. G., Lugovskoj E. V., Komisarenko S. V.

Acta Biochimica Polonica

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2003

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tom 50

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nr 1

Fibrin split product D-dimer (DD) is most probably involved in the development of vascular disorders. At 1.5 uM concentration DD inhibited the incorporation of D-[1-3H]glucosamine hydrochloride and [2-14C]acetate • Na into pericellular heparan sulphate (HS) of rabbit coronary endothelial cells without affecting other groups of glycosaminoglycans (GAGs). At the same time, DD reduced HS ability to bind antithrombin (AT) and suppressed NO production. The effect of DD on pericellular GAGs was similar to that of Nω-methyl-L-arginine, the competitive inhibitor of endothelial NO synthase (eNOS). L-Ascorbic acid, eNOS activator, increased the level of endogenous NO in the DD-treated cells, and restored HS accumulation and antithrombin binding. It is suggested that DD influence on endothelial HS may be mediated by NO production. Another effect of DD, namely, stimulation of plasminogen activator inhibitor-1 (PAI-1) secretion did not depend on the NO level. The decreased HS content, reduced anticoagulant properties of HS, and increased PAI-1 secretion disorganized the endothelial matrix, and promoted fibrin formation and vascular damage. This points to DD as an important factor in the development of vascular disorders.

Ograniczanie wyników

3 Acta Biochimica Polonica

3 Yevdokimova N. Y.

1 Buchanevich O. M.

1 Gogolinska G. K.

1 Gritsenko P. G.

1 Komisarenko S. V.

1 Kosyakova G. V.

1 Lugovskoj E. V.

1 Veselovska L. D.

1 Yefimov A. S.

1 2006

1 2003

1 2001

Elevated level of ambient glucose stimulates the synthesis of high-molecular-weight hyaluronic acid by human mesangial cells. The involvement of transforming growth factor beta1 and its activation by thrombospondin-1

Effects of wheat germ agglutinin and concanavalin A on the accumulation of glycosaminoglycans in pericellular matrix of human dermal fibroblasts. A comparison with insulin

Fibrin D-dimer impairs the accumulation and anticoagulant properties of heparan sulphate and stimulates secretion of plasminogen activator inhibitor-1 by rabbit coronary endothelial cells