Low-density lipoprotein stimulates mesangial cell proteoglycan and hyaluronan synthesis

Background. Hyperlipidaemia leads to glomerulosclerosis in small mammals an d may contribute to progressive renal disease in man. One prominent feature of lipid-induced glomerular injury in animal models is the accumulation of mesangial matrix. These studies were designed to investigate whether low-d ensity lipoprotein (LDL) enhanced mesangial cell (MC) matrix deposition by modulating the production of proteoglycans (PG) and hyaluronan (HA). Methods. Growth arrested human MC were metabolically labelled with either 5 0 mu Ci/ml Na-2[S-35]sulphate or 25 mu Ci/ml [H-3]glucosamine and stimulate d with LDL (10-100 mu g/ml). The radiolabelled PG and HA extracted from the cell layer and the culture medium were isolated, quantified and characteri zed. Comparison of the PG core proteins synthesized by MC was carried out u sing Western blot analysis. Results. LDL stimulation led to a dose- and time-dependent increase in [S-3 5]sulphate incorporation into PG in the culture medium and to a lesser exte nt in the cell layer. Analysis of the glycosaminoglycan (GAG) chains showed no difference in either their size or charge. Enzyme digestion studies dem onstrated that the synthesis of both chondroitin sulphate PG (CSPG) and hep aran sulphate PG (HSPG) was enhanced as was the production of the core prot eins of versican (a large CSPG), perlecan (a basement membrane HSPG) and to a lesser extent decorin (a small dermatan sulphate PG (DSPG)). An increase in HA synthesis was also demonstrated in [H-3]glucosamine labelled cells f ollowing LDL stimulation. Conclusion. LDL selectively enhances the synthesis of specific PG and HA by mesangial cells. Such effects may contribute to the expansion of the mesan gial matrix and modify cell-matrix interactions in lipid-induced renal dama ge.