Lipoprotein(a) stimulates growth of human mesangial cells and induces activation of phospholipase C via pertussis toxin-sensitive G proteins

Background. Renal disease is commonly associated with hyperlipidemia and co rrelates with glomerular accumulation of atherogenic lipoproteins, for exam ple, lipoprotein(a) [Lp(a)], and mesangial hypercellularity. Specific bindi ng of Lp(a) to mesangial cells and induction of c-myc and c-Sos expression has been demonstrated. Therefore, in this study, we investigated a possible growth stimulatory effect and mode of action of Lp(a) in human mesangial c ells. Methods. Lp(a) was purified from the regenerate fluid of a dextran sulfate column-based low-density lipoprotein apheresis system. Human mesangial cell s were isolated by a sequential sieving technique from patients undergoing tumor nephrectomy. DNA synthesis was measured by [H-3]-thymidine incorporat ion. The intracellular calcium concentration ([Ca2+](i)) was determined by Fura 2-fluorescence, and inositol 1,4,5-trisphosphate (1,4,5-IP3) concentra tion was measured by a radioreceptor assay. Results. The data show that Lp(a) bound to the cells with a K-d of 17.0 mu g/ml and increased DNA synthesis and cell proliferation. Lp(a) caused a rap id increase in 1,4,5-IP3 and [Ca2+](i) via a pertussis toxin-sensitive mech anism. The phospholipase C (PLC) inhibitor U73122 abolished Lp(a)-induced c ell proliferation. In contrast, vasopressin-induced increase in 1,4,5-IP3 a nd [Ca2+](i) was pertussis toxin insensitive. Conclusion. This study revealed that Lp(a) stimulates growth of human mesan gial cells. Lp(a)-induced signaling involves binding to a receptor and stim ulation of PLC via G(i) proteins. Stimulation of PLC appears to be essentia l for the growth stimulatory effect of Lp(a). Whether these effects of Lp(a ) contribute to the pathophysiology of renal disease needs to be determined .