Effects of lipoprotein(a) on mesangial cell proliferation and viability

Background. Lipoprotein abnormalities are considered to accelerate glomerular injury in various forms of renal disease, probably by affecting mesangial proliferation. Serum levels of the atherogenic Lipoprotein(a) (Lp(a)) are elevated in patients with nephrotic syndrome and Lp(a) deposits have been identified in diseased glomeruli. So far, the influence of LF(a) on mesangial cell function has not been defined. Methods. The influence of Lp(a) on mesangial cell proliferation was assessed in a rat mesangial cell culture model by direct measurement of cell growth as well as analysis of DNA-synthesis and mRNA levels of c-fos and c-myc, two growth-associated 'immediate early response genes'. Results. Lp(a) triggered a biphasic response on DNA synthesis: H-3-thymidine uptake was increased when cells were incubated with Lp(a) (2.5-10 mu g/ml) for 24 h. The response was dose dependent, a maximal effect was seen for Lp(a) 5 mu g/ml. The stimulatory properties of Lp(a) were comparable to 10% fetal calf serum (FCS). No additive effect of 10% FCS and Lp(a) on DNA synthesis was observed. Cell proliferation was moderately stimulated (120 +/- 9% of control) by low levels of Lp(a) in the presence of small amounts of FCS. Messanger RNA levels for c-fos and c-myc were upregulated as early as 15 min after incubation with Lp(a) 5 mu g/ml, a maximum response was observed after 30 and 240 min respectively. Stimulation of DNA synthesis was partly blunted when cells were incubated with Lp(a) in the presence of catalase 100 U/ml and superoxide dismutase 10(-7)M (SOD) but not in the presence of SOD alone. Lp(a) in concentrations above 10 mu g/ml depressed DNA-synthesis and elicted signs of cytotoxicity. The cytotoxic effects of Lp(a) were not blunted by oxygen radical scavengers. The stimulatory and cytotoxic effects of Lp(a) were not restricted to a specific isoform. Conclusion. Low concentrations of Lp(a) stimulated growth of mesangial cells, whereas higher concentrations had antiproliferative or toxic effects. The stimulation of mesangial cell proliferation as well as the cytotoxic effects causes by Lp(a) are both likely to have a negative impact on the course of renal disease.