EFFECTS OF LIPOPROTEIN(A) ON MESANGIAL CELL-PROLIFERATION AND VIABILITY

Background. Lipoprotein abnormalities are considered to accelerate glo merular injury in various forms of renal disease, probably by affectin g 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 infl uence of LF(a) on mesangial cell function has not been defined. Method s. The influence of Lp(a) on mesangial cell proliferation was assessed in a rat mesangial cell culture model by direct measurement of cell g rowth as well as analysis of DNA-synthesis and mRNA levels of c-fos an d c-myc, two growth-associated 'immediate early response genes'. Resul ts. Lp(a) triggered a biphasic response on DNA synthesis: H-3-thymidin e 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 co mparable to 10% fetal calf serum (FCS). No additive effect of 10% FCS and Lp(a) on DNA synthesis was observed. Cell proliferation was modera tely 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 respect ively. Stimulation of DNA synthesis was partly blunted when cells were incubated with Lp(a) in the presence of catalase 100 U/ml and superox ide 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 elict ed signs of cytotoxicity. The cytotoxic effects of Lp(a) were not blun ted by oxygen radical scavengers. The stimulatory and cytotoxic effect s 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 stim ulation of mesangial cell proliferation as well as the cytotoxic effec ts causes by Lp(a) are both likely to have a negative impact on the co urse of renal disease.