LIPOPROTEIN(A) INDUCES GLOMERULAR SUPEROXIDE ANION PRODUCTION

Background. Lipoprotein(a) (Lp(a)) is considered to accelerate glomeru lar injury in various forms of renal disease. Several tissue culture s tudies suggested that biological effects of Lp(a) are inhibitable by o xygen radical scavengers. Since reactive oxygen metabolites (ROM) are important mediators of renal disease, we studied the effects of native and oxidized Lp(a) on generation of the ROM superoxide anion in isola ted glomeruli and compared them with the effects of native (nLDL) and oxidized LDL cholesterol (oxLDL). Methods. The effect of native and ox idized Lp(a) and LDL on ROM production in isolated rat glomeruli was i nvestigated with a lucigenin chemiluminescence assay. Results. Native Lp(a) caused a moderate, dose dependent stimulation of glomerular ROM production: Maximum ROM production to 159 +/- 9% of control glomeruli was induced by nLp(a) 20 mu g/ml. Lp(a)-induced chemiluminescence was completely inhibited by the cell permeable oxygen radical scavenger Ti ron (10 Mm). Oxidized Lp(a) (20 mu g/ml) caused a more pronounced stim ulation of ROM production to 204 +/- 12% of control values. Interestin gly, only oxLDL, but not nLDL had a significant effect on glomerular R OM production (ox LDL 50 mu g/ml: 192 +/- 19% of control). Lp(a) stimu lated ROM production was completely inhibited by the protein kinase C inhibitor bis- indolyl malemide (BIM): BIM 10(-6) M inhibited 52 +/- 3 %, BIM 10(-5) M inhibited 94 +/- 5% of Lp(a)-induced ROM production. R OM production was also inhibited, when intracellular CAMP levels were elevated by forskolin. Conclusion. Lp(a) and oxLp(a) induce the activa tion of ROM in glomeruli by a pathway that is sensitive to inhibition of protein kinase C and elevation of intracellular CAMP levels.