Defective glomerular [3H]lysoPAF metabolism in the autologous phase of rabbit nephrotoxic nephritis

Glomerular infiltration of blood-derived mononuclear cells contributes to the glomerular injury in the autologous phase of nephrotoxic nephritis (NTN). LysoPAF has recently been shown to be chemotactic for human monocytes, thus its accumulation might account for monocyte recruitment. We investigated [3H]lysoPAF metabolism in isolated glomeruli from normal and NTN rabbits studied both in the heterologous and in the autologous phases of the disease. [3H]lysoPAF was converted to [3H]1-O-alkyl-glycerol and [3H]1-O-alkyl-2-acyl-GPC by phospholipase C and acyltransferase, respectively, both in normal and NTN glomeruli. Glomerular metabolism of [3H]lysoPAF was normal during the heterologous phase of NTN. By contrast, in isolated glomeruli from NTN rabbits studied in the autologous phase of the disease, a significantly lower [3H]lysoPAF degradation occurred with respect to normal ones. This defective degradation resulted in a significantly reduced formation of [3H]1-O-alkyl-glycerol. The apparent Km for enzymatic conversion of [3H]lysoPAF to [3H]1-O-alkyl-glycerol, determined at 15 minutes as a function of [3H]lysoPAF concentration, was doubled in glomeruli from rabbits studied in the autologous phase of NTN as compared to normal ones, while Vmax values were similar in the two groups. These results show a defective glomerular lysoPAF degradation in the autologous phase of NTN, likely due to a decreased affinity of phospholipase C to lysoPAF. Altered lysoPAF metabolism results in glomerular accumulation of lysoPAF in the autologous phase of NTN, as shown by significantly higher levels of lysoPAF measured in nephritic glomeruli as compared to normal ones.