Inhibition of renal permeability towards albumin: A new function of apolipoproteins with possible pathogenetic relevance in focal glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a degenerative renal disease c haracterized by the accumulation of extracellular matrix and lipids within the glomerular tuft. It has been proposed that an abnormal renal permeabili zation towards proteins induced by a putative plasma factor is, in some way , involved in the pathogenesis of the disease. In this paper, we measured t he plasma permeability activity (P-a/b) in several sera of patients with FS GS and found a mean activity of 0.82 +/- 0.03 which means a marked increase compared to a mean P-a/b of 0.16 +/- 0.03 in normal controls. Coincubation of FSGS and normal serum reduced the permeability activity within the norm al range; normal serum added to the incubation medium after the glomeruli h ad already been exposed to the FSGS serum had no effect, suggesting the pre sence of inhibitory substances with a direct effect on a circulating substr ate. Finally, the antipermeability activity was retained when heated to 60 degreesC but not to 100 degreesC. By serial fractionations of normal serum and reported activity measurements at each step, five natural occurring inh ibitors of albumin permeabilization were purified and characterized by matr ix assisted laser desorption/ionization-mass spectrometry (MALDI-MS), as co mponents of apolipoproteins (apo) (apo E-2 and E-4, apo L, the high M-r apo J and a 28 kDa fragment of apo A-IV). Coincubation of each apolipoprotein with FSGS serum inhibited permeability, but only apo J and apo E-2 and E-4 Were found to be crucial for the process. In conclusion, we have purified f rom normal serum five inhibitors of permeability induced by FSGS serum, all corresponding to apolipoproteins. An imbalance between permeability factor s and apolipoproteins may play a pathogenetic role in FSGS.