ELASTASE, BUT NOT PROTEINASE-3 (PR3), INDUCES PROTEINURIA ASSOCIATED WITH LOSS OF GLOMERULAR-BASEMENT-MEMBRANE HEPARAN-SULFATE AFTER IN-VIVO RENAL PERFUSION IN RATS

Elastase, but not PR3, induces proteinuria associated with loss of glo merular basement membrane (GEM) heparan sulphate after in vivo renal p erfusion in rats. PR3 and elastase are cationic neutral serine protein ases present in the azurophilic granules of polymorphonuclear leucocyt es. Release of these proteolytic enzymes along the glomerular capillar y wall may induce glomerular injury. Here, we investigated the effects of PR3 and elastase on the induction of proteinuria and glomerular in jury after renal perfusion of these enzymes in Brown-Norway rats. Perf usion of active elastase induced a dose-dependent proteinuria 24h afte r perfusion, while inactivated elastase did not. Perfusion of comparab le amounts of active PR3 did not induce proteinuria. Light and electro n microscopy showed no morphological abnormalities in any experimental group. However, immunohistology revealed that proteinuria occurring a fter perfusion of active elastase was associated with a strong reducti on in intraglomerular expression of the heparan sulphate side chain an d, to a lesser extent, of the protein core of heparan sulphate proteog lycans (HSPG). In vitro, both elastase and PR3 digested HSPG. However, PR3 bound to a lesser extent to HSPG than elastase. We conclude that elastase, but not PR3, induces proteinuria after in vivo renal perfusi on. This differential effect probably relates to different binding to the GBM of those enzymes due to differences in their isoelectric point s. Degradation of heparan sulfate proteoglycans, leading to the disapp earance of their side chains that contribute to the polyanionic struct ure of the GBM, appears to be involved in the induction of proteinuria after perfusion of elastase.