NDT Advance Access originally published online on June 8, 2004
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Nephrol Dial Transplant (2004) 19: 1969-1975
Nephrol Dial Transplant Vol. 19 No. 8 © ERA-EDTA 2004; all rights reserved
Original Article
The effect of proteinase inhibitors on glomerular albumin permeability induced in vitro by serum from patients with idiopathic focal segmental glomerulosclerosis
1 Department of Medicina Clinica, University of Trieste, Trieste, 2 Unit and Laboratory of Nephrology, Istituto G. Gaslini, Genoa and 3 Department BBCM, University of Trieste, Trieste, Italy
Correspondence and offprint requests to: Michele Carraro, MD, Dipartimento di Medicina Clinica, Università degli Studi di Trieste, Ospedale di Cattinara, Strada di Fiume 447, 34149 Trieste, Italy. Email: m.carraro{at}fmc.units.it
Background. The putative circulating factor responsible for the glomerular permeability alterations induced in vitro by serum from patients affected by focal segmental glomerulosclerosis (FSGS) remains unidentified. We have observed that a serine proteinase isolated from patient serum increases albumin permeability in isolated glomeruli. The objective of the present study was to determine the effect of various proteinase inhibitors on glomerular albumin permeability (Palb) in isolated glomeruli incubated with FSGS serum.
Methods. The study population consisted of 12 FSGS patients (eight males; mean age: 21±10 years) previously shown to have elevated serum albumin permeability activity. Palb was determined by measuring the change in glomerular volume induced by applying oncotic gradients to isolated healthy rat glomeruli treated with patient serum in comparison to control serum. Solutions of seven different proteinase inhibitors (0.5 mg/ml) were added to the incubation media with the sera (1:1 vol/vol): serine proteinase inhibitors (PMSF, leupeptin, aprotinin, gabexate mesylate), the cysteine proteinase inhibitor E-64, the metalloproteinase inhibitor EDTA and the aspartate proteinase inhibitor pepstatin. Sera from the same patients were also tested with the addition to the incubation media of quinaprilat, an inhibitor of the metalloproteinase angiotensin-converting enzyme.
Results. Mean Palb of the sera was 0.86±0.11, with the addition of PMSF 0.41±0.09, leupeptin 0.30±0.17, aprotinin 0.09±0.14, gabexate mesylate 0.27±0.25, E-64 0.81±0.09, EDTA 0.68±0.10 or pepstatin 0.76±0.11. The mean Palb of the sera combined with quinaprilat was reduced to 0.34±0.35. Thus, only the serine proteinase inhibitors consistently blocked the increased Palb induced by the FSGS sera.
Conclusions. In the cascade of events that lead to the initiation of glomerular fibrosis in FSGS, the putative glomerular permeability factor associated with FSGS may require a serine proteinase to effect its activity.
Keywords: circulating permeability factors; focal segmental glomerulosclerosis; glomerular permeability; proteinase inhibitors; serine proteinase; serum proteinases
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