Matrix metalloproteinase (stromelysin-1) increases the albumin permeability of isolated rat glomeruli.
Matrix metalloproteinases (MMPs) secreted by connective tissue cells are capable of acting on extracellular matrix components of glomerular basement membrane at a slow rate and thus may play a role in the control of protein permeability and in the progression of certain kinds of glomerulonephritis. We have used an in vitro assay to measure the direct effect of three MMPs and human neutrophil elastase on glomerular albumin permeability (Palbumin). Glomeruli were isolated from normal male Sprague-Dawley rats and suspended in isolation medium with or without interstitial collagenase, gelatinase-A, stromelysin-1, or elastase and were incubated at 37 degrees C for up to 4 hours. A tissue-specific inhibitor of matrix metalloproteinases (TIMP-1) and a plasma proteinase inhibitor, alpha2-macroglobulin (alpha2M), were used to block the activity of MMPs. Palbumin was calculated from the change in glomerular volume in response to an applied oncotic gradient. In this study stromelysin-1 (10 microg/ml) and elastase (5 microg/ml) increased Palbumin significantly. Stromelysin-1 increased Palbumin after 4 hours, whereas elastase had an effect after 2 hours. Lower concentrations of stromelysin-1 or shorter incubation time had no effect on Palbumin. Incubation for up to 4 hours with interstitial collagenase (10 microg/ml) or gelatinase-A (10 microg/ml) had no effect on Palbumin. Coincubation with TIMP-1 and alpha2M blocked the stromelysin-1-mediated increase in Palbumin. We conclude that stromelysin-1 is capable of affecting the glomerular filtration barrier directly and that it may play an important role in causing proteinuria in glomerular diseases.
Sharma
R
R
Division of Nephrology, Department of Medicine, Medical College of Wisconsin, Milwaukee 53226, USA.
Suzuki
K
K
Nagase
H
H
Savin
V J
VJ
D000418:Albumins / Q000378:metabolism*; D000818:Animals; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000502:physiology; D019272:Leukocyte Elastase / Q000494:pharmacology; D008297:Male; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010196:Pancreatic Elastase / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019714:Tissue Inhibitor of Metalloproteinases; D000511:alpha-Macroglobulins / Q000494:pharmacology
D000418:Albumins; D006023:Glycoproteins; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D000511:alpha-Macroglobulins; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3